Gastric Acid Calcium Absorbtion Bone Health J Geibel - 13

Physiol Rev 93: 189 –268, 2013
doi:10.1152/physrev.00015.2012
GASTRIC ACID, CALCIUM ABSORPTION, AND

THEIR IMPACT ON BONE HEALTH
Sascha Kopic and John P. Geibel
Departments of Surgery and Cellular and Molecular Physiology, Yale School of Medicine,
New Haven, Connecticut
Kopic S, Geibel JP. Gastric Acid, Calcium Absorption, and Their Impact on Bone
L
Health. Physiol Rev 93:189 –268, 2013; doi:10.1152/physrev.00015.2012.—Cal-
cium balance is essential for a multitude of physiological processes, ranging from cell
signaling to maintenance of bone health. Adequate intestinal absorption of calcium is a
major factor for maintaining systemic calcium homeostasis. Recent observations indi-
Downloaded from http://physrev.physiology.org/ by 10.220.32.246 on October 11, 2016

cate that a reduction of gastric acidity may impair effective calcium uptake through the intestine.
This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their
respective neuroendocrine regulation and explores the physiological basis of a potential link be-
tween these individual systems.
I. INTRODUCTION 189 which primarily consists of the calcitropic hormones: 1,25-

II. GASTRIC ACID SECRETION 189 dihydroxyvitamin D [1,25(OH)2-vitamin D], parathyroid
III. INTESTINAL CALCIUM ABSORPTION 203 hormone (PTH), and calcitonin.
IV. REGULATION OF CALCIUM HOMEOSTASIS 212
V. THE STOMACH AND CALCIUM 231 This review mainly focuses on the question as to how calcium
VI. CONCLUSIONS 238 enters the body through the intestine and how this mechanism
is regulated via the endocrine system. Furthermore, the process
of gastric acid secretion as related to calcium homeostasis will
I. INTRODUCTION be reviewed in detail. This may seem surprising, as gastric acid
secretion and intestinal calcium absorption are two distinct
The average adult human body contains ⬃1.6% calcium, physiological processes, which on first examination may not
which relates to ⬃1,120 g in a 70-kg individual (743). Ninety- seem to be interdependent. However, recent clinical studies
nine percent of the calcium is stored in bone and teeth and suggest that there may be a relationship between reduced gas-
is therefore inaccessible to most physiological processes tric acid secretion and increased risk for sustaining bone frac-
(743). Although the amount of the immediately accessible tures, which asks the question whether we need gastric acid to
11 g (1%) of calcium may seem miniscule, this fraction absorb calcium efficiently through the intestine, or whether the
represents a pivotal constituent of our body. It serves a stomach exerts endocrine functions that impact bone health.
broad diversity of roles, which range from intracellular sig- Indeed, it has been put forward several decades ago that gas-
naling and maintenance of membrane integrity to muscle tric acid solubilizes calcium that is then complexed with other
contraction and neuronal transmission. dietary constituents, thereby allowing for a more efficient ab-
sorption in the intestine (18, 520, 699, 797). Furthermore, it is
To allow for these calcium-dependent processes to func- long known that a partial or complete resection of the stomach
tion, our body undertakes extensive measures to keep the results in decreased bone density, also leading to fractures (58,
intracellular and extracellular calcium concentrations and 305, 732, 876). The stomach, the intestine, and bone are there-
the gradient between these two compartments stable. The fore functionally more intertwined than one may initially as-
extracellular calcium concentration is typically clamped at sume. This review will independently analyze the processes of
⬃1.1 mM, whereas the intracellular environment is kept at gastric acid secretion, intestinal calcium absorption, and their
a 10,000 times lower concentration. In consequence, rela- respective neuroendocrine control and will conclude with a
tively small disturbances in calcium homeostasis can lead to critical attempt at illustrating where these two seemingly inde-
severe symptoms, such as cardiac arrhythmias or cognitive pendent organ systems intersect in terms of calcium homeo-
dysfunctions. To maintain eucalcemia, our body is there- stasis and bone health.
fore tightly regulating the balance between calcium absorp-
tion by the intestine and calcium excretion by the kidney. In
addition, calcium is deposited in or extracted from bone, II. GASTRIC ACID SECRETION
which serves as a dynamic calcium reservoir. These three
organ systems, i.e., the intestine, the kidney, and bone, are The stomach is a unique organ that fulfills multiple roles.
precisely controlled by a complex endocrine network, The main function of the gastric mucosa is to secrete con-
0031-9333/13 Copyright © 2013 the American Physiological Society 189

SASCHA KOPIC AND JOHN P. GEIBEL
centrated hydrochloric acid, which provides a chemical bar- tion depends on the apical extrusion of three ions. Protons
rier against ingested pathogens and aids in the digestion of are pumped into the gastric lumen by a proton pump, the
foodstuffs. To achieve these functions, the gastric gland gastric H⫹-K⫹-ATPase, to acidify the gastric content to a
contains specialized cells that pump protons into the gastric pH of as low as 1. Chloride is secreted via apical chloride
lumen in an effort to acidify the contents of the stomach. channels to ensure formation of HCl and to provide the
These cells are known as parietal cells, or oxyntic cells. counter-ion conductance to protons. Lastly, potassium
Since concentrated acid is a noxious substance, the gastric leaves the parietal cell apically in a recycling mechanism,
mucosa has to undertake extensive measures to protect it- thereby fueling reciprocal proton transport by the H⫹-K⫹-
self from tissue injury. The protection is accomplished by ATPase (FIGURE 1). It has been demonstrated in numerous
secreting mucus from mucus neck cells, but also by tightly investigations that disruption of one of these ion transport
regulating the secretion of acid (see sect. IIB). A variety of mechanism renders the parietal cell incapable of secreting
specialized endocrine cells in the gastric mucosa are in- gastric acid (705, 820, 1013, 1029).
volved in the regulation of gastric acid secretion. A pertur-
bation of either protective mechanism can lead to severe 1. H⫹-K⫹-ATPase
tissue damage, resulting in gastric ulcers. This section dis-
The gastric H⫹-K⫹-ATPase belongs to the

A) STRUCTURE.
cusses the process of how gastric acid is secreted by review-
family of P2-type ATPases, which also includes the ubiqui-
ing the molecular mechanism underlying acid secretion in
tous Na⫹-K⫹-ATPase and the sarcoplasmic reticulum
the parietal cell and its neuroendocrine regulation.
Ca2⫹-ATPase (SERCA). As the name implies, it exchanges
one intracellular hydrogen ion for one extracellular potas-
A. Apical Ion Transport in the Parietal Cell sium ion at the expense of ATP. ATP is provided to the
pump by a large network of mitochondria, which occupy
The gastric parietal cell is responsible for acidifying the up to 40% of the cell volume, making the parietal cell one of
stomach by secreting concentrated acid. Gastric acid secre- the most mitochondria-rich cells in the body (292). In the
Apical Basolateral
PPIs
APAs
H+ SSTR SST
K+
K+
cAMP H2 Hist
KCNQ1
Kir
CCK2 Gast
Ca2+
M3 ACh
Cl–
CFTR
CIC-2?
SLC26A9
Parietal cell
FIGURE 1. Parietal cell model. The gastric parietal cell is equipped with apical ion transport mechanisms that
allow for the secretion of concentrated hydrochloric acid. Activation of basolateral secretagogue receptors
mainly leads to an increase in either cAMP (histamine) or calcium (acetylcholine, gastrin), causing apical
insertion and activation of the H⫹-K⫹-ATPase. Somatostatin reduces intracellular cAMP levels. ACh, acetyl-
choline; APAs, acid pump antagonists; Gast, gastrin; Hist, histamine; PPIs, proton pump inhibitors; SST,
somatostatin.
190 Physiol Rev • VOL 93 • JANUARY 2013 • www.prv.org

GASTRIC ACID, CALCIUM ABSORPTION, AND BONE HEALTH
process of proton extrusion, the H⫹-K⫹-ATPase can over- brane for recycling (336). It is plausible that the initial step
come a massive acid gradient of 6 pH units, which is nec- of this process relies on the formation of clathrin-coated pits
essary to achieve sufficient gastric acidification. The pump and subsequent vesicle budding. Indeed, clathrin was iden-
itself is a heterodimer, consisting of a ␣ subunit and a ␤ tified fairly early on H⫹-K⫹-ATPase containing tubulo-
subunit, while the individual pumps assemble as (␣␤)4 te- vesicles, although a functional role was not demonstrated
tramers on the parietal cell surface (1). The ␣ subunit con- (813). One of the multiple clathrin binding proteins is Hun-
sists of 10 transmembrane domains and contains the cata- tingtin interacting protein 1 related (Hip1r) which aids in
lytic site, which mediates ion exchange. The ␤ subunit sta- vesicle formation and membrane trafficking (309). It is
bilizes the ␣ subunit and is heavily glycosylated (41, 1105). strongly expressed in parietal cells, especially in the vicinity
Mutational analysis of the glycosylated asparagine residues of secretory canaliculi (522). Functionally, Hip1r-deficient
suggests that these sites are critical for adequate membrane animals present with a decreased number of parietal cells,
delivery of the entire pump (41, 1105). Furthermore, the ␤ loss of tubulovesicles, and decreased acid output (522,
subunit prevents a reversal of ion transport by a “ratchet”- 561).
like mechanism, which allows H⫹-K⫹-ATPase to pump
against the imposed high proton gradient (4, 294). Both 2. Chloride secretion

subunits share a significant degree of homology to Na⫹-K⫹-
ATPase (697, 1012). This close relationship to other P2- Apical chloride secretion provides the second component
type ATPase has historically been exploited for homology for the formation of concentrated HCl and maintains over-
modeling of H⫹-K⫹-ATPase based on the crystal structure all electroneutrality during acid secretion. The importance
of chloride efflux for the process of gastric acid secretion
of SERCA, which had been acquired in several conforma-
has been established in the 1980s. Patch-clamp measure-
tional states (762, 815, 1092, 1093). Recently, however,
ments demonstrated the presence of chloride conductance
direct structural information on H⫹-K⫹-ATPase has been
on the apical pole of the parietal cell in Necturus, the human
obtained by electron crystallography, also in the presence of
parietal cell line HGT-1, and rabbit parietal cells (259, 935,
the acid pump antagonist SCH28080 (2– 4).
940). All reports demonstrated a sensitivity of the chloride
current to cAMP or histamine, which is a common second
B) TRAFFICKING. In the resting parietal cell, H⫹-K⫹-ATPase is
messenger promoting acid secretion or a direct acid secre-
stored in tubulovesicles throughout the cell (292). Follow-
tagogue, respectively (259, 935, 940). Simple flux measure-
ing neuronal or hormonal stimulation (see sect. IIB), these
ments in isolated parietal cell vesicles had indicated the
vesicles are postulated to fuse with the apical pole, which is
presence of a chloride conductance pathway even earlier
characterized by multiple microvilli-lined membrane in- (232, 895, 1169). In these early experiments, inhibition of
vaginations, the so-called secretory canaliculi (292). This chloride flux with chloride channel blockers also abolished
distinct apical morphology of the parietal cells maximizes proton transport which underlines the necessity of intact
cell surface and thereby allows for insertion of a high num- chloride secretion for acid secretion to take place (232, 895,
ber of proton pumps per cell following stimulation. The 1169). However, the molecular identity of the chloride
changes in membrane morphology and insertion of H⫹-K⫹- pathway remained elusive. Today, at least three candidates
ATPase are extremely dynamic to ensure fine regulation of have been put forward as potential mediators of apical chlo-
gastric acid secretion (973). H⫹-K⫹-ATPase containing ride secretion in the parietal cell: the cystic fibrosis conduc-
tubulovesicle fusion relies on SNARE complex forma- tance regulator (CFTR), chloride channel protein 2 (ClC-2),
tion. In particular, the SNARE proteins syntaxin 3/7/12/ and solute carrier 26 A 9 (SLC26A9) (FIGURE 1).
13, VAMP2/8, and SNAP-25 were implicated to be candi-
dates mediating this process (548 –550, 624). The func- A) CFTR. CFTR represents a common apical chloride conduc-
tional significance of these proteins was, for example, tance pathway in a broad variety of epithelia, such as the
demonstrated in primary rabbit parietal cell cultures ex- airways, intestine, and pancreas. Its mutation is responsible
pressing a SNAP-25 mutation, which was shown to reduce for the most widespread inherited disease, namely, cystic
their capacity to secrete gastric acid (548). fibrosis (CF), which results in increased mortality due to
secretory defects and concomitant infections. The presence
Apart from SNARE proteins, the small GTPases of the rab of CFTR has been confirmed in gastric mucosa by in situ
family (rab2/11a/25/27b) are involved in the regulation of hybridization, albeit at low quantities (1044). Nevertheless,
H⫹-K⫹-ATPase vesicle trafficking (147, 293, 386, 387, functional measurements in isolated gastric glands demon-
1049, 1070). Functional data especially substantiate the strated a decreased acid secretory capacity in animals car-
importance of rab11a and rab27b. In parallel to SNAP-25 rying the most common mutation responsible for CF
defective cells, parietal cells transfected with a rab11a and (⌬F508) (1013). Furthermore, acid secretion was reduced
rab27b mutant secrete acid less effectively (293, 1049). in wild-type animals when a specific CFTR inhibitor was
applied (1013). Although these observations may suggest a
After stimulation, in the off-phase of gastric acid secretion, direct involvement of CFTR in the process of chloride se-
H⫹-K⫹-ATPase has to be retrieved from the plasma mem- cretion, it is plausible that CFTR rather has a regulatory
Physiol Rev • VOL 93 • JANUARY 2013 • www.prv.org 191

effect on H⫹-K⫹-ATPase (1013). In other tissues, CFTR K⫹-ATPase, potassium has to leak through potassium
can interact with a variety of ion transport proteins, such as channels or transporters into the gland lumen to ensure
NHE, forming regulatory complexes, making an interac- adequate supply to H⫹-K⫹-ATPase (FIGURE 1). This pro-
tion with H⫹-K⫹-ATPase plausible (1013). cess is referred to as potassium recycling. Early flux mea-
surements in isolated H⫹-K⫹-ATPase containing parietal
B) CLC-2. ClC-2 has been proposed as an alternative chloride cell vesicles had already indicated the presence of a large
secretion pathway to CFTR in other epithelia, such as the potassium conductance during H⫹-K⫹-ATPase activity
lung and intestine (207, 404, 675, 766). ClC-2 has been (1169). The exact molecular identity of the potassium efflux
cloned from rabbit gastric mucosa, which led to the hypoth- pathway is, however, under debate. The list of candidates
esis that the channel may also be involved in acid secretion that have been put forward to be responsible for potassium
(706). However, follow-up investigations revealed that the recycling during acid secretion is long and includes KCNQ1
role of ClC-2 is much less clear. The studies revealed con- (Kv7.1), KCNJ10 (Kir4.1), KCNJ15 (Kir4.2), KCNJ2
troversial results regarding the channel’s expression in the (Kir2.1.), and KCC4.
gastric mucosa (488, 706, 1001). While the initial observa-
tions reported mRNA and cDNA expression in rabbit gas- A) KCNQ1. KCNQ1 is a typical “shaker”-like six transmem-

tric mucosa, no protein could be detected in human and rat brane spanning domain voltage-gated potassium channel
gastric glands (488, 706, 1001). The importance of ClC-2 in (1144). It was initially identified in the heart, where its
the stomach has further been severely challenged by the mutation can be responsible for cardiac arrhythmias
creation of a ClC-2 (⫺/⫺) animal model. Although ClC-2- (1144). Yet, studies in KCNQ1 (⫺/⫺) animals revealed no
deficient animals present with a distinct phenotype charac- electrocardiographical abnormalities (641). Rather than
terized by testicular and retinal abnormalities, no defect in suffering from cardiac abnormalities, these animals surpris-
acid secretion was observed (118). ingly exhibited a distinct gastric phenotype with gastric hy-
perplasia, dilated gastric glands, vacuolated parietal cells,
C) SLC26A9. Lastly, evidence suggests that chloride may leave
hypochlorhydria, and hypergastrinemia (641). This obser-
the apical pole via SLC26A9, a chloride-bicarbonate anti- vation led to the speculation that KCNQ1 may be the chan-
porter. Both SLC26A9 and an antiporter from the same
nel responsible for potassium recycling. Subsequently, im-
anion exchanger family (SLC26A6) have been detected in
munohistochemical studies confirmed a colocalization of
the tubulovesicles of parietal cells (845, 1179, 1180). Con-
the channel with H⫹-K⫹-ATPase, and acid secretion was
cerning the functional involvement, the authors speculate
shown to be inhibited by pharmacological blockade (253,
about two potential roles SLC26A9 may play in parietal cell
391). Direct measurement of acid secretion in KCNQ1
physiology. Being a chloride-bicarbonate exchanger, its ac-
(⫺/⫺) mice with modified Ussing chambers (pH stat) later
tivation would entail alkalinization of the gastric lumen
confirmed the initially observed hypochlorhydria (1029).
by bicarbonate efflux and simultaneous chloride uptake
Interestingly, luminal substitution of potassium could res-
(1180). Since this would neutralize H ⫹ -K ⫹ -ATPase-
cue the acid secretory deficit, indicating that hypochlorhy-
mediated proton extrusion, it has been suggested that
SLC26A9 activates in the off-phase of acid secretion to dria ensued from a true lack of apical potassium secretion
neutralize tubulovesicular pH during vesicle retrieval rather than a general morphological defect of the KCNQ1
(1180). Alternatively, SLC26A9 may function as a chloride (⫺/⫺) parietal cell (1029).
secretion pathway that contributes to acid secretion. This
hypothesis is based on the observation that SLC26A9 can KCNQ1 is a peculiar channel in that it has a low conduc-
also exhibit the behavior of a bona fide chloride channel, tance in acidic environments. In the context of the extreme
rather than an anion antiporter (88, 281). Undoubtedly, acidic milieu surrounding the parietal cell, this would im-
further functional investigations are needed to delineate its pede its function as a potassium recycling pathway. To
exact role in the parietal cell. Its genetic disruption, how- circumvent this limitation, KCNQ1 attaches to a regulatory
ever, leads to a severely altered parietal cell morphology subunit (KCNE2), which modulates the channel’s gating
that is characterized by dilation of gastric glands, loss of properties and current amplitude (253, 391, 1087). Coas-
tubulovesicles, and decreased acid output (1180). Although sembly with KCNE2 activates KCNQ1 at acidic pH values
these results do not answer whether SLC26A9 serves as an and thus facilitates the process of potassium secretion into
apical chloride efflux pathway, they indicate that it may be the gland lumen (391, 436). The importance of KCNE2 for
necessary for normal parietal cell function. proper channel function is underlined by the observation
that KNCE2 (⫺/⫺) animals display a phenotype similar to
3. Potassium recycling KCNQ1 (⫺/⫺) mice, i.e., hypochlorhydria, altered parietal
cell morphology, and hypergastrinemia (917).
Even before the identification of H⫹-K⫹-ATPase, it has
been observed that potassium is necessary for acid secretion B) KIR CHANNELS.Apart from KCNQ1, several members of
to take place (335). To prevent the luminal depletion of the inward-rectifier potassium channel (Kir) family have
potassium, which would impair proton pumping by H⫹- been proposed to be involved in gastric acid secretion, albeit

the amount of functional evidence supporting a role of these line, histamine, and gastrin, directly or indirectly stimulate
channels is smaller and the field is divided about the relative the parietal cell by inducing insertion of H⫹-K⫹-ATPase at
contribution of each channel. Kir 2.1, 4.1, 4.2, and 7.1 were the apical membrane and are thus commonly referred to as
all confirmed on an mRNA level in gastric mucosa (353, acid secretagogues. The main inhibitor of parietal cell acid
431, 707). On a protein level, immunohistochemistry dem- secretion is somatostatin, which is secreted by the D-cells
onstrated colocalization of Kir 2.1, 4.1, and 4.2 with H⫹- of the gastric mucosa (FIGURES 1 AND 2). Because of the
K⫹-ATPase (353, 431, 556, 707). Cell fractionation exper- complexity of the network that controls the release of
iments further indicated trafficking of Kir 4.1 and 4.2 to the acid into the stomach, it has been historically challenging
cell surface, following parietal cell stimulation (431, 556). to dissect the relative role of each individual regulatory
A most recent observation monitored acid secretion in Kir component. Without a doubt, knockout models have
4.1 (⫺/⫺) mice (1028). Surprisingly, loss of Kir 4.1 results in greatly aided us in the last years to gain a more profound
augmented rather than impaired acid secretion, accompa- understanding of this process, despite their limitations of
nied by upregulated H⫹-K⫹-ATPase expression (1028). chronic compensation. The subsequent chapter aims to
This makes a contribution of Kir 4.1 to potassium recycling summarize the key players in our canonical model of acid
highly unlikely. Instead, it has been proposed that the chan- regulation.

nel may balance excessive potassium loss through KCNQ1
and may be involved in membrane recycling (1028). In sum- 1. Cholinergic stimulation/vagus nerve
mary, more investigations will be necessary to clarify the
roles of the individual Kir channels. Since the seminal experiments conducted by Pavlov on
dogs, we know that the mere prospect of food ingestion or
C) KCC4. Apart from being secreted through channels, potas- sham-feeding is sufficient to trigger the secretion of gastric
sium and chloride may exit the parietal cell through trans- acid (833). This first of three phases of acid secretion is
porters. This alternative hypothesis is corroborated by a called the cephalic phase and is mostly mediated through
recent observation of Fuji et al. (352). The group reported the vagus nerve (595, 725, 910). Hence, before the advent
that the K-2Cl cotransporter KCC4 coimmunoprecipitates of pharmacological inhibitors, vagotomy has been an effec-
with H⫹-K⫹-ATPase in apical membrane fractions of pari- tive surgical procedure to control acid-related disorders
etal cells (352). Furthermore, flux measurements in H⫹-K⫹- (301).
ATPase containing vesicles showed decreased chloride and
proton transport under pharmacological blockade of The parietal cell receives neuronal input from the vagus nerve
KCC4, suggesting a functional coupling of KCC4 to H⫹- that is relayed via cholinergic postganglionic enteric fibers in
K⫹-ATPase (352). Although the hypothesis that both po- the enteric nervous system (ENS) (FIGURES 1 AND 2). In ad-
tassium and chloride leave the cell via a transporter is in- dition, the vagus nerve activates G-cells to release gastrin,
triguing, the observation is, as of now, solitary and needs resulting in an indirect stimulation of the parietal cell. Di-
further experimental validation. rect cholinergic activation occurs mostly via muscarinic M3
receptors, which have been identified on the surface of the
parietal cell (507, 541, 846). The M3 receptor is a classic
B. Control of Acid Secretion seven-transmembrane domain GPCR. Predictably, knock-
out of M3 receptors leads to an impairment of gastric acid
Gastric acid secretion is subjected to precise regulation. The secretion and compensatory hypergastrinemia due to nega-
complex regulatory machinery that orchestrates the secretion tive feedback (9). Following acetylcholine binding, M3 re-
of gastric acid consists of hormonal (gastrin, somatostatin), ceptor activation mostly causes an increase in intracellular
paracrine (histamine, somatostatin), and neuronal compo- calcium concentrations (44, 1163). Calcium rises in re-
nents (FIGURE 2). The need for this tight regulation is high- sponse to PLC-mediated IP3 generation and subsequent mo-
lighted by conditions that lead to a hypersecretion of gastric bilization from intracellular stores (190). The primary ki-
acid, such as Zollinger-Ellisson syndrome (ZES; gastrinoma). nases activated by the M3 receptor are protein kinase C
Gastric hypersecretion can overcome the measures our body (PKC) and calcium/calmodulin-dependent protein kinase II
undertakes to protect itself from the acid and thereby lead to (CaMKII) (136, 196, 314 –316, 773, 774, 1095). While
peptic ulcers. A fine on-demand regulation of acid secretion is activation of CaMKII has a clear stimulatory effect on acid
thus pivotal to ensure the balance between an adequately low secretion, PKC has been reported to have dual effects, al-
intragastric pH and tissue protection. though reports of an inhibitory role predominate numeri-
cally (23, 73, 136, 196, 313, 314, 316, 597, 755, 773,
According to the well-established model of acid secretion, 1095). It has been postulated that the expression of differ-
the parietal cell is activated by neuronal input from the ent PKC isoforms may account for this dichotomy (313,
vagus nerve, endocrine input from gastrin-producing G 314). Current evidence suggests that the PKC-␣ isoform has
cells, and paracrine input from histamine-producing en- a suppressing effect by trans-inhibiting CaMKII activity,
terochromaffin-like (ECL) cells (FIGURES 1 AND 2). The whereas PKC-⑀ increases the baseline levels of intracellular
distinct substances released by these cells, i.e., acetylcho- calcium, thereby sensitizing the parietal cell to subsequent

Oxyntic mucosa Antrum

Lumenal Basolateral Lumenal Basolateral
D-cell D-cell ENS
VPAC PACAP
VIP
Somatostatin CCK1 CCK

?
Low Somatostatin
lumenal
pH
ECL-cell
SSTR SST
G-cell
SSTR SST
PAC1 PACAP
ENS

CaSR
CCK2 Gast CaSR
ENS
Histamine
Calcium ACh
Amino acids GRP
PPIs Gastrin
Polyamines
APAs
CaSR
H+ H2 Hist
H,K-ATPase Circulation
K+
CCK2 Gast
M3 ACh
ENS
SSTR SST
Parietal cell
Somatostatin
D-cell
FIGURE 2. Neuroendocrine regulation of gastric acid secretion. In addition to direct neuronal regulation, the
parietal cell receives paracrine signals from neighboring ECL- and D-cells. Gastrin is produced in the antral
mucosa of the stomach and reaches the oxyntic mucosa via the circulation (endocrine regulation). Gastrin-
mediated histamine release represents one of the major stimulatory pathways leading to the secretion of
gastric acid (gastrin-histamine axis). The secretion of gastrin is closely tied to intragastric pH (via somatosta-
tin), thereby creating a negative-feedback loop. ACh, acetylcholine; APAs, acid pump antagonists; ENS, enteric
nervous system; Gast, gastrin; Hist, histamine; PPIs, proton pump inhibitors; SST, somatostatin.
stimulation (313, 314). Apart from PKC and CaMKII acti- longed MAPK activation (72h) has been shown to serve as
vation, cholinergic signaling activates parietal cell MAPKs, a maturation and differentiation signal leading to a trans-
which is partially a downstream effect of PKC activation formation of parietal cell morphology in vitro (1039). The
(771, 1039, 1062, 1063). MAPK activation seems to have a change in morphology is accompanied by a downregulation
biphasic effect on acid secretion (acute inhibition and of H⫹-K⫹-ATPase gene expression (1039). As of now, it is
chronic augmentation) and also serves as a mediator of challenging to put these findings into a physiological per-
trophic responses in the parietal cell. For example, prospective.

In addition to M3 receptors, M1 receptors have also been cretory response to amidated gastrin, although they have no
implicated to play a role in the process of acid secretion. intrinsic ability to induce acid secretion (178). Third, pro-
This hypothesis was derived from the observation that the gastrin and glycine extended gastrins were shown to act as
M1 receptor is expressed in gastric mucosa and that its a proliferative signal, especially in the colon (20, 482, 994,
blocker pirenzepine can inhibit gastric acid secretion (29, 1145). This is also of pathophysiological relevance as both
466). Most evidence pointed to an expression of M1 on forms can promote cancer growth by presumably inhibiting
ECL-cells, where it was speculated to regulate the release of apoptosis and inducing angiogenesis (71, 87, 900). For ex-
histamine (437, 507). More recent findings somewhat sur- ample, it was shown that overexpression of progastrin in
prisingly report that pirenzepine also suppresses acid secre- mice is a predisposing factor for the development of colo-
tion in M1-deficient animals. Furthermore, these animals rectal or bronchoalveolar cancers (587, 1017).
show a normal phenotype in terms of acid output (10).
These observations question both the involvement of M1 B) REGULATION OF RELEASE. Gastrin is released by the G-cell in
receptors in acid secretion and the specificity of pirenzepine. response to a variety of stimuli of different origin. Direct
neuronal stimulation of the G-cell occurs via ACh and gas-
Lastly, knockout studies point towards a contribution of the

trin releasing peptide (GRP), which are released by postgan-
M5 receptor to the regulation of acid secretion, as its deletion
glionic neurons of the enteric nervous system. The postgan-
correlates with decreased acid output (10). Yet, M5 receptor
glionic fibers themselves receive input from the efferent
mRNA could only be detected in whole stomach homoge-
nates, but not in gastric mucosa per se, making its localization fraction of the vagus nerve (86, 485). On the other hand,
to the submucosal enteric plexus more likely (10). food-related signals, such as calcium, amino acids, and
amines, can also directly trigger gastrin secretion (FIGURE 2)
2. Gastrin/G-cell (257). The secretory stimuli culminate in an increase in
intracellular calcium concentrations, leading to vesicle
Gastrin has been discovered in 1906 by John S. Edkins, who fusion and gastrin secretion. The main inhibitory signal
injected gastric extracts of pig and cat stomachs into the for gastrin secretion is somatostatin, which reaches the
jugular vein of cats and observed a subsequent increase in G-cells in a paracrine fashion from neighboring D-cells
acid secretion (298). Gastrin is a peptide hormone that is (632, 975).
produced in specialized G-cells, located in the antral section
of the stomach (FIGURE 2) and endocrine cells in the duo- With regard to the neuronal control of gastrin secretion, it is
denum, small intestine, colon, pancreas, testis, and pitu- generally thought that vagal stimulation increases the re-
itary. It is the main mediator of the so-called gastric phase of lease of gastrin, although some conflicting evidence exists
acid secretion, which initiates when the ingested food enters (310, 694). Latest experiments that assessed local gastrin
the stomach. The gastric phase accounts for the majority of concentrations utilizing microdialysis, however, clearly
the acid secretory response of the stomach. show an increase in gastrin levels following acute electrical
vagal stimulation (310). The vagus nerve then synapses on
A) SYNTHESIS. The gastrin cDNA encodes a 101-amino acid neurons of the ENS, which are thought to release either the
pre-pro-hormone that undergoes extensive posttransla- neurotransmitter ACh or GRP on a G-cell, leading to secre-
tional processing (113, 519, 551, 552, 1161). In brief, the tion of gastrin (295, 635, 694, 960, 978). It should be noted
pre-pro-hormone is first cleaved NH2-terminally to create that a recent investigation failed to observe increased gas-
progastrin and then truncated to two main core proteins, trin levels, following exogenous GRP administration in hu-
G17 and G34, which can exist in glycine extended (G17-
mans (456). Yet, GRP itself serves as a clear acid secreta-
Gly; G34-Gly) or terminally amidated (G17-NH2, G34-
gogue, although potentially not via gastrin (456). Whether
NH2) forms. Furthermore, a fraction of progastrin (⬃47%
these conflicting observations are attributable to species dif-
in humans) is sulfated at Tyr66 in the course of its passage
ferences (most earlier observations utilized rodent models)
through the Golgi apparatus, thereby giving rise to sulfated
and nonsulfated isoforms of gastrin (22). Sulfation has no remains to be elucidated. The ENS is also thought to medi-
influence on the acid secretory response, as the affinity to ate parietal and G-cell activation in response to mechanical
the gastrin receptor remains unchanged (399, 596). G17- distension of the stomach (455, 962, 977). The neurohor-
NH2 is the main circulating form that mediates the secre- monal response to gastric stretch is an integral part of the
tory effects of gastrin. Although the glycine-extended forms gastric phase of acid secretion. Closer examination, how-
have a low affinity towards the gastrin receptor (CCK2) and ever, reveals that the reports are very conflicting in that it is
thus play no role in gastric acid secretion (they are four to not clear whether a pure mechanical distension stimulates
five orders of magnitude less potent in inducing acid secre- or inhibits gastrin release (455, 664, 803, 962, 977). A
tion), it is still important to acknowledge their existence biphasic model characterized by initial inhibition of gastrin
(178, 722). First, they serve as substrates for the synthesis of secretion under low volumes followed by stimulation under
amidated gastrin and are cosecreted with gastrin by the high volumes has been suggested, but awaits further confir-
G-cells (1040, 1051). Second, they potentiate the acid se- mation (977).

Dietary components, such as amino acids and calcium, can fashion. Its half-life is determined by its rate of elimination
directly promote the secretion of gastrin and can thus sus- from the plasma which mainly occurs by metabolism in the
tain acid secretion in the gastric and intestinal phase as kidney, gut, and brain (419, 420). The importance of renal
digestion progresses (652, 1074). A rise in serum calcium elimination is corroborated by the observation that patients
concentrations evokes a similar effect. The correlation be- with renal failure present with higher plasma gastrin levels
tween calcium and gastrin is discussed in a separate section (818, 1075).
(see sect. VD2). It has been unclear for a long time as to how
these dietary components activate the G-cell. An involve- The two primary target cells of gastrin are the histamine-
ment of the ENS has been proposed as the most likely ex- secreting ECL cell and the parietal cell. Gastrin exerts its
planation in the past. More recent observations, however, functions via binding to the cholecystokinin receptor type 2
strongly indicate that the calcium-sensing receptor (CaSR) (CCK2), a seven transmembrane domain G protein-coupled
represents the molecular link between luminal dietary con- receptor, which is expressed on mature parietal and ECL
stituents and G-cell activation (325). The CaSR and its role cells, but also on gastric stem cells (560, 596, 608, 769, 772,
in the stomach are discussed separately and shall only be 904). On the ECL cell, gastrin binding causes the release of
summarized at this point (FIGURE 8) (see sect. IVD). First, histamine, which in turn stimulates the parietal cell in a

the same dietary components, i.e., amino acids, amines, and paracrine fashion (FIGURE 2) (see sect. IIB3) (412). This
calcium, which have all been shown to trigger gastrin re- activation cascade is commonly referred to as the gastrin-
lease also function as activators of CaSR (652, 1074). Sec- histamine axis. Evidence for a direct, i.e., nonhistamine-
ond, CaSR is expressed on the apical and basolateral side of relayed, activation of H⫹-K⫹-ATPase in the parietal cell by
the G-cell, which allows it to act as nutrient sensor both in gastrin exists, but is far less substantiated (459, 1024,
the gastric lumen and the circulation (142, 182, 886). 1025). Gastrin may sensitize the parietal cell to subsequent
Third, direct activation of the CaSR is known to stimulate secretagogue stimulation, rather than acting as a bona fide
acid secretion (145, 291, 373). Finally, and most impor- secretagogue itself. Canonically it is widely accepted that
tantly, CaSR (⫺/⫺) animals lack the gastrin secretory re- gastrin exerts its physiological effects mostly via activation
sponse to intraluminal instillation of peptone, calcium, and of ECL cells (24, 1131). Knock-out of gastrin leads to a
phenylalanine (325). In light of this evidence, it is highly severe impairment of basal and stimulated acid secretion
likely that CaSR is the long elusive luminal nutrient sensor (179, 347). Apart from stimulating acid secretion, gastrin
that regulates the secretion of gastrin from the G-cell. serves as a pivotal proliferative signal for the gastric mucosa
in general (60, 410, 534, 631, 816). It is commonly ob-
The plasma levels of gastrin are closely tied to the intragas- served that elevated plasma gastrin levels lead to substantial
tric pH. Low intraluminal pH is a potent inhibitor of gastrin mucosal proliferation (60, 410, 534, 631, 816). This phe-
release, which serves as a negative-feedback mechanism to nomenon has been extensively described in various knock-
impede an overproduction of acid. Conversely, a more al- out animals suffering from hypochlorhydria and concomi-
kali intragastric pH induces the secretion of gastrin, which tant hypergastrinemia, but also in patients with ZES (39,
accounts for the commonly observed hypergastrinemia in 515, 584, 1066). The source of mucosal cell proliferation is
states of acid suppression, such as during proton pump progenitor cells located in the isthmus region of the gastric
inhibitor (PPI) therapy. The pH dependency of serum gas- gland (545). Expression of the CCK2 has been confirmed on
trin levels is mainly relayed via somatostatin, as acid di- several gastric progenitor cells (560, 769). Furthermore,
rectly stimulates somatostatin release (see sect. IIB4). Soma- gastrin has been shown to stimulate cell migration from the
tostatin, released by neighboring antral D-cells, in turn acts progenitor region along the gastric gland axis (578). Muco-
as the main inhibitor of gastrin secretion (FIGURE 2). The sal hyperplasia thus ensues most likely via a direct activa-
physical proximity to G-cells allows for a fine paracrine tion of precursor cells by gastrin. Although hypergastrine-
regulation of gastrin release. Although it is generally ac- mia causes a generalized mucosal hyperplasia, ECL cells
cepted that intragastric pH mostly modulates local soma- seem to be particularly regulated by gastrin, as their relative
tostatin levels, the G-cell may also directly sense intragastric fraction compared with other mucosal cells increases under
pH via CaSR. CaSR is acid sensitive, and it has been shown prolonged gastrin exposure (60, 410, 631). Conversely, the
that isolated rat G-cells secrete less gastrin when the extra- absence of the CCK2 almost entirely eliminates mature
cellular pH is dropped from 7.4 to 5.5 (569). However, ECL-cells from the gastric mucosa (177, 622). [Somewhat
more investigations are needed to substantiate this evi- surprisingly this does not occur when gastrin itself is
dence. Furthermore, gastrin release is also inhibited by neu- knocked out (179, 347).] It should be noted that the M3
ronal regulation by the ENS. The neurotransmitter galanin receptor seems to be necessary as a cofactor mediating the
has been demonstrated to exert a direct inhibitory effect on trophic effects of gastrin, as its absence is associated with a
isolated G-cells (695, 961). normal mucosal phenotype despite elevated serum gastrin
levels (see above) (9). The mechanism underlying this inter-
C) CELLULAR EFFECTS. Following secretion, gastrin enters the dependency between gastrin and the M3 receptor is as of
bloodstream and acts on its target cells in an endocrine now elusive. The cholinergic and gastrin systems also seem

to be intertwined with regard to acid secretion. In the ab- fairly well understood. Following CCK2 activation, in-
sence of the CCK2 receptor, the parietal cell’s acid secretory creased transcription of HDC is mediated via a PKC- and
response to the secretagogue carbachol (ACh analog) is ERK-dependent pathway (470, 472). The HDC gene pro-
abolished, while the response to histamine remains intact moter is then activated by at least three distinct nuclear
(543). Again, one can only speculate about the molecular factors which bind to gastrin response elements, resulting in
basis of this interaction. gene transcription (889, 890). Apart from augmenting gene
transcription, gastrin regulates the degradation of HDC,
In conclusion, gastrin is the most important activator of which further increases intracellular enzyme levels (331,
acid secretion in the stomach. The role of gastrin, and espe- 1214). Second, gastrin enhances the transcription of the vesic-
cially its glycine extended forms, has evolved beyond being ular monoamine transporter type 2 (VMAT2; SLC18A2),
a mere acid secretagogue to being an important global reg- which is responsible for accumulating histamine in the se-
ulator of cell growth and differentiation. Furthermore, the cretory vesicles (376). Similarly to HDC, this effect depends
regulation of gastrin by the levels of plasma calcium pro- on PKC and ERK activation and binding of a nuclear factor
vokes the question as to whether gastrin itself in turn has an to a gastrin response element in the VMAT2 promoter re-
impact on global calcium homeostasis. A subsequent sec- gion (164, 1154). It should be mentioned that gastrin reg-

tion makes an attempt at addressing this question (see sect. ulates the transcription of a plethora of other genes which
VD2). serve a diverse array of roles, ranging from growth to me-
tabolism (346). Amongst many others these include chro-
3. Histamine/ECL cell mogranin A, which is essential for granule packaging and is
a precursor of pancreastatin (see sect.VD3) (231). Third,
Histamine has been discovered as early as 1910 by Dale,
gastrin induces the fusion of secretory granules and the
Barger and Laidlow in extracts of ergot fungi (63, 237). In
release of histamine into the gland environment. Secretion
1920, Popielski for the first time described its effect on the
follows a biphasic elevation of intracellular calcium concen-
secretion of gastric acid (866). He observed that subcutane-
trations after activation of CCK2 (1201). The biphasic in-
ous administration of histamine resulted in increased acid
crease has been proposed to result from initial IP3-mediated
secretion (866). Furthermore, he concluded that this effect
release from intracellular stores, which is followed by sub-
was independent of the vagus nerve, as secretion still took
sequent influx of calcium via L-type calcium channels from
place after vagotomy and administration of atropine. This
the extracellular space (1201). The importance of intracel-
led Popielski to postulate that histamine exerts its effects
lular store mobilization has been contested by a different
directly on the level of the gastric gland (866). The hypoth-
group, which proposed that solely influx trough L-type, and
esis that histamine acts in a paracrine fashion on parietal
cells and that its release is regulated by the levels of gastrin to a lesser extent N-type, calcium channels triggers the se-
has been put forward for the first time by Emmelin and cretory response (673). Lastly, gastrin has a trophic effect
Kahlson in 1944 (306). At this point, the cellular source of on the ECL cell (see sect. IIB2).
histamine was still obscure. It was only in the late 1960s
that histamine had been histochemically localized to the Apart from gastrin, ECL cells are stimulated by pituitary
ECL cells of the gastric gland (413, 1084). adenylate cyclase activating polypeptide (PACAP), which is
a neuropeptide expressed in the ENS of the gastric mucosa
A) SYNTHESIS AND REGULATION OF RELEASE. Histamine is the (737, 1054). PACAP has homology to vasoactive intestinal
effector of the gastrin-histamine axis and directly stimulates polypeptide (VIP) and binds to a distinct receptor (PAC-1)
the parietal cell to secrete hydrochloric acid (FIGURE 2). on the ECL cell (1207, 1208). Binding of PACAP to PAC-1
Histamine is derived from the amino acid histidine, which is induces release of histamine (672, 798, 944, 1207). Similar
enzymatically converted to histamine by L-histidine decar- results have been obtained with VIP, which is attributable
boxylase (HDC) (957). The effects of genetic HDC deletion to partial agonism at PAC-1 (798, 941). Historically, inves-
are predictably severe: animals lacking HDC have a low tigations yielded controversial results with regard to the
basal acid output that does not respond to exogenous ad- effects of exogenously administrated PACAP on acid secre-
ministration of gastrin (1066). tion. Both an inhibition and stimulation of acid secretion
following PACAP injection are reported (760, 862, 944,
Histamine is stored in secretory granules of the ECL cell and 1207). This discrepancy is most likely attributable to the
is released into the surrounding milieu in response to stim- fact that PACAP can also act as an agonist of the VIP re-
ulation by gastrin and neuronal signals. Stimulation by gas- ceptor (VPAC) on the somatostatin-secreting D-cell, lead-
trin occurs via activation of its GPCR CCK2 (772, 904). ing to a concomitant suppression of acid secretion by soma-
Gastrin affects the ECL cell in multiple ways. First, gastrin tostatin release (1207). Indeed, if an anti-somatostatin an-
exposure increases the levels of HDC expression by enhanc- tibody is injected into rats simultaneously with PACAP,
ing its transcription and inhibiting its degradation, to allow acid secretion is elevated threefold from baseline (compared
for increased synthesis of histamine (268, 331). The molec- with 1.5-fold in the absence of an anti somatostatin anti-
ular mechanism underlying increased HDC transcription is body) (1207). Evidence points to the fact that the PACAP-

stimulated release of somatostatin is of particular impor- histamine-containing secretory vesicles. The molecular
tance in the mouse, as most studies showing a suppression mechanism of vesicle fusion with the apical membrane re-
of acid secretion after PACAP administration were con- lies on the formation of the core SNARE complex, consist-
ducted in murine models. ing of syntaxin, synaptobrevin, and SNAP-25. Synaptotag-
min presumably acts as a calcium sensor relaying the
PACAP has very similar effects on the ECL cell as gastrin. intracellular calcium signal to the vesicle fusion protein
Similarly to gastrin, PACAP causes histamine release by apparatus. The expression of all SNARE complex pro-
increasing intracellular calcium concentrations via calcium teins has been confirmed in the ECL cell (471, 477,
influx through L-type, but also ligand-gated calcium chan- 1215). In accordance with these findings, introduction of
nels (673). In further analogy to gastrin, PACAP upregu- the neurotoxins tetanus toxin light chain and botulinum
lates the expression of HDC and exerts trophic effects on toxin, which cleave constituents of the SNARE complex
the ECL cell (590, 729, 810). Contradictory results with apparatus and thereby render it nonfunctional, result in
regard to the effects of acetylcholine on histamine release inhibition of histamine secretion (477).
exist. It has been reported that acetylcholine can either stim-
ulate or has no effect on the secretion of histamine in in vitro Very small amounts of histamine are sufficient to induce

experiments on isolated ECL cells (481, 672, 674, 941, acid secretion. Histamine acts via the H2 receptor on the
946). In vivo application of muscarinic agonists, followed parietal cell, which has been discovered by Sir J. W. Black in
by measurement of histamine concentrations using micro- 1972 (106). For this seminal discovery, he was later
dialysis, also yielded no evidence for cholinergic stimulation awarded the Nobel Prize in Physiology and Medicine. The
(798). Conversely, it is well accepted that adrenergic stim- H2 receptor belongs to the family of seven-transmembrane
ulation leads to an increase in histamine release; however, domain GPCRs. Its activation predominantly leads to in-
the physiological relevance of adrenergic activation of ECL creases in the intracellular levels of cAMP, but also of cal-
cells is not entirely clear (636, 672, 674, 798, 871, 941). cium, which serve as stimulatory signals for H⫹-K⫹-ATPase
trafficking (67, 189, 738, 840, 1026, 1143). In analogy,
The ECL cell is inhibited by a variety of substances, the pharmacological agents that elevate cAMP, such as IBMX
most prominent of which is somatostatin (204, 590, 798, or forskolin, induce acid secretion (1026, 1191). The in-
941). Somatostatin is produced in D-cells of the oxyntic crease in cAMP is due to activation of adenylate cyclase via
mucosa and reaches the ECL cell in a paracrine fashion Gs. The role of calcium in the process of histamine secretion
where it binds to the somatostatin receptor (SST2 and po- remains a controversial matter. First, the mechanism lead-
tentially SST5) (FIGURE 2) (570, 873). Receptor binding ing to histamine-induced increases in intracellular calcium
leads to inhibition of histamine exocytosis via blockade of has been subject of discussion. Evidence exists that hista-
mostly L-type calcium channels (105). This impedes the mine can, apart from adenylate cyclase, also activate PLC,
elevation of intracellular calcium concentrations caused by leading to calcium release from intracellular stores (607,
ECL activators, such as gastrin (see above) (873). In addi- 1142, 1143). Conversely, it has been suggested that the
tion, somatostatin also inhibits the proliferation of ECL observed increases in intracellular calcium are a byproduct
cells (570). Somatostatin can thus be seen as the global of cAMP-mediated PKA activation, which in turn can reg-
hormonal antagonist to gastrin with regard to ECL cell ulate the opening of calcium channels (144, 189, 840). Sec-
function and proliferation. The neuronal inhibition of ECL ond, it is questionable to what degree the calcium signal is
cells is mainly carried out by the neuropeptide galanin (105, an integral and necessary part of the acid secretory response
672, 798, 1209). Galanin is localized to neurons of the ENS to histamine (738, 840). Chelation of the transitory calcium
and demonstrated an inhibitory effect on histamine secre- increases with BAPTA abolishes only the secretory response
tion in in vitro and in vivo models (105, 302, 672, 731, 798, of isolated gastric glands to histamine by ⬃40%, while it
1209). Similarly to somatostatin, the molecular mechanism completely eliminates the response to cholinergic stimula-
underlying its inhibitory effect is an interference with cal- tion (738). Also, live fluorescence imaging in isolated glands
cium signaling via closure of L-type calcium channels (105). showed no spatiotemporal correlation between the hista-
Lastly, prostaglandin E and nitric oxide also act as inhibi- mine-induced increases in calcium and the onset of acid
tors of histamine release (105, 554, 798, 1002). Although secretion, thereby questioning an involvement of calcium in
neuropeptide YY (PYY) and calcitonin gene-related peptide the secretory response (840).
(CGRP) have also been implicated in playing a role in ECL
cell regulation, a detailed discussion is omitted in light of H2 receptor knockout animals effectively illustrate the sig-
contradictory results which range from stimulation to inhi- nificance of the histamine-gastrin axis in gastric physiology.
bition of secretion (672, 674, 798, 1210). Lack of the H2 receptor leads to a complete failure of gas-
trin or histamine to induce acid secretion (584). The secre-
B) CELLULAR EFFECTS. As mentioned earlier, stimulation of the tory response to carbachol, however, remains intact (584).
ECL cell is translated into an elevation in intracellular cal- Hypergastrinemia develops as a feedback mechanism with
cium concentrations, leading to exocytosis of preformed the aim of reestablishing acid secretion, leading to mucosal

hypertrophy (584). In light of the central role of the H2 substantiated (749, 905, 967, 1202). Cholecystokinin is
receptor in parietal cell physiology, it has been successfully structurally closely related to gastrin (both share an identi-
used as a pharmacological target with the aim of suppress- cal 5-amino acid COOH terminus) and also exists in vari-
ing gastric acid output (see sect. IIC2). ous peptide lengths (767). It is secreted by I-cells of the small
intestine following protein and fat-rich chyme entering the
4. Somatostatin/D-cell duodenum, and thus represents a classical mediator of the
intestinal phase of acid secretion (594). As its name implies,
Somatostatin was isolated for the first time in 1973 from cholecystokinin has originally been described as a stimula-
ovine hypothalamus and characterized as an inhibitor of tor of gallbladder contraction; however, its inhibitory influ-
growth hormone release from the pituitary gland (124). A ence on gastric acid secretion is now well accepted and
few years later somatostatin was identified in endocrine extensively described (593, 1203). Cholecystokinin can
cells of the stomach, which we now know as D-cells (638). bind to both the CCK1 and CCK2 receptor with almost
equal affinity, whereas the actions of gastrin are almost
A) SYNTHESIS AND REGULATION OF RELEASE. Somatostatin is a
exclusively mediated by the CCK2 receptor. The dual affin-
peptide hormone that exists in two primary forms that dif- ity of cholecystokinin would imply a possible stimulatory

fer in their respective peptide length. The most abundant effect on acid secretion via activation of CCK2 on ECL cells;
form in the gastric mucosa is somatostatin-14 (consisting of however, in vivo the inhibitory effect mediated by activa-
14 amino acids), whereas somatostatin-28 only constitutes tion of CCK1 and CCK2 on D-cells prevails (593, 966,
a minute fraction of the total gastric somatostatin content 1202, 1203).
(198, 1125). The two forms of somatostatin are cleavage
products of a larger 116-amino acid pre-prohormone (pre- One of the most important stimulators of D-cell secretion is
prosomatostatin), which in turn is processed to the 92-
the intragastric pH. A seminal observation demonstrating a
amino acid-long prosomatostatin (1000). It should be men-
correlation between gastric acidity and the amount of se-
tioned that other cleavage products, such as antrin or so-
creted somatostatin was made in dogs in the 1970s. It has
matostatin-28(1–12) exist and are secreted together with
been shown that the amount of somatostatin directly in-
somatostatin (77, 885). Their physiological significance is,
creases in antral venous blood following gastric HCl infu-
however, less well understood.
sion, while somatostatin levels were unaffected in venous
blood from the oxyntic mucosa (982). Similar observations
Somatostatin is the global antagonist of the acid secreta-
were later made in isolated mouse stomach, however with-
gogues. It is produced by intestinal and gastric D-cells, the
out topographic discrimination (975). Two main hypothe-
latter of which exist in two populations in the stomach (61):
ses as to how somatostatin is regulated by intragastric pH
an antral population locally inhibits the release of gastrin
from G-cells, whereas a population localized to the acid- exist. The first states that the D-cell can directly act as a pH
producing oxyntic mucosa directly regulates the parietal sensor, and the second postulates that the pH sensing is
cell and inhibits histamine release from the ECL cell (FIG- mediated by neurons, which in turn act on D-cells. To ac-
URE 2) (19). The morphology of the D-cell is characteristic
complish putative direct pH sensing, several antral D-cells
in that it possesses long cytoplasmic processes, which allow are equipped with a distinct morphological feature. They
it to communicate with and regulate neighboring cells in a possess apical projections that are in contact with the glan-
paracrine fashion (620, 632). It is worthwhile to distinguish dular lumen, potentially allowing them to constantly mon-
the two populations of gastric D-cells, as each population itor the intraluminal milieu (620). These D-cells have been
possesses unique physiological properties (1202). termed open type. Conversely, the D-cells of the oxyntic
mucosa are mostly of the closed type, meaning that they are
The antral D-cell is mostly regulated by the local concen- embedded in the mucosa without luminal contact. The mo-
trations of gastrin, cholecystokinin, and intraluminal pH. lecular identity of the putative apical pH sensor remains
Gastrin induces somatostatin secretion from D-cells, which elusive. However, the presence of CaSR, which has pH
causes reciprocal inhibition of gastrin release from neigh- sensing properties, was recently confirmed in preliminary
boring G-cells, thereby creating a local negative-feedback studies on the D-cell and may represent a possible candidate
loop (976, 1011, 1202). The molecular mechanism under- for this mechanism (770). Apart from directly acting on
lying this loop is, however, less clear. CCK2 receptor is, if at D-cells, the effect of pH on somatostatin secretion may be
all, only expressed at very low levels in the antral mucosa mediated via afferent spinal neurons. Over 80% of the spi-
(749, 905, 967). It has been proposed that gastrin stimu- nal afferent neurons contain the neuropeptide CGRP (397,
lates somatostatin release in the antrum in a receptor-inde- 758, 1047, 1116). Perfusion models of antral sleeves have
pendent mechanism (1202). This may be accomplished via shown that the acid-induced rise in somatostatin is accom-
direct cell-cell contacts between the G- and the D-cell, panied by a concomitant increase in the concentrations of
which have been demonstrated with electron microscopy the neuropeptide CGRP (708). Furthermore, application of
(620). Conversely, evidence for cholecystokinin and its a CGRP receptor blocker inhibited the release of somatosta-
stimulatory role for somatostatin release via CCK1 is more tin following acid exposure (708). As D-cells are known to

express the CGRP receptor, an involvement of CGRP in interest of conciseness, their physiological effects will only
acid sensing is plausible (558). Again, this provokes the be discussed briefly at this point.
question of how CGRP-containing neurons may sense acid-
ity on a molecular basis. The acid-sensitive channels tran- A) SECRETIN. Secretin is a 27-amino acid peptide hormone
sient receptor potential vanilloid channel (TRPV1) and the that is synthesized in duodenal S-cells and secreted into the
acid-sensing ion channel 3 (ASIC3) had been proposed as circulation in response to a low duodenal pH or passage of
molecular acid sensors; however, latest experiments have digestive products, such as fat (195, 955, 1153). A subpop-
shown that the increase in CGRP still occurs in the genetic ulation of secretin-producing cells is also present in the
absence of the channels (47, 96, 163). gastric mucosa, where it may influence acid secretion in a
paracrine manner (191–193). Given its secretory stimulus,
Neuropeptides of the gastric ENS that stimulate the secre- it is regarded as a classic effector of the intestinal phase of
tion of somatostatin include PACAP and VIP, which both acid secretion. When it was first discovered in 1902 by
bind to the VPAC receptor expressed on D-cells (199, 657, Bayliss and Starling (interestingly secretin was the first hor-
1207). The presence of VIP and PACAP containing neu- mone ever to be discovered), it was noted that secretin in-
rons, which integrate signals from the vagus nerve, has been duces pancreatic bicarbonate secretion, which leads to a

demonstrated in the gastric mucosa (302, 737). Further- buffering of the gastric acid entering the duodenum (68). In
more, cholinergic signals can act on the antral D-cell via the the stomach, secretin acts as an inhibitor of gastric motility
M3 receptor to promote secretion of somatostatin (140). and acid secretion (141, 194, 269, 374, 532, 564, 656, 677,
This is in sharp contrast to D-cells from the oxyntic mucosa 1107). The exact mechanism as to how secretin attenuates
that are inhibited by cholinergic signals (197, 200, 1182). the secretion of acid is not exactly known, and several hy-
As mentioned earlier, the D-cells in the oxyntic mucosa also potheses have been put forward. For example, it has been
differ in their morphology. D-cells in the oxyntic mucosa shown that secretin induces the secretion of somatostatin
are of the closed type and have thus not been implicated to from isolated D-cells (141). Increases in somatostatin levels
participate in acid sensing. They exert their acid-suppres- were also observed in isolated perfused stomach models (205,
sive effects by the paracrine regulation of ECL and parietal 374). Others have proposed that secretin activates vagal pri-
cells. Further functional divergence between antrum and the
mary afferent neurons, which in turn leads to neuronal mod-
oxyntic mucosa has been demonstrated in the regulation of the
ulation of acid secretion (656, 659). In opposition to this the-
somatostatin mRNA. For example, suppression of acid secre-
ory, it has also been demonstrated that the inhibitory effects of
tion with omeprazole in fasted animals markedly decreased
secretin are independent of vagotomy (677).
somatostatin mRNA levels in the antrum, whereas the levels in
the oxyntic mucosa were affected to a much lesser extent,
B) OXYNTOMODULIN. Oxyntomodulin is a peptide hormone
which further corroborates the hypothesis that the antral cells
produced in the mammalian intestine. It is closely related to
are involved in luminal chemosensation (945).
glucagon and contains its entire amino acid sequence, ex-
tended by a COOH-terminal octapeptide (66). In isolated
B) CELLULAR EFFECTS. The effects of somatostatin on its target
parietal cells, oxyntomodulin acts as an activator of acid
cells are mediated by the SST2 receptor. Knockout of the re-
ceptor causes a 10-fold increase in basal acid output, which secretion (959). The integrated response to oxyntomodulin
exemplifies the pivotal role somatostatin plays as a global sup- is, however, opposite. Systemic injection decreases gastric
pressant of acid secretion (715). Somatostatin acts on all main acid secretion in rat, cat, and human test subjects (53, 157,
cell types that are involved in the process of acid secretion, i.e., 285, 524, 525, 965). The inhibitory effect is most likely
parietal cells, ECL cells, and G-cells (FIGURE 2). The inhibition mediated via somatostatin release (53).
of the G- and ECL cells has been discussed in the respective
C) SEROTONIN. It was recognized in the early 1950s that se-
sections. In the parietal cell, somatostatin has a clear direct
inhibitory effect on secretagogue-induced acid secretion (827, rotonin was present in the antral mucosa of dog stomachs
1177). This effect is partially attributable to activation of Gi, (323). Serotonin is stored in granules of enterochromaffin
leading to inhibition of adenylate cyclase and a subsequent cells of the antrum (1099). It is released into the circulation
decrease in intracellular cAMP levels (827). and the gastric lumen in response to vagal stimulation (107,
649). Intraluminal acidification serves as another stimulus
In conclusion, somatostatin acts as the global brake on acid for serotonin release (1196). Serotonin has an inhibitory
secretion. By acting on G-cells, ECL cells, and parietal cells, effect on the secretion of gastric acid (107, 153, 521, 650,
it exerts its inhibitory action on every link in the regulatory 720, 903). It is still poorly understood where serotonin
chain leading to the secretion of gastric acid. interferes with acid secretion.
5. Other substances D) NEUROTENSIN. Neurotensin is a 13-amino acid neuropep-

tide that was originally isolated from calf hypothalamus
A variety of other substances have been shown to have (161). In the periphery, it is also produced and secreted
either direct or indirect effects on acid secretion. In the postprandially by specialized endocrine cells (N-cells) of the

small intestine (863). Various investigations have demon- concentrations have been observed in both cell types after
strated that neurotensin suppresses the secretion of gastric NO exposure, suggesting that guanylate cyclase is an intra-
acid and delays gastric emptying (25, 108, 486, 985). This cellular target for NO (82, 1002).
has been shown by direct systemic injection, but also by
immunoneutralization of endogenous neurotensin in a re- G) INTERLEUKINS. Interleukins (IL) are cytokines that mainly
verse approach (25, 108, 486, 985). In disagreement with coordinate immune responses. In particular, IL-1␤ has been
these findings, other investigators could only inhibit acid shown to impact gastric acid secretion. IL-1␤ is a general
secretion at unphysiologically high serum concentrations of proinflammatory cytokine that plays an important role in
⬃750 pmol (747). Of note, physiological postprandial neu- the stomach in the context of Helicobacter pylori infection.
rotensin levels were measured to be ⬃15 pmol by the same H. pylori infection triggers an elevation of IL-1␤ levels as
investigators, questioning the role of neurotensin as a phys- part of the host’s immune response (65). Peripheral injec-
iological endocrine inhibitor of acid secretion (747). Neu- tion of IL-1␤ can profoundly suppress gastric acid secretion
rotensin is also located to nerve fibers of the enteric nervous (912, 947, 1059, 1101, 1132). Multiple explanations for
system in the stomach, indicating that it may act as a local this observation have been put forward. It has been sug-
neuronal rather than an endocrine regulator. It has been gested the IL-1␤ acts in the CNS, as intrathecal injection

proposed that neurotensin may induce the secretion of so- also has an acid-suppressive effect (948, 949). Others have
matostatin and thereby exert its inhibitory action on acid suggested that IL-1␤ promotes formation of prostaglandins
secretion (53, 414). Most recently, however, the low-affin- or NO, which in turn inhibit acid secretion (312, 947,
ity neurotenstin type 2 receptor (NTS2) has been identified 1101). Yet, a direct effect on parietal cells and ECL cells is
on the parietal cell, suggesting a direct influence. the most likely explanation, as both cell types express the
IL-1 receptor and have been shown to be inhibited in their
E) GHRELIN. Ghrelin is a recently discovered 28-amino acid
function in isolated cell models (69, 70, 872, 958).
peptide hormone that is synthesized in P/D1 cells of the
fundus (242). Since its discovery, multiple functions have C. The Pharmacological Suppression
been ascribed to it, ranging from being a regulator of appe- of Acid Secretion
tite to being a modulator of bone remodeling. Its effects on
bone are described in a separate section of this review (see Decreasing gastric acidity is indicated in many pathological
sect. VD1). Apart from these functions, ghrelin also has contexts, including gastric reflux disease or peptic ulcer dis-
been implicated to affect gastric acid secretion, although it ease. This target can be achieved by two main pharmaco-
remains a matter of discussion in which direction, as periph- logical approaches: 1) the inhibition of gastric acid secre-
erally administered ghrelin has been reported to stimulate, tion or 2) the intraluminal neutralization of already secreted
inhibit, or not affect acid secretion (278, 355, 654, 719). gastric acid (antacids). Gastric acid secretion can be atten-
The reason for these dichotomic results is largely unclear. uated by either directly blocking its final molecular effector,
The fact that ghrelin circulates in acylated and desacylated namely, H⫹-K⫹-ATPase (PPIs and acid pump antagonists),
forms adds further complexity to the subject (491). Indeed, or by interfering with the neurohormonal signaling path-
acylated ghrelin has been shown to stimulate acid secretion way leading to its secretion (H2 antagonists). The following
following peripheral injection, whereas desacylated ghrelin section attempts to discuss the four most common sub-
remained without effect (938). Further investigations are stance classes employed to increase intragastric pH.
needed to clarify the controversy surrounding ghrelin and
its influence on gastric acid secretion. 1. Direct pharmacological inhibition of H⫹-K⫹-ATPase
F) NITRIC OXIDE. Nitric oxide (NO) is an important signaling The inhibition of H⫹-K⫹-ATPase-mediated proton trans-
molecule that plays a role in multiple physiological pro- port represents the main contemporary pharmacological
cesses, such as vasodilation or the immune response. In- strategy for reducing gastric acidity. An increase of gastric
deed, NO has been shown to mediate the hyperemic re- pH is the main factor ameliorating acid-related disorders
sponse of the gastric mucosa that occurs during acid secre- and has been show to directly correlate with healing rates of,
tion (553). However, NO also directly influences the for example, GERD (74). Two main substance groups exert
production of acid. The effect of NO on acid secretion is their acid-reducing effect via inhibiting H⫹-K⫹-ATPase func-
most likely inhibitory (81, 82, 555, 1002; opposed by Ref. tion: PPIs and acid pump antagonists (APAs). Both substances
426). NO is produced by various forms of NO synthases, achieve this aim by distinct mechanisms.
one of which has been localized at high concentrations in
cells in the vicinity of parietal cells, allowing for a putative Omeprazole was the first clinically available PPI (324). The
paracrine regulation (80). NO has been proposed to exert first patent on omeprazole was filed in 1979 by the Swedish
its inhibitory action by either directly inhibiting the parietal company Astra AB (today AstraZeneca). The introduction
cell or by suppressing the release of histamine from ECL as a prescription PPI followed in 1989. Today, the omepra-
cells (81, 82, 555, 1002). Intracellular increases in cGMP zole enantiomer esomeprazole (S-omeprazole) generates the

second highest revenue of all pharmaceuticals in the United duration of inhibition is thus directly dependent on the
States and is only surpassed by the statin atorvastatin (512). plasma concentration of the inhibitor. As predicted by ho-
Furthermore, in the United States, PPIs are available as mology modeling, mutational analysis, but also recent
over-the-counter formulations, making them accessible for structural data, APAs bind in the luminal cavity of H⫹-K⫹-
the broad public. This is partially made possible by the high ATPase in the vicinity of the potassium entry site where they
safety profile of PPIs with a low incidence of unspecific exert their inhibitory action (2, 42, 761, 1104, 1106). Al-
adverse effects. Recently, however, concerns about the though the inhibition of acid secretion has been shown to be
long-term effects of chronic acid suppression have emerged very effective, these substances are generally not in clinical use
with regard to its impact on bone health (see sect. VA). (577). For example, clinical trials of the APA AZD08650 have
shown no additional therapeutic effect compared with the PPI
PPIs are delivered as pro-drugs through the bloodstream to gold-standard, which resulted in abandonment of the drug in a
the parietal cell. They are weak bases (pKa ⬃4), which can clinical setting (262, 539).
easily pass the cell membrane and accumulate in acidic com-
partments, such as the secretory canaliculus of the parietal 2. H2 antagonists
cell. The pro-drug is then converted to the pharmacologi-

cally active cyclic sulphenamide by the acidic pH in the The development of H2 blockers is inseparably intertwined
secretory canaliculus (670, 1007, 1135). Their specific ac- with Sir Black’s discovery of the H2 receptor on the gastric
cumulation in acidic milieus and their pH-catalyzed conver- parietal cell at the Smith Kline and French Laboratories
sion to active substances confers specificity and thus a high (now GlaxoSmithKline) (106). In his original publication,
safety profile to PPIs. Once activated, PPIs bind covalently Sir Black also describes burimamide as a competitive H2
via disulfide bonds to H⫹-K⫹-ATPase, thereby inhibiting its antagonist that can effectively inhibit pentagastrin-stimu-
capacity to pump protons (89, 90, 1005, 1006, 1008). The lated gastric acid output in human volunteers (106). Further
pattern of the cysteine residues, which are involved in PPI development of the antagonist led to the synthesis of cime-
binding, differ among the respective members of the PPI tidine, which was first commercially introduced in 1976 in
family: cysteine-813 reacts with all PPIs. In addition, the United Kingdom, followed by the United States in 1977.
omeprazole reacts with cysteine-892, lansoprazole with Other commonly used members of H2-antagonist family
cysteine-321, and pantoprazole and tenatoprazole, respec- now include ranitidine, famotidine, and nizatidine.
tively, with cysteine-822 (89, 90, 1005, 1006, 1008). Since
the binding is covalent and irreversible, the inhibitory effect H2 antagonists prevent histamine-mediated stimulation of
of PPIs lasts long beyond their plasma half-life, which usu- the parietal cell by competitively interfering with its recep-
ally ranges between 0.5 and 2 h depending on the specific tor. Although this effectively terminates the gastrin-hista-
PPI (581, 1036). PPIs are generally metabolized by the he- mine axis, the parietal cell is still susceptible to cholinergic
patic cytochrome P-450 system, in particular CYP2C19 stimulation via the M3 receptor. This partial inhibition
and CYP3A4. This is of particular clinical importance, as mainly accounts for the lower clinical efficacy of H2 antag-
CYP2C19 polymorphisms are known to exist. These poly- onists compared with PPIs, which directly target H⫹-K⫹-
morphisms can impact the pharmacokinetics of PPIs by ATPase as the final target of all parietal cell stimuli (384).
affecting the metabolic rate of CYP2C19, which may have For example, a meta-analysis concluded that patients
consequences for the optimal therapeutic regimen (582). treated for bleeding peptic ulcers are about twice as likely to
Esomeprazole and rabeprazole seem to be less dependent on suffer from persistent or recurrent bleeding if treated with
CYP2C19 metabolism (516, 983). Apart from the pattern H2 antagonists compared with PPIs (384). Another meta-
of cysteine reactivity, half-life and metabolism, PPIs also analysis also demonstrated a higher efficacy of PPIs in treat-
vary in oral bioavailability (581). ing esophagitis (83% healing rate with PPIs compared with
52% with H2 antagonists)(567). Today, H2 antagonists are
Suppression of acid secretion can never be complete, as largely superseded by PPIs due to their higher clinical effi-
H⫹-K⫹-ATPase is subjected to a constant turnover (half-life cacy. Furthermore, with the exception of famotidine, H2
⬃50 h) and needs to be stimulated for the conversion of the antagonists are extensively metabolized in the liver by the
PPI to take place (936). Nevertheless, PPIs are highly effec- CYP-450 system, leading to substantial drug-drug interac-
tive in reducing gastric acidity. Depending on the PPI and tion profile (for review, see Ref. 506).
the regimen, overall intragastric pH can be elevated by sev-
eral pH units, up to a pH of 6 (compared with 1–2 at 3. Antacids
baseline) (137, 425, 1036). For an excellent summary of PPI
efficacy, please refer to Reference 1036. Antacids directly neutralize gastric acid allowing immediate
short-term control of heartburn. They exist in various salt
APAs represent the second class of H⫹-K⫹-ATPase inhibi- formulations, the most common of which are carbonate
tors. Unlike PPIs, they do not undergo irreversible binding, salts, such as CaCO3, MgCO3, or NaHCO3. The use of
but rather act as potassium competitive antagonists. The calcium carbonate as a dietary calcium supplement is dis-

cussed in a separate section (see sect. VC). Although each Since a concentration gradient is not a prerequisite for this
formulation possesses its own spectrum of side effects, a process, transcellular transport allows us to absorb calcium
notable condition in the context of this review is the milk- even when the calcium concentration in the chyme is fairly
alkali syndrome, which is the result of a concomitant over- low. The relative importance of each respective absorption
ingestion of calcium and alkali, such as CaCO3. Although pathway thus alternates with the amount of ingested cal-
the syndrome became less prevalent with the introduction cium (46, 824, 1224). The rate of paracellular calcium up-
of modern ulcer therapies, it still poses a significant risk for take is canonically thought to remain constant, while tran-
patients that may ingest CaCO3 as a calcium supplement scellular transport can be upregulated under conditions of
for the prevention of osteoporosis or as an antacid on a dietary calcium restriction (46, 824, 1224). This regulation
regular basis. Milk-alkali syndrome presents with the triad occurs via the active metabolite of vitamin D [1,25(OH)2-
of metabolic alkalosis (carbonate), hpercalcemia (calcium), vitamin D], which serves as a stimulator for transcellular
and renal insufficiency. The above average ingestion of cal- calcium uptake to prevent systemic calcium depletion.
cium leads to increased plasma calcium levels due to excess
absorption and impaired renal secretion. PTH levels are low
due to negative feedback (6). Hypercalcemia further causes A. Transcellular Calcium Absorption

renal vasoconstriction, which decreases the glomerular fil-
tration rate, and renal fluid loss because of activation of the 1. Calcium entry
CaSR, which in turn has loop-diuretic-like effects (see sect.
IVD3). The activation of the CaSR is further potentiated by Evidence for active transport of calcium across the intestinal
the metabolic alkalosis, which increases its sensitivity to epithelium was established very early. With the use of a cal-
calcium. All abnormalities are usually reversible after with- cium radioisotope, various groups demonstrated 1,25(OH)2-
drawal of the offending agent and adequate treatment. vitamin D-dependent calcium transport against an imposed
concentration gradient in the small intestine of the rat (952,
954, 1150). It has also been observed that active transport
III. INTESTINAL CALCIUM ABSORPTION can be induced by a low-calcium diet, which we now know
to stimulate the production of 1,25(OH)2-vitamin D (1133,
The intestine is responsible for the absorption of dietary 1134). The degree of transport was highest in the duode-
calcium into our systemic circulation. Although the kidney num and decreased in the more distal segments (952). The
also plays a pivotal role in calcium homeostasis by retaining duodenum is still considered the primary site where the bulk
and balancing systemic calcium via regulating its excretion of transcellular transport occurs. To conduct active transcel-
into the urine, renal calcium handling will not be the subject lular calcium absorption, the enterocyte has to be equipped
of this review. with an apical calcium entry pathway, a mechanism for cyto-
solic calcium shuttling, and a basolateral calcium exit pathway
Current recommendations suggest that an average 40-yr- (FIGURE 3). As the cytosolic concentration of free calcium
old adult should ingest ⬃1,000 mg of calcium on a daily is kept at a constant low level with typical concentrations
basis (218). In the United States, this requirement is mostly of ⬃100 nM, apical calcium influx follows its electro-
met (57). Up to 72% of the dietary calcium intake is attrib- chemical gradient into the cell. In contrast, the extrusion
utable to dairy products (218). Typically, the intestine ab- of calcium on the basolateral membrane against an uphill
sorbs between 25 and 35% of the ingested calcium (1193). gradient either directly requires ATP or energy stored in
This occurs via two distinct pathways: 1) a paracellular the sodium gradient.
pathway and 2) a transcellular pathway.
A) THE SEARCH FOR THE APICAL CALCIUM ENTRY PATHWAY. The mo-
Calcium absorption via the paracellular route is tied to a lecular identity of the apical calcium entry pathway was un-
downhill concentration gradient between the luminal and clear for a long time. Early experiments in isolated duodenal
the extracellular compartment and occurs throughout the brush-border vesicles revealed that calcium uptake was pas-
entire intestine (although solvent drag induced paracellular sive, saturable, sensitive to ruthenium red, 1,25(OH)2-vitamin
flux may also play a role at low luminal calcium concentra- D dependent, and functionally optimal at a pH of 7.5 (740).
tions; Refs. 266, 1071, 1098). Conversely, transcellular ab- This black box characterization suggested that a “specific
sorption can also take place against an uphill gradient, but carrier” was responsible for calcium absorption and in ret-
requires molecular machinery in the form of distinct cal- rospect already provided us with accurate key characteris-
cium transport proteins which are expressed on the apical tics of the transient receptor potential vanilloid channel
and basolateral membranes of the enterocyte. This process type 6 (TRPV6), which was later established as the primary
directly requires energy in the form of hydrolyzable ATP apical calcium uptake channel (740). In subsequent at-
and is alternatively termed “active” transport (versus “pas- tempts to further unravel the nature of the calcium uptake
sive” paracellular transport). The proximal small intestine, mechanism, various voltage-gated L-type calcium channel
i.e., the duodenum and the jejunum, is the main site for blockers were used (474, 717, 838). Although isolated du-
transcellular calcium absorption (825). odenal cells accumulated less calcium following application

Enterocyte
D
VDR
D
RXR VDR Transcription
Ca2+
PMCA
Transcription

Ca2+
Na+
Ca2+ Ca2+
Calbindin-D 9k
NCX
TRPV6
Ca2+
FIGURE 3. Transcellular and paracellular calcium absorption in the intestine. The transcellular intestinal
absorption of calcium relies on apical calcium entry through TRPV6, intracellular calcium transport by calbin-
din-D9k, and basolateral calcium extrusion via either NCX or PMCA. 1,25(OH)2-vitamin D regulates most of
these ion transport proteins on a transcriptional level. 1,25(OH)2-vitamin D passes the plasma membrane of
the enterocyte and binds to its receptor (VDR), which then heterodimerizes with RXR to initiate transcription.
Evidence also suggests that 1,25(OH)2-vitamin D regulates the permeability of tight junctions, which gate the
paracellular absorption of calcium. D, 1,25(OH)2-vitamin D.
of the inhibitors and 1,25(OH)2-vitamin D stimulation CaT1 was identified by a similar approach. A rat duodenal
(717), in vivo calcium entry proved to be fairly insensitive to cDNA library was functionally screened using a calcium
their effects (with the exception of verapamil, which dem- uptake assay in a Xenopus oocyte expression system (838).
onstrated some degree of inhibition if applied at very high This screening process yielded the 727-amino acid protein
concentration in the millimolar range) (474, 838). The con- CaT1, which showed a 75% sequence homology to rabbit
flicting reports may be attributable to the different experi- ECaC. Homology analysis also demonstrated a relationship
mental models that were used, as isolated single cells do not to the vanilloid reptor type 1 (VR1), a nonspecific cation
allow discrimination between apical and basolateral trans- channel that is activated by capsaicin, the pungent ingredi-
port mechanisms. Furthermore, it has been argued that L- ent in chili peppers, and mostly mediates pain signaling
type calcium channels may play a role in the stimulatory through afferent sensory neurons (838). The nomenclature
pathway of vitamin D, rather than in calcium uptake per se changed over time as new channel proteins were identified,
(717). In conclusion, an involvement of L-type calcium and today we consider CaT1, ECaC, and VR1 to be mem-
channels seemed rather inconclusive and the identity of the bers of the same transient potential receptor vanilloid
calcium entry channel remained elusive. (TRPV) ion channel family. Literature now refers to ECaC
as TRPV5, to CaT1 as TRPV6, and to VR1 as TRPV1.
B) TRPV6. The cloning of the calcium transport protein sub-
type 1 (CaT1) in 1999 finally marked a turning point in the The structure of TRPV6 was predicted to have six trans-
search for the elusive intestinal calcium entry channels membrane domains and four ankyrin repeat domains,
(838). The work was pioneered by Hoenderop and col- which serve as cytoskeletal linking sites (838). Channel con-
leagues who had identified the main calcium entry protein ductance was not dependent on other ions and was inhib-
in the kidney (epithelial calcium channel type 1, ECaC) via itable by a low extracellular pH (838). Calcium uptake was
an expression cloning strategy a few months earlier (474). reduced by as much as ⬃70% at a pH of 5.5, which con-

firmed the early black box data observations made in intes- TRPV6 gating is sensitive to intracellular calcium. Increases
tinal brush-border vesicles (838). This behavior seemed in calcium were shown to inhibit the channel, resembling a
counterintuitive to the investigators, as TRPV6 expression negative-feedback mechanism (475). Although global cal-
was highest in the duodenum, which is exposed to an acid cium concentrations in the cell largely remain constant, the
load from the stomach (838). Duodenal pH has been re- channel microenvironment is exposed to fluctuations in lo-
ported to be as low as ⬃6.1– 6.6 but is even lower acutely cal calcium. This feedback loop may be important for finely
after gastric emptying (⬃5.4), which would entail signifi- tuning the amount of calcium influx and preventing calcium
cant inhibition of TRPV6-mediated calcium uptake (284, overload of the enterocyte. The putative mechanism of this
290, 838). Conductance was also modestly sensitive (10 – regulation will be discussed later in this section.
15% inhibition) to L-type calcium channel blockers at high
concentrations, which partially clarified the preceding am- In 2001 it was demonstrated that ATP modulates TRPV6
biguous observations made by other groups with these in- activity by preventing channel rundown (475). Recent work
hibitors (318, 337, 717, 838). by Al-Ansary et al. (15) suggests that ATP directly binds to
the channel, thereby inhibiting inactivation by locking the
Subsequently, the human analog of rat TRPV6 was cloned channel in the open conformation. Binding of ATP may be

(it had 97% sequence homology and was rather confusingly antagonized by channel phosphorylation through PKC
named ECaC2), and its expression was confirmed in human (15). In conclusion, TRPV6 is precisely regulated by its own
duodenum (64). The generation of a TRPV6 antibody al- microenvironment. Calcium, magnesium, and protons have
lowed for first localization studies, which confirmed an api- an inhibitory effect on the channel, whereas ATP prevents
cal localization of TRPV6 and thus reaffirmed its role as the channel inactivation.
primary apical calcium entry pathway in the intestine
(1220). Tissue expression of TRPV6 varies among species It is important to remember that apart from being a nutri-
(461). In humans, TRPV6 was identified in the duodenum, ent, calcium is a crucial intracellular messaging molecule.
jejunum, stomach, esophagus, kidney, placenta, mammary Therefore, the enterocyte has to tightly control its intracel-
gland, pancreas, prostate, testis, and salivary gland, but was lular concentration and adapt uptake to energy status and
also found to be upregulated in a series of malignancies, basolateral extrusion. To ensure this delicate intracellular
including prostate, breast, colon, and ovarian cancer (461, homeostasis, TRPV6 is associated with and regulated by a
792, 836, 839, 1168, 1220). The role of TRPV6 in these variety of auxiliary proteins. The first protein that has been
tissues mostly remains to be elucidated. identified to interact with TRPV6 was the S100A10-an-
nexin2 complex (1112). The S100A10-annexin2 complex
TRPV6 displays some unique biophysical properties. As has been implicated to play a role in protein trafficking and
mentioned earlier, TRPV6 consists of six transmembrane membrane anchoring. Its association with TRPV6 is essen-
segments, like many voltage-gated cation channels. Unlike tial for channel trafficking to occur, as a disruption of the
these channels, TRPV6 lacks the voltage sensor domain in interaction leads to cytosolic scattering of the channel
the fourth ␣-helix and is in a constitutively open state at (1112). Formation of the S100A10-annexin2 complex and
resting membrane potential. Analysis of the quarterny its association with TRPV6 involves activation of PKA and
structure shows that it assembles in tetramers (476). The calcineurinA (CnA) (117). Another protein that is required
ankyrin domains were implicated to be responsible for te- for TRPV6 membrane insertion is rab11a (1111). In anal-
tramer formation; however, more recent structural data ob- ogy to S100A10-annexin2, perturbation of rab11a binding
tained by crystallography question this hypothesis (311, results in decreased surface expression of TRPV6 and chan-
848). It is thought that heterotetramers can also be formed nel retention in the cytosol (1111). Furthermore, the protein
with subunits of closely related TRPV5 (476). In contrast to kinases SGK1 and WNK3 are known to promote mem-
most other members of the TRP channel family, TRPV6 is a brane insertion of TRPV6; however, their exact site of ac-
very selective channel for calcium (475, 1058, 1197). The tion is still unclear (114, 1031). Once trafficked to the mem-
relative permeability of TRPV6 for calcium over sodium brane, physical channel stability is maintained by a variety
(PCa/PNa) is ⬎100, whereas TRPV1, for example, has a of auxiliary proteins. The COOH-terminal tail of TRPV6
selectivity of PCa/PNa ⬃10 (although this has recently been contains a PDZ protein binding motif. PDZ proteins serve
shown to be variable) (206, 475, 1197). This high selectiv- as membrane anchors and protein scaffolds and mediate the
ity is crucial for the maintenance of a constant membrane assembly of multiprotein complexes, thereby regulating
potential in the enterocyte during calcium absorption. channel activity. The PDZ protein sodium hydrogen ex-
TRPV6 is strongly inward rectifying, which has been attrib- changer regulating factor (NHERF4) (aka PDZK2) has re-
uted to magnesium ions plugging the channel pore for out- cently been identified to interact with TRPV6 (574, 1113).
ward ion movement during states of depolarization (1126). It has been speculated that NHERF4 serves as a scaffold for
Magnesium also exerts a voltage-independent inhibitory ef- TRPV6 at the apical pole, which is underlined by the obser-
fect on TRPV6 current; however, the mechanism underly- vation that knockdown of NHERF4 by RNAi leads to de-
ing this observation is unclear (475, 1126). Furthermore, creased TRPV6 current in HEK293 cells (574, 1113). Apart

from trafficking to the apical membrane, channel number most likely mediates the channel’s sensitivity to intracellu-
can be regulated by internalization and degradation. One lar calcium.
possibility of decreasing functional channels at the cell sur-
face is protein ubiquitination. The process of ubiquitination Phosphorylation by kinases and dephosphorylation by
involves enzymatic tagging of target proteins, thus directing phosphatases represent a common cellular strategy for rap-
them to the proteasome or lysosome for rapid degradation. idly modulating channel gating properties. The non-recep-
The degradation tag is transferred to the target protein by tor tyrosine kinase Src has emerged as a candidate for the
E3 ubiquitin protein ligases, such as Nedd4 –2. It is already direct phosphorylation of TRPV6, thereby increasing chan-
well understood how Nedd4 –2-mediated ubiquitination nel conductance (1042). Src was previously shown to mod-
can decrease the number, but also directly modulate the ulate TRPV4 activity (1178). The effects of Src are antago-
activity, of the epithelial sodium channel (ENaC) in the nized by the phosphatase PTP1B. Both enzymes act on the
kidney (825). A recent study demonstrated that a similar tyrosine residues Y161/162, which are located in the NH2-
mechanism applies to TRPV6 (1212). Coexpression of terminal tail of the channel (1041).
Nedd4 –2 and TRPV6 in oocytes resulted in decreased cal-
cium flux and channel numbers (1212). Nedd4 –2-mediated An interesting interaction without direct relevance for the

TRPV6 ubiquitination could thus serve as a mechanism of intestine has been reported between renal TRPV5 and
rapidly regulating channel retrieval from the plasma mem- klotho (170). Klotho is a ␤-glucuronidase with a transmem-
brane (1212). brane anchor that can be cleaved, resulting in shedding of
the enzymatically active domain of the protein into the
Several other proteins have been identified to associate with urine (170, 612). Klotho can then increase TRPV5-medi-
TRPV6 that do not affect channel numbers, but rather diated calcium uptake by hydrolyzing N-linked oligosaccha-
rectly regulate channel activity. The nisnap1 gene was iden- rides on extracellular channel domains, thereby preventing
tified in the late 1990s; however, its function remained elu- channel retrieval from the plasma membrane (170). Al-
sive (992). Recently, TRPV6 was shown to interact with though a recent report indicates that klotho can also affect
nisnap1 (971). It is expressed in the intestine, but not the TRPV6 activity in vitro, it is not expressed in the intestine
kidney, which is unusual as TRPV6 and TRPV5 are gener- and thus may only interact with renal TRPV6 (612, 683).
ally regulated by similar auxiliary proteins. Electrophysio- Although this finding has no implications for intestinal cal-
logical measurements showed that nisnap1 inhibits TRPV6 cium uptake, various bacteria and neutrophils produce
without affecting its surface expression (971). Very similar ␤-glucuronidase, which may affect TRPV6 activity in the
functional properties were attributed to RGS2, a protein intestine (359, 1004).
that is mainly known to alter the GTPase activity of G
proteins. In analogy to nisnap1, RGS2 can inhibit TRPV6 Recently, Stumpf et al. (1046) described an association be-
at the plasma membrane without affecting its trafficking tween cyclophilin B (CyB) and TRPV6 in the placenta. Co-
dynamics (970). expression of both proteins in oocytes increased calcium
uptake (1046). CyB was also detected by Western blot anal-
As previously discussed, the activity of TRPV6 is finely ysis in the small intestine and colon; however, colocaliza-
regulated by intracellular calcium concentrations. Eleva- tion and functional studies in intestinal tissue remain to be
tions in intracellular calcium levels exert an autoinhibi- performed (1046).
tory effect on channel opening (475). Shortly after the
identification of TRPV6, calmodulin (CaM) was shown C) THE TRPV6 KNOCKOUT CONUNDRUM. As will be discussed in
to bind to the channel in a calcium-dependent manner, more detail later, 1,25(OH)2-vitamin D is one of the key
and it was speculated that it mediates the calcium feed- hormonal regulators of systemic calcium homeostasis (see
back response (461, 791). Subsequent investigations dem- sect. IVA). Increased levels of 1,25(OH)2-vitamin D lead to
onstrated that CaM may indeed represent the molecular enhanced intestinal calcium absorption. Shortly after clon-
calcium sensor (263, 619). Elegant FRET studies reported ing of TRPV6, it was recognized that the channel is posi-
that CaM dynamically associates with TRPV6 in the pres- tively regulated at the mRNA level by 1,25(OH)2-vitamin D
ence of calcium and that this association is terminated when (614, 1030, 1109, 1110). The TRPV6 promoter has mul-
intracellular calcium is depleted (263). The association be- tiple binding sites for the 1,25(OH)2-vitamin D receptor
tween TRPV6 and CaM also correlates with decreased cur- (VDR) and is thus directly sensitive to increases in
rent flux through the channel (263). Although the ankyrin 1,25(OH)2-vitamin D levels (736). Consequently, VDR-de-
repeat domains of the channel were thought to possibly ficient animals display a marked decrease in TRPV6 mRNA
serve as binding sites for CaM, more recent structural in- levels, whereas administration of 1,25(OH)2-vitamin D in
sights provide rebutting evidence for this hypothesis (848). wild-type animals results in an increase in mRNA transcrip-
Instead, the COOH-terminal tail of TRPV6 has been sug- tion (1030, 1109, 1110). In conjunction with the rapidly ex-
gested as the site where CaM binding occurs (263, 619, panding characterization of the channel itself, these observa-
791). Hence, CaM can tune ion flux through TRPV6 and tions supported the dogma that TRPV6 is the essential player

in transcellular calcium uptake and that this pathway is uptake through the paracellular pathway (76, 615). In con-
strongly regulated by 1,25(OH)2-vitamin D. clusion, the generation of TRPV6 (⫺/⫺) animals has sus-
tainably challenged our model of transcellular calcium ab-
With the introduction of novel genetic techniques, a TRPV6 sorption by questioning the relative importance of TRPV6
(⫺/⫺) mouse was created in 2007 by Bianco et al. (94). The and by introducing new potential targets of 1,25(OH)2-
animals presented with decreased intestinal calcium uptake, vitamin D regulation.
as measured by serum concentrations of a calcium radioiso-
tope following gavage, decreased femoral bone density D) GENETIC POLYMORPHISMS OF TRPV6. Single nucleotide poly-
(9.3%) and increased 1,25(OH)2-vitamin D levels, as a re- morphisms (SNPs) are variations in the genomic sequence
sult of feedback regulation (94). These findings were in that occur in one single base. If the frequency of a SNP or a
accordance with the postulated role of TRPV6 as the pri- specific set of SNPs (haplotype) increases in a population
mary 1,25(OH)2-vitamin D-sensitive calcium uptake mech- over time compared with other SNPs, it can be concluded
anism in the intestine. However, the generation of another that this set of SNPs is associated with an evolutionary
TRPV6 (⫺/⫺) animal line by Benn et al. (76) a year later advantage, meaning that this gene locus was under selec-
spawned a controversy in the field. In these animals, base- tion. Recent reports from various groups indicate that

line calcium uptake was identical between wild-type and TRPV6 was subjected to strong selection (12, 502, 1023,
(⫺/⫺) groups. Surprisingly, calcium uptake could be in- 1050). Traces for selection can be found in any non-African
creased in the (⫺/⫺) group by a low calcium diet and, more population (12, 502, 1023). The selective event in Euro-
importantly, by 1,25(OH)2-vitamin D (an observation that peans has presumably occurred ⬃7,000 years ago and
was also confirmed by another group; Ref. 615) (76). These coincides with the development of agriculture (502). This
findings profoundly questioned the role of TRPV6 in cal- correlation also holds true for other populations (502). It
cium absorption and suggested that a different molecular has been speculated that a change in diet or resistance to
target of 1,25(OH)2-vitamin D mediates the increase in cal- emerging disease led to selection and fixation of the now
cium uptake after exposure. All these observations were in conserved haplotype (502). Interestingly, selection took
sharp contrast to the initial report by Bianco et al. (94). place in parallel in many populations, pointing towards a
However, Benn et al. (76) also reported that compared with strong selective stress that developed independently in
wild-type animals calcium uptake was reduced in TRPV6- each region (502).
deficient animals that were fed a low-calcium diet. This
suggests that the animals may not be able to adequately The electrophysiological properties of ancestral and derived
increase absorption, when confronted with a low dietary TRPV6 were investigated by two groups (502, 1050).
availability of calcium, which in turn suggests a role of Hughes et al. (502) observed no statistically significant di-
TRPV6 during states of dietary calcium insufficiency. vergence in channel behavior. The derived channel only
displayed a tendency towards decreased sensitivity to the
These controversial findings allow several conclusions and autoinhibition by calcium, albeit not significant (P ⫽
speculations. 1) As with any model of targeted gene disrup- ⫺0.094) (502). The authors speculated that differences in
tion, a compensatory mechanism may be in place that protein-protein interactions may have led to selection
masks and distorts the physiological importance of TRPV6. (502). Conversely, Sudo et al. (1050) reported increased
The animals may upregulate other, yet unidentified, cal- calcium influx through the derived channel, which may con-
cium transport mechanisms to compensate for the loss of stitute an evolutionary advantage by facilitating dietary cal-
TRPV6 function. 2) Rather than being a constitutively cium uptake. Regardless of the controversial functional
active pathway, transcellular calcium absorption through data, these insights indirectly underline the importance of
TRPV6 only occurs in states of low dietary calcium intake. TRPV6 and provide a counterweight to the conclusions
This hypothesis has been put forward very early and has been drawn from the TRPV6 (⫺/⫺) animal model. It is unques-
reaffirmed by a recent study that observed an increase in bone tionable that TRPV6 was under parallel independent selec-
turnover in TRPV6 (⫺/⫺) animals on a low-calcium diet tion in many regions across the planet. This provokes the
(46, 666, 824, 1224). Mobilization of bone calcium may be question of how strong selection can occur for a derived
necessary in these animals to maintain systemic calcium channel whose physiological difference to the ancestral
concentrations, which are double challenged by the lack of form seems to be very subtle, yet complete disruption of the
TRPV6 and the insufficient calcium intake (666). Further- channel in the mouse model only causes a very mild pheno-
more, it has been extensively described that a low-calcium type. This inconsistency adequately exemplifies the caveat
diet induces gene expression of TRPV6 [presumably that underlies the conclusions drawn from (⫺/⫺) animals
through an increase in 1,25(OH)2-vitamin D levels], sug- and reminds us of the fact that we are far from understand-
gesting a role of the channel during states of insufficient ing the exact physiology of transcellular calcium uptake.
dietary calcium supply (76, 132, 639). 3) 1,25(OH)2-vita-
min D may have many more targets in the intestinal mucosa E) CAV1.3. TRPV6 may not be the only channel mediating
than previously anticipated and may also regulate calcium apical calcium absorption in the intestine. A recent investi-

gation provides another explanation for the initially ob- which had a lower molecular mass of ⬃9 kDa (hence the
served partial sensitivity of transcellular calcium uptake to name calbindin-D 9k), compared with the 28 kDa of the
L-type calcium channel blockers. The voltage-gated cal- avian isoform, was later identified (138, 280, 283, 358).
cium channel Cav1.3, a member of the L-type calcium chan- Concerning the functional role of calbindin-D 9k, it had
nel family, was recently identified in the apical membranes already been speculated very early after its discovery that it
of the distal jejunum and proximal ileum (751). Previous may serve as a calcium shuttling protein (951). Indeed, ini-
observations were emulated, as the investigators again dem- tial calculations and later very basic experimental data con-
onstrated a decrease in calcium absorption following appli- firmed that calbindin-D 9k may mediate facilitated diffu-
cation of L-type calcium channel inhibitors in the corre- sion of calcium between the two poles of the enterocyte, in
sponding segments (751). The authors argued that uptake analogy to the transport of oxygen by myoglobin in the
through Cav1.3 may have previously been misinterpreted as muscle (321, 602). In a very fundamental investigation,
paracellular calcium uptake (751). However, it should be calcium flux was measured between chambers that were
noted that the calcium uptake assay used in this report did separated by dialysis membranes. A 51% increase in trans-
not discriminate between transcellular and paracellular cal- chamber calcium flux occurred in the presence of calbin-
cium movement. Subsequently, it has been observed that din-D 9k (321). However, it is hard to relate this number to

L-type inhibitor-sensitive calcium flux is linked to stimula- physiological values, given the simplification underlying the
tion of glucose uptake through the glucose transporter type experimental model. It has subsequently been calculated
2 (GLUT2) (692, 750). Cav1.3 may serve as an alternative that calbindin-D 9k may facilitate diffusion of calcium by a
calcium entry pathway that is active in states of luminal factor of up to ⬃60 (129). Rather than envisioning calbin-
calcium abundance and that coregulates glucose absorption din-D 9k as a protein that individually shuttles calcium ions
(692, 750). Further investigations will be needed to deter- across the cell, one should imagine calbindin-D 9k as a
mine the contribution of Cav1.3 to dietary calcium absorp- calcium gradient amplifier (129, 602). As the intracellular
tion. concentration of free calcium is in the nanomolar range, the
intracellular gradient of free calcium between the apical and
2. Calbindin-D 9k
basolateral pole can also only be in the nanomolar range.
Diffusional flux, however, directly correlates with the con-
The following section will address the question of what
centration gradient and can in consequence only be very
happens to dietary calcium after it enters the enterocyte. It
small. Calbindin-D 9k is expressed in the enterocyte in the
should be considered that transcellular calcium uptake and
micromolar range and dynamically binds and releases cal-
cytosolic calcium homeostasis are two contradicting re-
cium (714). Since the association between calbindin-D 9k
quirements for the enterocyte. A prominent transcellular
flux of free calcium will inevitably interfere with housekeep- and calcium is dynamic, the local concentration of calbin-
ing functions of the cell, such as intracellular signaling. din-D 9k-bound calcium will directly correlate with the
Furthermore, it has been calculated from in vivo data that if concentration of free calcium. It is thus the concentration
calcium were to diffuse freely (simple diffusion) through the gradient of calbindin-D 9k-bound calcium throughout the
cytosol, uptake rates would only be 1/70th of the actually cell that determines the flux rate of calcium. As this gradient
measured values (129). Simple diffusion would constitute a can be in the micromolar range, calbindin-D 9k serves as a
bottleneck in the process of transcellular calcium absorp- calcium gradient amplifier (129, 602). It should be noted
tion if cytosolic calcium concentrations should be kept low. that the real experimental data on calbindin-D 9k are fairly
A partial solution to this problem was found as early scarce and that the bulk of scientific effort has gone into
as 1966, when Wasserman et al. (1151) identified a mathematical modeling of facilitated diffusion and calcium
1,25(OH)2-vitamin D-inducible calcium binding protein in binding kinetics (129, 321, 322, 602, 1021).
the chick intestine. The authors observed that calcium ra-
dioisotopes traveled faster across a cellophane membrane if Functionally, several correlations between calbindin-D 9k
suspended in intestinal homogenates from rachitic, i.e., and calcium uptake were identified. The calbindin-D 9k
1,25(OH)2-vitamin D deficient, chicks than if suspended in content of each intestinal segment correlates linearly with
the homogenates from rachitic animals treated with its ability for calcium uptake (129, 824, 1021). Although
1,25(OH)2-vitamin D (1151). This indicated that calcium this relation holds true on the experimental and the math-
was bound to a protein in the enterocyte and that expres- ematical modeling level, it does not prove causality (129,
sion of this protein was controlled by 1,25(OH)2-vitamin D 824, 1021). Furthermore, 1,25(OH)2-vitamin D and a low-
(1151, 1152). Subsequently, the calcium binding protein calcium diet induce calbindin-D 9k on both the mRNA and
was further characterized (1073, 1149, 1152). Expression protein level, suggesting that it is involved in the process of
levels were shown to be highest in the duodenum and to regulated calcium absorption (289, 604). In accordance
gradually decrease in more distal segments, which corre- with these findings, VDR-deficient animals have a de-
lated with the degree of calcium uptake that has been at- creased calbindin-D 9k mRNA content that cannot be res-
tributed to each intestinal segment respectively in prior cued by exogenous 1,25(OH)2-vitamin D administration
functional investigations (1073). The mammalian isoform, (663, 1194). Although a 1,25(OH)2-vitamin D responsive

element (VDRE) had been identified in the 5=-flanking re- show no disturbances in calcium homeostasis, although,
gion of the calbindin-D 9k gene, later mutational analysis similarly to TRPV 6 (⫺/⫺) animals, they cannot increase
demonstrated that this site was not essential for transcrip- calcium uptake in response to a dietary calcium challenge to
tional regulation of calbindin-D 9k by 1,25(OH)2-vitamin the same extent as wild-type animals (76).
D (217, 240). Hence, it is not clear how 1,25(OH)2-vitamin
D exactly regulates calbindin-D 9k on a molecular level. In light of the insights gained through knockout animals,
Interestingly, intestinal calbindin-D 9k mRNA levels can be the role of calbindin-D 9k remains somewhat unclear.
rescued in VDR (⫺/⫺) animals by a high-calcium/phospho- Again, it is difficult to dissect the physiological function of
rus/lactose diet, while extraintestinal calbindin-D 9k calbindin-D 9k in these animal models, given the assump-
mRNA levels are unaffected (663). This suggests that, apart tion that the organism will pursue compensation for the loss
from endocrine regulation through 1,25(OH)2-vitamin D, of a gene product. In conclusion, it is undisputed that cal-
intestinal calbindin-D 9k is also regulated by local factors bindin-D 9k is regulated by 1,25(OH)2-vitamin D, that it
(663). A direct short-term stimulatory effect of oral calcium can bind calcium and that theoretical modeling and very
intake on calbindin-D 9k levels had been observed before in fundamental experimental models verify that it can facili-
a wild-type background (647). The mechanisms underlying tate diffusion of calcium across the enterocyte. The (⫺/⫺)

the effect of diet on calbindin-D 9k levels are, however, still models suggest that animals can compensate for the loss of
obscure. calbindin-D 9k and maintain normal calcium homeostasis
(13, 76, 613, 639). Furthermore, TRPV6, calbindin-D 9k
Despite the correlation between calbindin-D 9k levels and and double (⫺/⫺) animals can still increase their calcium
1,25(OH)2-vitamin D and the mathematical and experi- uptake in response to 1,25(OH)2-vitamin D or a low-cal-
mental models, which support its role as a calcium shuttling cium diet, respectively, albeit not to the same extent as
protein, no clear evidence for the involvement of calbin- wild-type animals (13, 76, 615). One may conclude that
din-D 9k in transcellular calcium absorption existed. This neither of these proteins is necessary for transcellular up-
had sparked controversy among investigators. In fact, a take; however, it seems more likely that 1,25(OH)2-vitamin
very early study concluded that although 1,25(OH)2-vita- D has more targets than previously postulated and that
min D induced both calbindin-D 9k and calcium absorp- compensatory mechanisms are in place.
tion, a discrepancy existed in the time course of both effects
(424). Later, synthetic 1,25(OH)2-vitamin D derivatives, 3. Basolateral calcium extrusion
designed for a maximized effect on cell differentiation and
suppressed calciotropic activity, failed to increase serum Once calcium reaches the basolateral membrane, it is ex-
calcium levels while causing a sevenfold increase in calbin- truded into the extracellular space, which completes the
din-D 9k mRNA [native 1,25(OH)2-vitamin D increases process of intestinal absorption. As extracellular calcium
both serum calcium and calbindin-D 9k mRNA](604). In concentrations are higher than cytosolic concentrations,
2006, a calbindin-D 9k (⫺/⫺) mouse was created by Kutu- this process requires energy. Two proteins are responsible
zova et al. (613). The animals presented with no apparent for this task. 1) The PMCA extrudes calcium at the direct
phenotype abnormalities and had normal serum calcium expense of ATP, whereas 2) the sodium-calcium exchanger
concentrations (613). Subsequent analysis of these animals (NCX) utilizes the energy stored in the sodium gradient to
showed that they responded equally well to 1,25(OH)2- transport calcium out of the cell (FIGURE 3). It is this baso-
vitamin D with regard to calcium absorption as wild-type lateral exit process that requires energy during transcellular
animals (13). Of note, calcium absorption was assessed by calcium uptake and that allows us to absorb calcium against
measuring serum calcium following gavage of a calcium an uphill gradient when dietary concentrations are low.
radioisotope and did not discriminate between transcellular
and paracellular absorption (13). A different group repli- A) THE PLASMA MEMBRANE CALCIUM ATPASE. The plasma mem-
cated the findings made in the calbindin-D 9k (⫺/⫺) mouse brane calcium ATPase (PMCA) is a virtually ubiquitous
and also did not find any appreciable variation in pheno- protein that is responsible for intracellular calcium homeo-
type or serum calcium concentrations (639). However, the stasis by pumping calcium into the extracellular milieu,
investigators observed that during preweaning, when both thereby keeping intracellular concentrations low. The
calcium demand and absorption are at their peak, gene pump belongs to the family of P-type primary ion transport
expression of TRPV6 and the basolateral calcium extruder, ATPases, which among others also includes gastric H⫹-K⫹-
plasma membrane calcium ATPase isoform 1b (PMCA1b), ATPase (see sect. IIA1). Four isoforms of the protein exist;
were highly induced in the calbindin-D 9k (⫺/⫺) animals however, variety is increased by splicing (562, 1043). The
(128, 639). This has been interpreted as a compensatory PMCA1b splice variant is most predominant in the small
upregulation of calcium transport proteins to ensure suffi- intestine and the duodenum in particular, which suggest an
cient uptake in a state of high metabolic demand for cal- involvement of this isoform in the process of transcellular
cium (639). Subsequently, a TRPV6 and calbindin-D 9k calcium absorption (341, 492). Given the ubiquitous ex-
double (⫺/⫺) animal was created. The mature animals pression of PMCA, a detailed review of its structure and

function will be omitted. For a current and detailed review, For a recent review on the structure and function of NCX,
please refer to Reference 1043. please refer to Reference 687. In brief, NCX exists in three
isoforms (NCX1–3), which are expressed in a broad variety
PMCA was first characterized in the 1960s in the membrane of cell types (687). The function of NCX has mainly been
of erythrocytes (956). Very early experiments in basolateral investigated in excitatory tissues, given its role as a high-
membranes isolated from enterocytes identified a calcium- capacity calcium extrusion mechanism following excita-
dependent enzyme with phosphatase activity, which served tion. To transport calcium against its strong electrochemi-
as first evidence for PMCA in the intestine (100, 742). Sub- cal gradient, NCX has to utilize three sodium ions to ac-
sequent investigations in basolateral vesicles from rat intes- complish extrusion of one calcium ion (85, 460). NCX1 is
tine concluded that two distinct calcium transport mecha- the predominant isoform in the small intestine, where it has
nisms existed in their membranes: an ATP-dependent been detected on the mRNA and the protein levels (275,
(PMCA) and a sodium-dependent (NCX) mechanism (382, 688). However, NCX had been postulated to play a more
457, 573). Furthermore, it was shown that inhibition of important role during calcium absorption in the kidney
calmodulin halved the amount of ATP-dependent calcium than in the enterocyte, hence not much data on intestinal
transport (573). Today, we know that PMCA is highly reg- NCX are available to us (473). Furthermore, genetic dis-

ulated by CaM, which can increase both the affinity of the ruption of NCX1 is embryonically lethal, which imposes
pump to calcium and its turnover speed by a factor of up to some limitations on our experimental methodology (600).
10 (526, 627, 628, 756). A more recent study provides some functional evidence for
NCX in the intestine. By measuring intracellular calcium
Interestingly, it has also been suggested that calbindin-D 9k concentrations with a fluorescent indicator dye, Dong et al.
can directly stimulate calcium transport via PMCA (1136, (275) demonstrated that calcium uptake in a sodium-free
1137). In addition to intracellular proteins, PMCA is also environment (to run NCX in its reversed configuration) was
quantitatively regulated by endocrine factors. 1,25(OH)2- significantly decreased when NCX was pharmacologically
vitamin D can increase both the PMCA mRNA and protein inhibited. Despite our knowledge that NCX exists in en-
content in enterocytes (35, 36, 62, 146, 382, 489, 614, 823, terocytes and that it can extrude calcium under experimen-
1109; contested by Ref. 1138). The data on the effects of a tal conditions, it is difficult to assess its relative contribution
to transcellular calcium absorption.
low-calcium diet on PMCA transcription are more controver-
sial, as one study suggests induction whereas two other studies
In addition, NCX is not subjected to regulation by 1,25(OH)2-
observed reduced mRNA levels (146, 583, 639). Of note,
vitamin D, which further contributes to the ambiguity con-
these observations were made in different species (chick vs.
cerning its importance in the process of calcium absorption.
mouse). The sensitivity of the tissue to 1,25(OH)2-vitamin D is
This has been observed very early, when exogenous admin-
also reported to decrease with age, which may represent
istration of 1,25(OH)2-vitamin D to vitamin D-deficient
another confounding factor underlying these observations
animals did not increase sodium-dependent calcium trans-
(35, 36). In conclusion, the transcriptional regulation of
port, while doubling transport through PMCA (382). Fur-
PMCA1b by 1,25(OH)2-vitamin D and its decreasing ex-
thermore, it was recently shown that a calcium-depleted
pression along the length of the small intestine correlate diet decreases duodenal NCX1 mRNA levels (583).
well with the canonical model of transcellular calcium ab-
sorption. It is challenging to investigate the functional Of note, two members of the potassium-dependent sodium
contribution of PMCA1b in the process of calcium ab- calcium exchanger (NCKX) family, namely, NCKX 3 and
sorption, given its role as a housekeeping protein. 4, were also identified in the small intestine (658, 687, 688).
PMCA1 is crucial during development, which results in However, further functional investigations will be needed
embryonic death if knocked out (814, 1198). Conversely, to clarify their role.
heterozygote (⫹/⫺) animals present with no apparent
phenotype, albeit parameters linked to calcium homeo-
stasis were not assessed (814). B. Paracellular Calcium Absorption
B) THE NCX. Long before the molecular identities of PMCA If we plot the amount of duodenal calcium absorption as a
and NCX were known, it had been observed that calcium function of the luminal calcium concentration, we can ob-
uptake in the intestine was dependent on extracellular so- serve that the absorption curve is comprised of two distinct
dium (713). The authors concluded that “a sodium, calcium- kinetic components: a saturable/exponential component
exchange diffusion carrier may exist at the basal membrane and a nonsaturable/linear component (824, 825, 1134).
of the cell,” which proved to be a remarkably accurate The saturable component represents transcellular calcium
prediction (713). As mentioned before, later investigations uptake through the enterocyte, as both the number of cal-
delineated between an ATP and a sodium-dependent trans- cium transport proteins and their turnover rate is limited.
port of calcium on the basolateral enterocyte membrane The nonsaturable component reflects calcium uptake
(382, 457, 573). through the paracellular pathway. The saturable compo-

nent is less pronounced in the jejunum and disappears com- an epithelia-like monolayer with tight junctions. This
pletely in the ileum, indicating that transcellular calcium conclusion is based on the observations that 1,25(OH)2-
absorption is restricted to the proximal segments of the vitamin D decreased the transepithelial electric resis-
intestine, as discussed previously (825) [this has been con- tance, which is often used as a measure of tight junction
tested more recently, when transcellular flux was also noted permeability, and induced bidirectional, i.e., also “serosal”
in the ileum (46)]. Compared with the transcellular path- to “mucosal,” calcium flux in the cultured monolayers
way, the paracellular route has not received much scientific (201). A more recent investigation further substantiated
attention. It has been put forward that the rate of paracel- this hypothesis. It has been shown that 1,25(OH)2-vitamin
lular calcium absorption is constant across the length of the D regulates the mRNA levels of some tight junction proteins
intestine and is neither sensitive to 1,25(OH)2-vitamin D in rat duodenum, which may alter their gating characteris-
nor a low-calcium diet (824, 825, 1224). However, pro- tics (354, 614). For example, the mRNA levels of claudin-3,
vided that enough dietary calcium is available to saturate a protein that directly determines tight junction permeabil-
the transcellular pathway, observations indicate that net ity, were decreased 2.2-fold following 1,25(OH)2-vitamin
calcium absorption is highest in the ileum, which has been D administration (614). Conversely, claudin-2 and -12
attributed to the sojourn time, rather than alterations in mRNA and protein levels were increased (354). Functional

paracellular permeability (290, 710). In the rat, the chyme observations in Caco-2 monolayers further demonstrate
spends some 74% of its transit time in the ileum, which that overexpression of claudin-2 and -12 increases electrical
allows for a long exchange period between lumen and conductivity and facilitates paracellular calcium flux (354).
plasma (290). The diffusion rate itself is fairly low and only All of these events are tied to a 1,25(OH)2-vitamin D-me-
amounts to 2% of the rate if calcium were to diffuse freely diated promotion of transcriptional events. However, it is
between intestinal lumen and plasma (290). This effect is a known that 1,25(OH)2-vitamin D can also exert short-term
consequence of the diffusion barrier that tight junctions, nongenomic effects (1122) (see sect. IVA6B). A recent inves-
which act as functional gating molecules of the paracellular tigation presents evidence for augmented solvent-drag
pathway, impose on calcium flux. paracellular calcium flux after acute administration of
1,25(OH)2-vitamin D (1098). Solvent-drag mediated flux
may occur at low calcium concentrations in the absence of
Epithelial tight junctions are adhesion points between two
a calcium gradient. In this model, calcium is dragged
neighboring cells that seal their intercellular space against a
through the paracellular space by water flux that is fueled
lumen, thereby restricting ion and water movement be-
by the hyperosmolar milieu in the paracellular space (266,
tween the two compartments. As water cannot be directly
626). 1,25(OH)2-vitamin D was shown to induce this cal-
transported, its movement is tied to ion fluxes, which in
cium flux in the presence of initially equimolar calcium
turn are determined by their respective concentration gra-
concentrations between the mucosal and serosal compart-
dients across the epithelium. Each epithelial cell expresses
ments (1098).
an annulus of tight junction proteins at the apical end of the
lateral membrane. Tight junctions are protein complexes
Over the last years, evidence for the regulation of the para-
that consist of a variety of intra- and transcellular proteins.
cellular pathway by 1,25(OH)2-vitamin D has slowly accu-
A detailed review of their structure would exceed the scope mulated. It is apparent that the canonical dogma which
of this article (for a recent review, please refer to Ref. 999). postulates that 1,25(OH)2-vitamin D only targets the tran-
Briefly, the composition of the involved proteins determines scellular pathway has to be revisited. Still, more experimen-
the pore size, ion selectivity, and thereby the relative leaki- tal investigations will be needed to ultimately clarify the
ness of each tight junction and the whole epithelium in effects of 1,25(OH)2-vitamin D on paracellular calcium
general. Furthermore, tight junctions create a lateral diffu- transport. Should tight junctions indeed be subjected to regu-
sion barrier for membrane proteins and help to maintain the lation by 1,25(OH)2-vitamin D, this mechanism may partially
functional polarity of the epithelial cell. It is important to explain the sensitivity of calcium uptake in TRPV6 and cal-
recognize that tight junctions are not static complexes, but bindin-D 9k (⫺/⫺) animals to 1,25(OH)2-vitamin D.
can be rather dynamically regulated (999). This allows the
epithelium to change its ion and water permeability in re-
sponse to various stimuli (999). C. Alternative Models of Transcellular
Calcium Absorption
As discussed previously, the rate of the nonsaturable
component of calcium absorption is documented to be Two alternative models of transcellular calcium absorption
fairly constant and insensitive to 1,25(OH)2-vitamin D, have been put forward. One suggests that calcium is trans-
which indicated that 1,25(OH)2-vitamin D may have no ported through the enterocyte by vesicles (vesicular trans-
effect on paracellular transport (824, 825, 1224). How- port model) rather than facilitated diffusion, and the other
ever, in the late 1990s, Chirayath et al. (201) postulated postulates that 1,25(OH)2-vitamin D can induce intestinal cal-
that 1,25(OH)2-vitamin D can increase paracellular calcium absorption in a rapid, nongenomic fashion via a putative
cium flux in confluent Caco-2 cell cultures, which form 1,25(OH)2-vitamin D surface receptor (transcaltachia).

The assumption that calcium is transported through the cell Nomenclature in this case is fairly misleading, as vitamins are
in vesicles is corroborated by a handful of observations. It per definition substances that cannot be generated by our body
has been demonstrated that 1,25(OH)2-vitamin D treat- and have to be ingested from an external source. The fact that
ment increased the number of supranuclear lysosomes in we can synthesize vitamin D3 in our skin classifies the sub-
rachitic chicks, compared with nontreated animals (247). It stance as a prohormone rather than a vitamin. As we will see,
was later shown that the calcium content of lysosomes can our current nomenclature is a byproduct of the historic events
more than double following treatment with 1,25(OH)2-vi- leading to the discovery of vitamin D.
tamin D, suggesting that they may play a role in the process
of transcellular calcium movement (780). Compared with 1. Historical perspective
the cumulative evidence that is in accordance with our ca-
nonical model of calcium absorption, the role of vesicular From a historical perspective, the identification of vitamin
transport of calcium is still fairly obscure. D is closely intertwined with attempts to understand the
pathophysiology of rickets. Rickets is characterized by
The model of transcaltachia mainly relies on the observa- childhood skeletal deformities resulting from inadequate
tion that 1,25(OH)2-vitamin D can exert effects that are too osteoid mineralization and calcification of cartilage due to

acute to be attributable to transcriptional events. For exam- decreased serum calcium levels during development. The
ple, intestinal calcium absorption was increased in chicks adult form equivalent of rickets is termed osteomalacia.
within 14 min of 1,25(OH)2-vitamin D exposure, an onset With the onset of industrialization, rickets became a prev-
which is too rapid as to be of a genomic nature (785). It alent problem in the 18th, 19th, and the beginning of the
should be noted that rapid effects of 1,25(OH)2-vitamin D 20th century. In fact, the disease was so widespread at the
have also been suggested to influence the paracellular path- beginning of the 20th century that an investigation con-
way (see above). Undoubtedly a careful evaluation of the ducted by the German pathologist Schmorl on 386 children,
route of calcium flux, i.e., transcellular versus paracellular, who had died before the age of 4 years, concluded that 90%
is necessary. At least, isolated intestinal cells respond with of them had had rickets (968). Even in present times nutri-
increased uptake of radiolabeled calcium to acute 1,25(OH)2- tional rickets still remains a major public health concern in
vitamin D exposure (568). It has been postulated that apart developing countries (303, 757, 809). The seminal observa-
from the VDR, a membrane-bound 1,25(OH)2-vitamin D ex- tions that led to the identification of vitamin D were pro-
posure receptor, the 1,25(OH)2-vitamin D-MARRS (mem- vided by Mellanby in 1919 (733). He observed that dog
brane-associated, rapid response, steroid binding) protein, me- pups who were fed a severely restricted diet consisting of
diates the acute effects of 1,25(OH)2-vitamin D (568, 779, porridge or bread were consistently developing rickets
785). (733). Development of rickets could be averted if their diet
was supplemented with cod liver oil, which we now know
to contain a high concentration of vitamin D (733). Mel-
IV. REGULATION OF lanby (733) concluded that “rickets is a deficiency disease
CALCIUM HOMEOSTASIS which develops in consequence of the absence of some ac-
cessory food factor or factors.” Vitamin A had been discov-
Eucalcemia is maintained by the concerted effort of vitamin ered shortly before, and it was subsequently speculated that
D, PTH, and, to a lesser extent, calcitonin. All three hor- it may represent the factor promoting bone formation
mones can influence serum calcium concentrations by act- (733). This hypothesis was later rebutted by American bio-
ing on the intestine, the kidney, or bone. 1,25(OH)2-vita- chemist McCollum who concluded that “a substance which
min D, the active vitamin D metabolite, primarily modu- is distinct from fat-soluble [vitamin] A” must be responsible
lates the intestinal absorption of calcium and will therefore for preventing rickets (727). Furthermore, he stated that his
be discussed in most detail (FIGURE 4). Apart from hor- experiments “demonstrate the existence of a fourth Vita-
monal regulators that influence the absorption, excretion, min [vitamin D] whose specific property [. . .] is to regulate
and deposition of calcium, our body needs a mechanism the metabolism of bones” (727). In parallel to the unravel-
that allows it to sense the current levels of plasma calcium. ing of the dietary component of rickets, scientists were in-
This task is fulfilled by the CaSR. It oversees the precise dependently discovering the importance of sunlight for dis-
regulation of the calcitropic hormones. ease prevention. The Polish pediatrician Raczynski was most
likely the first to demonstrate evidence for this hypothesis ex-
perimentally (881). He kept one dog pup in the shade while a
A. Vitamin D littermate was kept in the sunlight. Both dogs were breastfed
by their mother. After 6 wk, the bones of the dog that was kept
As discussed previously, vitamin D is one of the key regu- in the shade contained 36% less calcium (881). These obser-
lators of calcium homeostasis. Our body has two sources vations were followed up by the German pediatrician Huld-
for vitamin D, namely, a dietary source (vitamin D2⫹3) and schinsky, who healed rachitic children after exposing them
an endogenous source that relies on ultraviolet (UV) light intermittently for 2 months to the UV rays generated by a
catalyzed synthesis in the skin (vitamin D3) (FIGURE 5). mercury vapor quartz lamp (504). Hess and Unger (447) rep-

Hypocalcemia
Stimulates PTH secretion
Parathyroid glands
Increases bone resorption

Bone

PTH
Increases renal calcium absorption
Stimulates 1,2
1,25(OH)2-D synthesis
Kidney
Intestine
eases renal
Increases
calcium absorption
Increases intestinal
calcium absorption
1,25(OH)2-D
FIGURE 4. Endocrine regulation of serum calcium levels. Calcium homeostasis is mainly regulated by PTH and
1,25(OH)2-vitamin D. Both hormones act at their respective target organs to increase serum calcium levels.
licated these findings by using sunlight treatment. Hess (446) pro-vitamin. It was Windaus and Hess (in collaboration
later summed up the impact of these revolutionary observa- with Rosenheim) who were the first to uncover its exact
tions, which now seem intuitive to us: “We have known that a molecular identity. They stated: “We conclude from our
growing plant cannot thrive in the dark, but have failed to experiments with complete certainty that ergosterol [. . .]
realize that the same laws apply to growing animals.” represents the anti-rachitic provitamin (1166). In 1928,
Windaus received the Nobel Prize in Chemistry for “the
It was later recognized that it was sufficient to irradiate the services rendered through his research into the constitution
food administered to animals rather than the whole animal of the sterols and their connection with the vitamins.” The
to prevent development of or heal rickets. Thus initially irradiation product of ergosterol was later purified and
“inert” dietary substances with no antirachitic properties named vitamin D2 (ergocalciferol) (43, 896, 1164, 1167).
could be activated by UV light (385, 448 – 450, 505, 1037). Although these findings solved the question as to how UV
It was concluded that irradiation caused the conversion of a irradiation generates Vitamin D2 from ergosterol, which has
biological precursor to an active form and that the same antirachitic properties if ingested, the molecular mechanisms
mechanism was physiologically taking place in the skin. underlying the antirachitic effects of cutaneous sunlight expo-
Initially, it was speculated that cholesterol may serve as this sure still remained obscure. Since ergosterol is an exclusive

Keratinocyte
7-dehydrocholesterol Dietary vitamin D

UV-B (290-315nm)
Intestinal uptake
Previtamin D
Isomerization
Vitamin D DBP
Vitamin D
Vitamin D DBP
Hepatocyte

1,25(OH)2-vitamin D Vitamin D
Mitochondria: ER:
CYP27A1 CYP2R1
25(OH)-vitamin D
25(OH)-vitamin D DBP
Proximal tubule
Glomerular
filtration
25(OH)-vitamin D
PTH
25(OH)-vitamin D DBP Mitochondria:

CYP27B1
Megalin
Calcium
1,25(OH)2-vitamin D Target organs
FIGURE 5. Vitamin D metabolism. Vitamin D can either be synthesized in the skin or absorbed from our diet.
It is then transported to the liver where it undergoes 25-hydroxylation by one of two hepatic enzymes (CYP27A1
or CYP2R1). During transport through the circulation, vitamin D is bound to a carrier protein (DBP). The
25(OH)-vitamin-D-DBP complex passes the glomerular filter and is scavenged from the primary urine by the
apical megalin receptor of the proximal tubule. Here, 25(OH)-vitamin D is converted to the active vitamin D
metabolite 1,25(OH)2-vitamin D. DBP, vitamin D binding protein.
component of yeast and fungal membranes, a different precur- day, the main portion of dietary vitamin D ingestion in the
sor substance had to exist in animal skin. Again, it was United States stems from fortified dairy products (150).
Windaus and colleagues who identified 7-dehydrocholesterol
as the provitamin in porcine skin, which is converted to vita- 2. Intestinal vitamin D absorption
min D3 (cholecalciferol) under irradiation (1165). After these
discoveries, industrially produced vitamin D has rapidly been To exert its antirachitic effects, dietary vitamin D has to be
used in medical applications and as a food fortification. To- absorbed into our circulation. Early everted gut sack exper-

iments demonstrated that this process has linear, nonsatu- take of 25(OH)-vitamin D is more effective than that of
rable, and passive kinetics, suggesting that no specific car- vitamin D, which is partially attributable to a comparably
rier mechanism for vitamin D is in place (484). These ob- lower dependency on bile acid secretion (219, 245, 287,
servations were later replicated in in vivo models (483). 645, 1018, 1019). The observation that patients with
Absorption is highest in the proximal and mid small intes- cholestasis still absorb 25(OH)-vitamin D effectively,
tine (484). Since vitamin D is fat soluble, its absorption whereas vitamin D absorption is impaired, corroborates
mechanism is similar to that of dietary lipids. In an aqueous this hypothesis (1018). There is some controversy with re-
media, vitamin D aggregates in micelle-like structures gard to the transport of 25(OH)-vitamin D following its
(735). Its absorption is aided by the secretion of bile acids, absorption (287, 701, 1019). It has been argued that it may
which is underscored by the observation that patients suf- be transported predominantly in the protein fraction of the
fering from cholestasis can present with vitamin D defi- lymph (287), i.e., not in chylomicrons, or that it is directly
ciency and develop bone disease, such as osteomalacia or absorbed into the portal blood (701, 1019).
osteoporosis (245, 445, 563, 721, 894, 953, 1018, 1080).
Apart from bile salts, formation of mixed micelles contain- 3. Cutaneous vitamin D synthesis
ing monoglycerides and free fatty acids represents another

factor that aids in vitamin D absorption (884, 1082; con- Cutaneous synthesis is our second source of vitamin D.
tested by Ref. 483). These substances increase micelle size, Cutaneous production depends on exposure to UVB (290 –
which promotes the solubilization of vitamin D, thereby 315 nm) light (FIGURE 5). The UVB photons convert 7-de-
increasing uptake (884). Clinically, pancreatic insuffi- hydrocholesterol, which is located in the plasma membrane
ciency, causing an impairment of triglyceride breakdown of keratinocytes, to previtamin D3 (1117–1120). This de-
through insufficient lipase secretion, leads to decreased vi- pendency on sunlight causes a seasonal variation in vitamin
tamin D absorption (1080, 1127). This is a particular prob- D3 production, with synthesis being low during the winter
lem in cystic fibrosis patients, who often develop pancreatic months when the radiation angle of the sun flattens (187,
and concomitant vitamin D insufficiencies (33, 230, 625, 478, 538, 1035, 1156). In consequence, changes in latitude
678, 924). result in similar variability in production. Further factors
that decrease production include pigmentation of the skin
Following uptake into the enterocyte, vitamin D is packed and application of sunscreen (209, 723), whereas an in-
into chylomicrons and secreted into the lymph (288, 953). It crease in altitude promotes production (478). Following
has been demonstrated that after intestinal administration conversion from 7-dehydrocholesterol, previtamin D3
of radioactive labeled vitamin D3, up to 90% of the recov- isomerizes to vitamin D3 (479). The isomerization process
ered radioactive tracer was associated with the chylomicron is temperature dependent and fairly slow (479, 1117). It has
fraction of the collected intestinal lymph (288). Further- been calculated that the half-life for the formation of vita-
more, patients suffering from the autosomal recessive chy- min D3 is ⬃2.5 h (1085). Interestingly, in vitro experiments
lomicron retention disease (Anderson disease; OMIM conducted in isotropic medium demonstrated that the
246700), which causes impairment of chylomicron process- isomerization rate was 10 times slower than in in vivo ex-
ing and secretion in the enterocyte, can present with insuf- periments (1085). This was later attributed to the fact that
ficient levels of fat-soluble vitamins, such as vitamins D and amphiphatic interactions with phospholipids of the cell
E (535). The chylomicron remnants, which include vitamin membrane stabilize the previtamin D3 conformer which
D, are then scavenged by the liver after the lymph has en- then isomerizes to vitamin D3 (1086). The cellular microen-
tered the circulation through the thoracic duct (287, 407). vironment of the reaction thus greatly optimizes the isomer-
However, it has been demonstrated in vitro and in vivo in ization to vitamin D3. After its synthesis, vitamin D3 is
hepatectomized and normal rats that vitamin D can directly bound to DBP and carried though the bloodstream to its
transfer from chylomicrons to a vitamin D binding protein target organs. Observations made in patients indicate that
(DBP; see sect. IVA5) in the blood plasma (286, 288). It has the vitamin D3 plasma levels peak ⬃2 days after sunlight
therefore been suggested that at least a fraction of hepatic exposure, which is due to the slow isomerization rate in the
vitamin D uptake is mediated through DBP rather than skin (7).
chylomicrons (286; contested by Ref. 407). In the liver,
vitamin D is then hydroxylated at its 25 position to 4. Vitamin D metabolism and its regulation
25(OH)-vitamin D. The metabolism of vitamin D will be
the subject of a later section. Irrespective of the source (endogenous or exogenous), vita-
min D is metabolized in the liver to 25(OH)-vitamin D
The intestinal absorption of 25(OH)-vitamin D has been (FIGURE 5). Evidence for the existence of biologically active
investigated by many groups, with the aim of optimizing vitamin D metabolites emerged in the 1960s (686, 799).
vitamin D administration in a therapeutic context by by- 25(OH)-vitamin D was identified by means of injecting rats
passing the first metabolic step in the liver (219, 245, 287, with radiolabeled vitamin D and subsequent silicic acid col-
445, 645, 721, 1018, 1019, 1127). In general, enteric up- umn chromatography of lipid extracts from serum and var-

ious tissues (686). Chromatography revealed the presence (933, 1078). Higher expression in females was also con-
of a vitamin D metabolite in serum, liver, bone, and feces in firmed in biopsy samples from human subjects (370). A
rats and in human serum (256, 686). Furthermore, it was regulation via sex hormones may underlie this phenome-
shown that the vitamin D metabolite was biologically active non, as injection of estradiol was shown to induce
by reverting rickets in diseased animals and by increasing CYP27A1 activity (933). Interestingly, seasonal variations
intestinal calcium transport and bone metabolism (686, in expression were also observed, which may represent a
752). The metabolite was characterized as 25(OH)-vitamin confounding factor for decreased 25(OH)-vitamin D levels
D and subsequently successfully synthesized (111, 112). It during the winter months (370).
was soon recognized that hepatectomized rats were not ef-
fectively converting vitamin D to 25(OH)-vitamin D, sug- It should be noted that CYP27A1 can also hydroxylate
gesting that the liver was the main organ responsible for vitamin D3 at other positions (402, 950). These include
25-hydroxylation (864, 865). The ability of the liver to positions 27 and 26; however, the ratio for 25-:27-:26-
metabolize vitamin D was also confirmed in perfused livers hydroxylation has been estimated to be only 100:15:3,
and tissue homogenates (490). Historically, a long contro- which demonstrates that 25-hydroxylation of vitamin D3 is
versy existed with regard to the subcellular localization of the most essential reaction catalyzed by the enzyme (950).

the enzyme that hydroxylates vitamin D (25-hydroxylase) More importantly, CYP27A1 can also use its own product
in the liver, as enzyme activity was observed in both mito- 25(OH)-vitamin D as a substrate to further act as a 1␣-
chondrial and microsomal fractions of liver homogenates hydroxylase and produce the hormonally active form of
(93, 102, 103, 258, 696, 1053). Extensive investigations vitamin D, namely, 1,25(OH)2-vitamin D (50, 51, 950). As
indicated that both the microsomal and mitochondrial 25- will be discussed later, this reaction is normally catalyzed in
hydroxylase are members of the cytochrome P-450 family the kidney by another CYP family member (CYP27B1). At
(102–104, 696, 835). Both fractions demonstrated distinct the moment, it is not clear what the physiological signifi-
enzymatic kinetics. The mitochondrial enzyme was charac- cance of 1␣-hydroxylation by CYP27A1 is.
terized as a low-affinity high-capacity enzyme, whereas the
microsomal fraction displayed high-affinity low-capacity Mutations in CYP27A1 cause the autosomal recessive dis-
characteristics (103, 104, 356, 696). order cerebrotendinous xanthomatosis (CTX; OMIM
213700). The disease was first described in 1937 and is
The mitochondrial 25-hydroxylase (CYP27A1) was first characterized by cholestanol deposits that are most promi-
purified to homogeneity from rabbit liver mitochondria nent in tendons, especially the Achilles tendon, the brain,
(235). It was demonstrated that this cytochrome P-450 was and the lung. Patients present with progressive neurologic
not specific to vitamin D and could also hydroxylate other defects, atherosclerosis, and cataracts and commonly suffer
substrates, most notably cholesterol (27-hydroxylation), from diarrhea. The inadequate bile acid synthesis was first
which represents an important step in the formation of bile noted in 1974 by Setoguchi et al. (993). Shortly after the
acids (235). In retrospect, CYP27A1 had been purified 4 cDNA of CYP27A1 was cloned, it was demonstrated that
years earlier; however, only the 27-hydroxylation of cho- mutations of this enzyme were responsible for CTX (148).
lesterol had been investigated and its effects on vitamin D In agreement with the dual role of CYP27A1, CTX patients
had remained obscure (1162). Subsequently, the enzyme’s also suffer from osteoporosis, low 25(OH)-vitamin D lev-
cDNA was cloned from rabbit, rat, and human, and its dual els, and impaired intestinal calcium absorption (83, 320).
role in vitamin D and steroid conversion was confirmed (26, Three CYP27A1 mutations that are known to cause CTX
149, 1048, 1103). The full gene structure was identified a and still lead to protein expression were recreated in vitro,
few years later (646). Although no crystal structure of the and enzymatic activity was assayed. Depending on the ex-
enzyme is available to us, a homology model based on other pression system, these mutants showed lower or higher 25-
CYP family members has been proposed (874). In the liver, hydroxylation activity than the wt enzyme, which led the
CYP27A1 is expressed on the mRNA level in hepatocytes, authors to questions the enzyme’s role in vitamin D metab-
endothelial, stellate, and Kupffer cells (1078). Furthermore, olism (403). It should be considered that 1) many more
CYP27A1 expression was confirmed in a variety of other (⬃38) mutations underlying CTX exist, 2) by far not all
tissues, including duodenum, adrenal glands, kidney, lung, patients exhibit disturbances in bone or vitamin D homeo-
vascular endothelium, brain, retina, skin, muscle, and os- stasis, and 3) the investigated mutant enzymes may only
teoblasts; however, their potential contribution to vitamin cause disturbances in cholesterol, rather than vitamin D
D metabolism remains unclear (26, 51, 135, 184, 370, 383, metabolism (83, 320, 403). In the light of these limitations,
508, 640, 898, 979). Interestingly, an extrahepatic conver- it should be questioned whether CTX represents an apt
sion of vitamin D had been suggested previously to occur in model system to evaluate CYP27A1 in the context of vita-
the kidney and the intestine (1097). Marked differences in min D metabolism.
CYP27A1 activity can be observed between males and fe-
males. For example, CYP27A1 enzyme activity and mRNA With the introduction of novel genetic tools, a cyp27a1
expression were demonstrated to be increased in female rats (⫺/⫺) mouse was created in 1998 (918). However, the phe-

notype of CTX could not be reproduced, albeit fecal bile of these observations is beyond the scope of this review, but
acid content was markedly decreased (918). Rather surpris- the most recent investigation should be considered in more
ingly, serum 25(OH)-vitamin D levels were increased in detail, given the advances in our experimental repertoire: it
(⫺/⫺) animals, which either pointed to compensatory up- has been demonstrated in the rat that 1,25(OH)2-vitamin D
regulation of other, maybe microsomal, enzymes or a non- can downregulate hepatic CYP27A1 transcription with a
involvement of cyp27a1 in vitamin D metabolism in the concomitant reduction in enzyme activity (1078). These
mouse (918). The (⫺/⫺) mouse model was later character- observations strongly corroborate the hypothesis that the
ized in more detail, but no new conclusions with regard to 25-hydroxylation step is subjected to negative-feedback
vitamin D were drawn (902). regulation. The exact mechanism of this regulatory mecha-
nism remains elusive, especially since the CYP27A1 gene is
Another caveat that needs to be considered when assessing not under control of a VDRE (369, 988, 1078).
the physiological importance of CYP27A1 for vitamin D
metabolism is that the enzyme cannot 25-hydroxylate di- Following its synthesis, 25(OH)-vitamin D binds to DBP
etary vitamin D2 (402). This observation underlines the and is transported to the kidney, where it undergoes further
necessity for another 25-hydroxylase which physiologically conversion to 1,25(OH)2-vitamin D, the hormonally active

metabolizes vitamin D2. The microsomal 25-hydroxylase form of vitamin D (FIGURE 5). Historically, 1,25(OH)2-
was a clear candidate for this process; however, it has only vitamin D was first identified in the nuclei of intestinal cells
recently received more extensive scientific attention. as an uncharacterized vitamin D metabolite (429, 634). The
biological activity of the metabolite was determined to be
The molecular identity of the microsomal 25-hydroxylase much higher than that of vitamin D, and it was eventually
was unclear, until it was unmasked by Cheng et al. (184) in isolated and identified as 1,25(OH)2-vitamin D (480, 586,
2003 as CYP2R1. CYP2R1 is expressed on the mRNA level 633, 800). 1,25(OH)2-vitamin D is up to 10 times more
in a plethora of tissues, but most prominently in the liver potent than vitamin D. The importance of the kidney for the
and testes (184). As illustrated by a recent investigation, the synthesis of 1,25(OH)2-vitamin D was soon discovered, as
testes may play a role in calcium homeostasis. Patients with nephrectomized rats were neither able to convert 25(OH)-
testiculopathy (and concomitant lower CYP2R1 expres- vitamin D, nor absorb calcium effectively (339, 458).
sion) were shown to have decreased 25(OH)-vitamin D lev- Briefly thereafter, patients with chronic renal insufficiency
els and osteoporosis (333). The protein’s crystal structure were shown to lack the capability to metabolize 25(OH)-
has recently been resolved in complex with vitamin D3 vitamin D, which further established the role of the kidney
(1045). Unlike CYP27A1, CYP2R1 has been shown to 25- as the major conversion site (724). The impairment of
hydroxylate both vitamin D2 and vitamin D3, which may be 1,25(OH)2-vitamin D synthesis in the course of chronic
a solution to the enigma of vitamin D2 metabolism (184). renal deficiency is a cofactor in the development of renal
The physiological relevance of CYP2R1 was underscored osteodystrophy, a bone mineralization deficiency due to
by the characterization of a patient who presented with low deranged mineral balance. Of note, the kidney is not the
25(OH)-vitamin D levels and was shown to have a transi- exclusive site of CYP27B1 expression. 1␣-Hydroxylase has
tion mutation in the CYP2R1 gene (183). Furthermore, a been detected in a variety of other tissues, including the
remarkable large-scale study has recently tried to establish a placenta, decidua, skin, brain, vascular endothelium, pan-
correlation between 25(OH)-vitamin D status and the ge- creas, colon, but also in monocytes and dendritic cells (451–
notype of 33,996 individuals. It was found that lower 453, 603, 1204 –1206). The role of extrarenal 1,25(OH)2-
25(OH)-vitamin D levels correlated with variants in the vitamin D synthesis is not entirely clear. Beyond modulating
CYP2R1 gene (1146) (a smaller study came to similar con- calcium homeostasis, vitamin D has been shown to have immu-
clusions, Ref. 139). This represents an outstanding finding, nomodulatory and antiproliferative effects (see sect. IVA6).
as the influence of CYP27A1 mutations on 25(OH)-vitamin Given these observations, it has been speculated that extrare-
D production is far less conclusive. Given the dispropor- nal local 1,25(OH)2-vitamin D production and paracrine se-
tionate quantity of scientific data, it is at this moment dif- cretion may represent important factors for the maintenance
ficult to evaluate the relative contribution of each 25-hy- of the “barrier function” in these tissues (451, 453).
droxylase to vitamin D metabolism, but more and more
evidence for the importance of CYP2R1 is accumulating. In the kidney, 1␣-hydroxylation of 25(OH)-vitamin D
takes place in the inner mitochondrial membrane of the
The regulation of 25-hydroxylation has been the subject of epithelial cells of the proximal tubule (393).
controversy in the past, which is partially due to the fact
that multiple enzymes may metabolize vitamin D, and that The cellular uptake mechanism of 25(OH)-vitamin D by the
it was challenging to experimentally discriminate between tubule cells will be subject of a later section. The 1␣-hy-
these enzyme entities. Thus evidence which supports (91, droxylase responsible for the conversion is also a member of
92, 741, 1078) and questions (258, 1097) the existence of the cytochrome P-450 family (CYP27B1) and was first
25-hydroxylase regulation can be found. A detailed analysis cloned in 1997 by St-Arnaud et al. from rat cDNA (1034).

The human homolog was cloned shortly thereafter (349, Apart from regulating the synthesis of the vitamin D
748). Interestingly, mapping of the CYP27B1 gene revealed metabolites, our body also tightly controls their degrada-
that the locus was identical to the gene locus of the auto- tion. The first step of vitamin D catabolism is 24-hy-
somal recessive disorder pseudo vitamin D deficiency rick- droxylation, which is carried out by the mitochondrial
ets, type 1A (PDDR1A, OMIM 264700) (1034). PDDR is enzyme CYP24A1. The primary site for vitamin D catab-
characterized by low serum calcium, secondary hyperpara- olism is the kidney, but CYP24A1 is also strongly expressed
thyroidism, and low 1,25(OH)2-vitamin D levels (869) (of in other extrarenal tissues, such as the intestine, osteoblasts,
note, the original article wrongly suggests an autosomal keratinocytes, prostate, placenta, brain, and heart (11, 181,
dominant inheritance pattern). Patients can exhibit rickets 796). CYP24A1 can hydroxylate both 25(OH)-vitamin D
or osteomalacia due to increased mobilization of calcium. and 1,25(OH)2-vitamin D, thereby creating 24,25(OH)2-
The gene locus of PDDR1A had been mapped by linkage vitamin D and 1,24,25(OH)3-vitamin D, respectively (14).
analysis; however, before the cloning of CYP27B1, it was 24-Hydroxylation is followed by a series of oxidation/re-
duction reactions which finally yield the excretable product
not clear whether a defect in the enzyme itself or distur-
calcitroic acid (703, 893). At least in the proximal tubule of
bances in its regulation were responsible for the disease
the kidney, the regulation of CYP24A1 is reciprocal to that

(617, 618, 1223). The clear-cut phenotype of PPDR1A ef-
of CYP27B1. 1,25(OH)2-vitamin D upregulates CYP24A1,
fectively illustrates the pivotal role of CYP27B1 and the
thereby stimulating its own breakdown, whereas PTH inhibits
lack of redundancy at this essential step of vitamin D me- CYP24A1 (37, 180, 812, 1069, 1222). While 1,25(OH)2-vi-
tabolism. The characteristic features of PDDR1A can essen- tamin D increases the transcription of CYP24A1 (the gene has
tially be emulated if cyp27b1 is knocked out in a mouse two upstream VDREs), PTH exerts its inhibitory effects by
model (238, 822). The serum calcium levels and the second- decreasing CYP24A1 mRNA stability (1222). In osteoblastic
ary hyperparathyroidism can be normalized if these animals and distal convoluted tubule cell lines, PTH has synergistic
are fed a high-calcium, phosphorus, lactose diet, albeit bone effects with 1,25(OH)2-vitamin D in inducing CYP24A1 (37,
growth remains impaired (239). 1189). In analogy to CYP27B1, CYP24A1 is further regulated
by FGF23, calcitonin, and phosphate (361, 513, 1175).
The activity of CYP27B1 is subjected to tight hormonal
regulation. The key regulator of 1,25(OH)2-vitamin D syn- 5. Vitamin D transport and cellular uptake
thesis is PTH, which is secreted by the parathyroid glands in
response to low serum calcium concentrations in an effort The hypothesis that vitamin D may be bound to a carrier
to increase calcium uptake and release bone calcium into substance in serum was first expressed in the late 1950s,
the circulation. The regulation of calcium homeostasis by when it was demonstrated that the alpha fraction of human
the parathyroid glands and the CaSR will be covered in serum had high anti-rachitic properties (1079). It was later
subsequent sections (see sect. IV, B and D). Apart from this shown that DBP is identical to the group specific component
stimulatory input, CYP27B1 is under negative control by its (Gc) protein, which had been characterized independently
own product. 1,25(OH)2-vitamin D represses CYP27B1 on by Hirschfeld and colleagues around the same time (236,
a transcriptional level (116, 125, 443, 591, 764). Although 464, 465). DBP (⬃58 kDa; 458 amino acids) is synthesized
studies in (⫺/⫺) animals suggest that the VDR is essential in the liver and is closely related to albumin and ␣-fetopro-
for autoinhibition to take place, the promoter region of tein, which are all derived from the same ancestral gene
CYP27B1 does not include a canonical VDRE (125, 591, (221, 875, 1158, 1187, 1188). The crystal structure of DBP
has been resolved at a resolution of 2.3 Å in complex with
764). It is thus most likely that the transcriptional regu-
25(OH)-vitamin D (1121). DBP can bind vitamin D and all
lation through 1,25(OH)2-vitamin D is indirect (125,
of its metabolites (408). There is, however, a difference in
591). Alternatively, so-called E-box-type elements were
the relative affinity for the vitamin D steroids, with the
recently proposed to act as negative VDREs (575). More-
affinity for 25(OH)-vitamin D being highest (Kd ⬃10⫺8 M),
over, CYP27B1 can be directly regulated by the local
followed by 1,25(OH)2-vitamin D and vitamin D (Kd
calcium concentrations. High extracellular calcium inhib- ⬃10⫺7 M) (408). In humans, vitamin D2 and D3 metabo-
its 1,25(OH)2-vitamin D synthesis, whereas low calcium lites are bound with equal affinity to DBP (406). Given its
concentrations induce its production (109). It has been pro- long plasma half-life, 25(OH)-vitamin D is also measured
posed that changes in calcium modulate VDR expression as the primary clinical parameter to assess the vitamin D
and thereby the sensitivity of cell to the local negative feed- status of patients. Although the plasma concentration of
back by 1,25(OH)2-vitamin D (702). Some evidence sug- DBP is ⬃4 – 8 ␮M, only ⬍5% of the binding sites are occu-
gests that the CaSR mediates the regulatory effects of cal- pied by vitamin D sterols (408, 409). DBP has a very fast
cium on CYP27B1 activity (FIGURE 8) (702). Other factors turnover rate. It has been estimated that up to 28% of DBP
that regulate CYP27B1 activity include fibroblast growth are replaced every day (557). This turnover entails a high
factor 23 (FGF23), calcitonin, prolactin, sex steroids (at demand for synthesis output by the liver. In consequence,
least in avian species), and phosphate (716, 913, 1067, patients with liver disease demonstrate lower DBP and total
1068, 1217). vitamin D levels than healthy subjects (97, 409). This rela-

tionship is reversed during pregnancy, when the levels of cells, which can also convert 25(OH)-vitamin D to
DBP and vitamin D sterols are increased (97, 409, 609, 685, 1.25(OH)2-vitamin D(926).
892). Of note, DBP is not the exclusive carrier substance for
vitamin D sterols. Albumin and lipoproteins were shown to 6. Cellular effects of vitamin D
transport a fraction (⬃15%) of vitamin D (1015).
The cellular effects of 1,25(OH)2-vitamin D can be catego-
Given its multitude of functions, DBP has been regarded as an rized into two major pathways, which are defined by their
essential protein. Indeed, an analysis of over 80,000 human respective speed of onset: 1) slow genomic responses and
serum samples showed that DBP was present in all of them, 2) rapid nongenomic responses. Both pathways require
which led to the hypothesis that deleterious mutations of binding of 1,25(OH)2-vitamin D to its intracellular recep-
DBP were lethal (213). Rather surprisingly, DBP (⫺/⫺) tor, the VDR (503, 787). The VDR (NR1I1, nuclear recep-
mice thrive well with growth curves identical to their tor subfamily 1, group I, member 1) belongs to the super-
littermates, although their 25(OH)-vitamin D and family of nuclear receptors, which amongst others also
1,25(OH)2-vitamin D levels (total) are severely decreased includes the estrogen, testosterone, or glucocorticoid recep-
(937). If challenged with a low vitamin D diet, the DBP tors. VDR was first identified in the late 1960s in the chro-

(⫺/⫺) animals develop secondary hyperparathyroidism, matin fraction of chick intestinal mucosa, where
leading to defects in bone mineralization (937). It is un- 1,25(OH)2-vitamin D increases the rate of intestinal cal-
clear, however, to what extent albumin and lipoproteins cium uptake (430). The 427-amino acid protein (molecular
compensate for the loss of the primary vitamin D carrier mass 48.3 kDa) was cloned in 1988 by Baker et al. (59). The
substance. crystal structure of the VDR is available to us with
1,25(OH)2-vitamin D bound to the receptor’s ligand bind-
ing domain (914).
Not much is known about the cellular uptake of vitamin D.
As all other steroids, free vitamin D can passively diffuse
A) GENOMIC EFFECTS. Following ligand binding, nuclear recep-
through the plasma membrane because of its lipohilic na-
tors typically act as transcription factors and induce or re-
ture. However, due to the high concentration of DBP and its
press the transcription of certain target genes. In the case of
affinity towards vitamin D ligands, only a fraction of vita-
VDR, 1,25(OH)2-vitamin D binds to the receptor, which
min D circulates in the free form. For example, 0.003% of
subsequently heterodimerizes with the retinoid X receptor
25(OH)-vitamin D is transported as an unbound sterol in
(RXR) (FIGURE 3) (1027, 1083). The VDR-RXR complex
serum, which raises the question whether passive diffusion
then interacts with a VDRE in the 5= promoter region of the
represents a sufficient uptake pathway (98). At least
regulated gene resulting in transactivation. Alternatively, it
25(OH)-vitamin D has been proposed to be delivered to
has been proposed that VDR can bind to the VDRE before
the proximal kidney tubule for further conversion to ligand binding occurs (920).
1,25(OH)2-vitamin D by a different and remarkable mech-
anism. Rather than diffusing passively, it has been proposed I) Intestine. The intestine is one of the primary target sites of
that the 25(OH)-vitamin D-DBP complex passes the glo- 1,25(OH)2-vitamin D. 1,25(OH)2-vitamin D upregulates
merular filter and is endocytosed by the epithelial cell of the the expression of intestinal TRPV6, calbindin-D 9k, and
proximal tubule (FIGURE 5) (805). The endocytotic process PMCA, which are canonically regarded to mediate the pro-
is mediated by megalin (aka gp330), which is a multifunc- cess of transcellular calcium absorption (FIGURE 3) (see sect.
tional clearance receptor on the luminal membrane. Mice IIIA). Furthermore, 1,25(OH)2-vitamin D may modulate
lacking functional megalin were shown to lose DBP and calcium uptake through the paracellular route (see sect.
vitamin D in the urine and develop vitamin D deficiency IIIB). By increasing the amount of absorbed calcium,
(805). A kidney specific megalin (⫺/⫺) animal was recently 1,25(OH)2-vitamin D directly elevates serum calcium lev-
created, and the observations made in the global (⫺/⫺) els. This represents one of the final links in the regulatory
animal, which had a very low perinatal survival rate of 2%, chain of calcium homeostasis which starts with sensing of
could essentially be replicated (643). Furthermore, defects low calcium levels by the parathyroid gland and ends with
in cubulin, a membrane protein that colocalizes with mega- increased synthesis of 1,25(OH)2-vitamin D by the kidney.
lin, cause a similar phenotype (806). The experimental data The significance of 1,25(OH)2-vitamin D for intestinal cal-
are further supported by clinical observations made in pa- cium absorption is illustrated by 1,25(OH)2-vitamin D-de-
tients suffering from Fanconi syndrome. Fanconi syn- ficient patients, which absorb up to 80% less calcium from
drome is a global reabsorption deficiency of the proximal their meal compared with healthy individuals (996). Al-
tubule, which can develop as a result of heavy metal though similar results were obtained in animal models,
poisoning and/or drugs or may have inherited causes. probably one of the more illustrative observations has been
These patients were shown to lose DBP in their urine, made in VDR-deficient animals (825, 1110). Deletion of
which may reflect the inability of the tubule cell to endo- VDR correlates with a massively impaired capacity to ab-
cytose DBP (805, 1076, 1100). A similar endocytotic sorb intestinal calcium resulting in low plasma calcium lev-
uptake mechanism has been proposed for mammary els and hyperparathyroidism (1110). This phenotype is re-

versible by intestine-specific expression of VDR on a VDR duct. The mechanism by which the distal tubule conducts
(⫺/⫺) background (712, 1181). Thus animals that lack the transcellular calcium absorption is highly analogous to the
VDR, except in the intestine, present with normal serum proximal intestine. The epithelial cells of the distal tubule
calcium and PTH levels (1181). In conclusion, it is unques- express TRPV5 (the “sister” channel of TRPV6) as the api-
tionable that 1,25(OH)2-vitamin D and its receptor are the cal calcium entry channel, calbindin-D 28k and NCX1 and
key regulators of intestinal calcium absorption. PMCA1b as basolateral calcium extruders (203, 474, 610,
837, 922). In analogy to the intestine, 1,25(OH)2-vitamin D
II) Bone. Some evidence exists that 1,25(OH)2-vitamin D upregulates the majority of these proteins in an effort to
may have direct influences on the formation of bone (FIG- increase renal calcium reabsorption (203, 474, 610, 837,
URE 4). The VDR is expressed in osteoblasts, osteoclasts, 922).
and chondrocytes (115, 533, 623, 730). Most of the direct
effects of 1,25(OH)2-vitamin D are thought to be mediated B) NONGENOMIC EFFECTS. In contrast to the genomic effects of
by osteoblasts. 1,25(OH)2-vitamin D has been shown to 1,25(OH)2-vitamin D, which have been known for decades,
promote osteoblast differentiation from mesenchymal stem the rapid cellular responses have only recently received
cells and to regulate the synthesis of various osteoblast pro- more scientific attention. While the transcriptional events of

teins, such as osteocalcin, alkaline phosphatase, collagen I, 1,25(OH)2-vitamin D take place on a time scale of a few
osteopontin, and RANKL (45, 78, 79, 665, 709, 804, 870, hours to days, the rapid nongenomic responses occur within
925). In general, however, the effects of 1,25(OH)2-vitamin minutes of exposure. One of the first evidences, which in
D on osteoblast maturation and protein synthesis are very retrospect can be attributed to a nongenomic response, was
pleiotropic and depended on the duration of the exposure the observation made in 1941 by Selye that intraperitoneal
and the differentiation stage at which the osteoblast is ex- injection of steroids had an anesthetic effect (990). Interest-
posed (817). Effects of 1,25(OH)2-vitamin D on the miner- ingly, the rapid responses to 1,25(OH)2-vitamin D also re-
alization of bone have also been reported. For example, an quire the presence of the VDR, as these responses cannot be
increase in the mineralization of extracellular matrix was elicited in VDR deficient animals (503, 787). It should be
observed following concomitant 1,25(OH)2-vitamin D and noted that other proteins such as 1,25(OH)2-vitamin-D-
vitamin K exposure (599, 745). Yet, the overall direct influ- MARRS have also been suggested as candidates for a mem-
ence of 1,25(OH)2-vitamin D on bone metabolism is some- brane associated 1,25(OH)2-vitamin D receptor (782). At-
what obscure. This is illustrated by VDR-deficient animals. tempts at identifying the subcellular localization of the
Naturally, these animals develop rickets and osteomalacia VDR in the rapid response context have yielded that VDR is
due to impaired intestinal calcium absorption. If the ani- also present in plasma membrane invaginations, the so-
mals are, however, maintained normocalcemic, the skeletal called caveolae (503, 802). These VDR-containing mem-
phenotype is completely rescued (21, 661). Although, these brane microdomains have been identified in multiple tis-
observations question the importance of 1,25(OH)2-vita- sues, including the intestine, kidney, and lung, and are iden-
min D as a direct regulator of bone metabolism, a subse- tified by coexpression of caveolin-1, which is used as a
quent investigation by Panda et al. (821) came to a different marker protein for caveolae (503, 802). Functionally, not
conclusion. The authors reported that osteoblast numbers, many rapid response effects of 1,25(OH)2-vitamin D have
mineral apposition rates, and overall bone volume were been characterized. For example, it has been demonstrated
reduced in normocalcemic (rescue diet) cyp27b1/VDR that 1,25(OH)2-vitamin D can influence ion channel gating
(double ⫺/⫺) animals, suggesting that the 1,25(OH)2-vita- in osteoblasts, modulate the contraction of cardiomyocytes,
min D system is necessary for intact bone formation (821). lead to insulin secretion in pancreatic ␤-cells via elevating
The reason for these discrepant findings is generally un- intracellular calcium, and cause photoprotection in keratin-
clear; however, differences in the length of exposure to the ocytes (273, 540, 1088, 1200, 1216). In the intestine, the
rescue diet have been put forward as a possible cause (821). phenomenon of transcaltachia (see sect. IIIC) has been at-
For a more detailed review of the effects of vitamin D on tributed to rapid actions of 1,25(OH)2-vitamin D (801).
bone, please refer to References 1033, 1114.
In addition to 1,25(OH)2-vitamin D, the VDR also binds
III) Kidney. The kidney is not only the major site of the secondary bile acid lithocholic acid (704). Secondary
1,25(OH)2-vitamin D synthesis (see above), but also repre- bile acids are bile acids that have been metabolized by the
sents a vitamin D target organ. The kidney acts as key intestinal gut flora. Lithocholic acid is toxic and has been
regulator of calcium homeostasis by changing the amount implicated to play a role in intestinal carcinogenesis (601).
of calcium that is reabsorbed from the primary urine. The It has been suggested that the VDR may serve as a second-
majority of the calcium that is filtered through the glomer- ary bile acid sensor and induce lithocholic acid breakdown
ulus is reabsorbed in the proximal tubule through the para- through CYP3A activation (537). The noncanonical VDR
cellular space, with the amount of absorbed calcium grad- stimulation by lithocholic acid may thus serve as an auto-
ually decreasing along the nephron. Fine regulation of cal- protective mechanism (704). Apart from inducing CYP3A,
cium absorption occurs in the distal tubule and collecting lithocholic acid has been demonstrated to increase expres-

sion of TRPV6 in intestinal cell lines, which corroborates its secretion is extremely tight, given the body’s need to main-
role as a physiological VDR agonist (517). tain the calcium concentration within a narrow window
(1.1–1.3 mM). Small alterations in calcium homeostasis can
We are far from understanding the full spectrum of the have deleterious effects, for example, on the excitability of
effects of 1,25(OH)2-vitamin D, and unfortunately, the neurons and muscles. The low plasma half-life of PTH of ⬍5
scope of this review does not allow a detailed analysis of min allows for a precise regulation of this balance (95). To
these processes. In general, our knowledge concerning the achieve controlled and rapid on-demand secretion of PTH, the
physiological role of 1,25(OH)2-vitamin D is massively ex- parathyroid is equipped with an ultrasensitive extracellular
panding beyond the horizon of calcium homeostasis. Evi- CaSR, which constantly monitors the plasma calcium levels
dence is accumulating that 1,25(OH)2-vitamin D can influ- and triggers intracellular signaling events and PTH release
ence the renin-angiotensin-aldosterone system and may upon imminent drops in calcium levels (FIGURE 6) (see sect.
thereby act as a regulator of blood pressure (660, 662, IVD). PTH is further regulated on a transcriptional level by
1219). Furthermore, low vitamin D status is associated with 1,25(OH)2-vitamin D, creating a negative-feedback loop
an increased incidence of colorectal, ovarian, and breast (154, 930, 931).
cancer(363, 364, 642, 984). Vitamin D also acts as a potent

modulator of the immune response and cell proliferation. 2. PTH1R
B. PTH PTH exerts its physiological effects via activation of a mem-

brane-bound GPCR, the parathyroid hormone receptor
Experiments dating back to the beginning of the 1900s have type 1 (PTH1R) (PTH2R is mostly expressed in the CNS
demonstrated that surgical removal of the parathyroid and tissues that are not involved in calcium handling and
gland results in tetany. It was recognized very early that will thus not be reviewed). Of note, PTH1R is not exclu-
administration of calcium could ameliorate or prevent the sively located at the plasma membrane but can also localize
manifestation of tetany, and it was subsequently concluded to the cell nucleus. The physiological significance of nuclear
that the parathyroid glands play an important role in cal- PTH1R is currently unclear but may represent a novel sig-
cium metabolism (690, 826, 939). In 1925, extracts from naling paradigm for the actions of PTH (830, 856, 857,
the parathyroids were for the first time shown to control 1155).
tetany in dogs (216). This finding marked the discovery of
PTH, which is one of the three prime hormones regulating Full-length PTH is not required to activate PTH1R. The
calcium homeostasis. NH2-terminal domain of PTH mediates most of the physi-
ological effects of the hormone and is responsible for bind-
1. Production and secretion ing in the ␣-␤-␤␣ binding fold of PTH1R (861). This is why
clinically PTH(1–34) is used as a PTH analog with identical
PTH is a 84-amino acid peptide hormone produced in the biological activity (753, 867, 919, 1094). Conversely, NH2-
parathyroid glands. Its amino acid sequence was first estab- terminal truncation of PTH(1–34) to PTH(2–34) changes
lished in 1970 in bovine (126, 788). Cloning of the human the characteristics to a partial receptor agonist, whereas
cDNA followed a decade later (440). The PTH gene en- further truncation to PTH(3–34) results in loss of biological
codes a 115-amino acid precursor hormone (preproPTH), activity (1094).
which is enzymatically cleaved in a two step process to its
mature 84-amino acid secreted form (565). The NH2-ter- PTH1R was first cloned from opossum in 1991, which was
minal prepro-signaling sequence is necessary for correct followed by identification of the highly homologous human
hormone processing and trafficking (340, 546). This cDNA shortly thereafter (536, 964). In the nonactivated
knowledge is mainly founded on truncation studies and state the receptor is expressed as a homodimer at the cell
observations made in patients with mutations in the PTH surface, which dissociates upon PTH binding (860).
gene, which can result in familial isolated hypothyroidism, PTH1R is a member of the class B (class 2, secretin family)
a disorder characterized by hypocalcemia and low PTH GPCRs. As many other GPCRs, it undergoes N-linked gly-
levels (38, 340, 828, 1055). For example, a well-character- cosylation at four asparagine residues (1218). Mutational
ized T-to-C point mutation in the prepro signaling sequence analysis revealed that site-specific mutation of all four sites
that causes FIH leads to accumulation of the precursor hor- decreases cell surface expression, whereas impairment of
mone in the ER (243, 546). The impaired processing trig- fewer glycosylation sites does not seem to have significant
gers ER stress, ultimately apoptosis and PTH insufficiency effects on trafficking or ligand binding (1218). Further-
(243). more, the extracellular domain of the receptor includes a
characteristic disulfide bond pattern involving six cysteine
Following its cleavage to mature PTH, the hormone is residues (392). These residues are thought to be essential for
stored in secretory vesicles and released into the circulation stabilizing the hydrophobic ␣-␤-␤␣ binding pocket for
in response to low plasma calcium. The regulation of PTH PTH, which is conserved among all members of class B

Ca
Ca Calcium
Ca
Ca
PLC PIP2 DAG

Gq
Kinase phosphorylation
Inhibition of
cell growth IP3

1,25(OH)2-D D Calcium
ER PLA2
D
VDR
D
AA
RXR VDR Increases VDR expression
Nucleus
Inhibits PTH
secretion
Reduces PTH
synthesis
Parathyroid gland
PTH
FIGURE 6. CaSR signaling in the parathyroid gland. Increased serum calcium levels lead to an inhibition of
PTH secretion. Serum calcium levels are measured by the CaSR receptor. Activation of CaSR causes
generation of arachidonic acid (AA) metabolites, which inhibit the release of PTH and increase the expression
of VDR, thereby increasing the cell’s sensitivity to the negative feedback exerted by 1,25(OH)2-vitamin D.
1,25(OH)2-vitamin D suppresses the synthesis of PTH. Furthermore, CaSR activation inhibits parathyroid gland
growth.
GPCRs and has recently been crystallized in the presence of example, knockout of ␤-arrestin causes increased and sus-
PTH (861). tained levels of the second messenger cAMP in primary
osteoblast cultures upon PTH stimulation (327). PTH1R
Binding of PTH causes activation of at least two distinct G also associates with the scaffolding protein NHERF1,
proteins. G␣q/11 mediates intracellular calcium release via which stabilizes the receptor at the cell membrane and pre-
phospholipase C (PLC) activation and increases in inositol vents its endocytosis and desensitization (1022, 1139). This
trisphosphate (IP3), whereas G␣s activates adenylyl cyclase effect of NHERF1 is partially attributable to a prevention of
leading to rises in cAMP (5, 188, 808, 859). an interaction between ␤-arrestin and PTH1R (1140). Co-
localization of NHERF1, ␤-arrestin, and PTH1R has been
PTH1R can be regulated on a variety of levels, ranging from demonstrated and suggests that NHERF1 is constitutively
trafficking and internalization to direct protein interactions bound, whereas ␤-arrestin association is more dependent
at the cell surface. Desensitization of PTH1R is mediated by on receptor activation (580). Interestingly, it has recently
GRK2 binding/phosphorylation and ␤-arrestin binding, become apparent that ␤-arrestin not only plays a role in
which uncouples the receptor from its associated G proteins receptor desensitization, but also mediates activation of
and triggers its internalization (267, 326, 330, 1123). For downstream signaling cascades, such as MAPKs, in a G

protein-independent manner (380). Current scientific effort intestinal and renal uptake of calcium in an effort to coun-
thus focuses on the development of so-called “biased” teract hypocalcemia, which initially led to secretion of PTH.
PTH1R agonists, which can selectively trigger G protein- or The PTH-stimulated increase in 1,25(OH)2-vitamin D lev-
␤-arrestin-dependent signaling events, allowing for a more els is achieved on a transcriptional level. PTH upregulates
selective therapeutic repertoire (381, 1160). Furthermore, the transcription of CYP27B1, the mitochondrial enzyme
NHERF may also modulate the cell’s response to PTH bind- which is responsible for the conversion from 25(OH)-vita-
ing. In the presence of NHERF2, the cell’s calcium response min D to 1,25(OH)2-vitamin D. Transcriptional upregula-
via PLC is augmented, whereas the cAMP response is damp- tion occurs via PTH binding to PTH1R, leading to increases
ened, presumably via recruitment of G␣i (698). Both in the second messenger cAMP and activation of PKA (125,
NHERF and ␤-arrestin provide effective examples of how 442, 763, 764, 921).
receptor-associated proteins can modulate canonical signal-
ing events or even, as is the case with ␤-arrestin, initiate Apart from inducing the synthesis of 1,25(OH)2-vitamin D,
signaling events in their own right. PTH can directly upregulate the renal reabsorption of cal-
cium. The regulation of calcium absorption by PTH occurs
PTH1R can also be regulated by its external environment.

in distal segments of the nephron, mostly in the distal con-
The extracellular receptor domain can be cleaved by metal-
voluted tubule and the connecting tubule (99, 379, 1003,
loproteases, resulting in receptor degradation (579). PTH
1172). In close analogy to the duodenum, these segments
binding prevents this proteolytic cleavage, thus stabilizing
PTH1R at the cell surface. The physiological importance of express calcium transport proteins, which are responsible
this mechanism is not yet fully understood. However, for mediating the process of active transcellular calcium
MMPs are involved in bone remodeling and may in conse- absorption in the kidney, namely, TRPV5, calbindin-D
quence locally regulate the sensitivity of osteoblasts to PTH 28k, and NCX1. PTH can regulate all of these protein levels
(579). on a transcriptional level (1108). Interestingly, this seems to
be accomplished independently of 1,25(OH)2-vitamin D,
3. Cellular effects which also positively regulates most of these transporters
(see sect. IVA6) (1108). It is therefore difficult to dissect the
PTH exerts its effects in two primary target tissues: bone relative contribution of each of the two hormones in the
and the kidney. physiological regulation of the calcium transport proteins.
In addition to transcriptional activation, PTH was shown to
In the kidney, PTH causes phostphaturia, increases calcium cause direct phosphorylation of TRPV5, thereby increasing
absorption, and induces the synthesis of 1,25(OH)2-vita- its opening probability (249). The channel is phosphory-
min D. In-detail analysis of renal phosphate handling is lated at threonine-709 in a PKA-dependent fashion (249).
beyond the scope of this review and has been summarized Elevation of intracellular cAMP levels and concomitant
previously (334, 765). In brief, phosphaturia mainly results PKA activation are classical downstream effects of PTH1R
from downregulation of the Na-Pi transporter type IIa activation in the kidney (248, 1172).
(NaPi-IIa) at the apical membrane of the proximal tubule,
thereby reducing the amount of reabsorbed phosphate from In bone, PTH exerts a dichotomous effect depending on the
the primary urine. Rather than directly modulating the pattern of exposure. It is well documented that pulsatile
transporter’s activity, PTH exposure mainly affects the PTH exposure has anabolic effects on bone mass, whereas
number of active cotransporters on the plasma membrane. continuous release increases plasma calcium by bone catab-
Activation of basolateral PTH1R causes retrieval of NaPi-
olism (FIGURE 7) (27, 348, 401, 469, 1065). The observa-
IIa and targets it for lysosomal degradation, resulting in
tion that intermittent PTH administration increases bone
diminished Pi reuptake (566, 682, 847). Apart from NaPi-
mass has led to the use of PTH as a treatment strategy for
IIa, at least two other apical phosphate transporters are
osteoporosis (621, 671, 897). The enhanced bone forma-
present in the proximal tubule: NaPi-IIc and PiT-2 (986,
1124). Currently, there is some evidence that PTH can also tion mainly results from an increase in osteoblast numbers.
regulate NaPi-IIc and PiT-2, but additional studies remain This phenomenon has been partially attributed to a PTH-
to be conducted (855, 987). Although a contribution of mediated induction of osteoblast differentiation and an in-
these transporters to renal phosphate reabsorption is highly hibition of their apoptosis (75, 274, 518, 530, 531, 684,
likely, knockout studies suggest that NaPi-IIa is responsible 969, 1032). Multiple mechanisms underlying the anti-apo-
for ⬃80% of total phosphate transport, thus representing ptotic effects of intermittent PTH on osteoblasts have been
the major uptake mechanism (72, 468). suggested. Among others, these include runt-related tran-
scription factor 2 (Runx2)-mediated transcription of sur-
It has been recognized for over 30 years that PTH can vival genes and increased DNA repair (75, 969). It has
stimulate the synthesis of the active vitamin D metabolite further been shown that fibroblast growth factor 2 (FGF2)
1,25(OH)2-vitamin D in the kidney (116, 338) (see sect. is partially needed as an endogenous cofactor for the ana-
IVA4). 1,25(OH)2-vitamin D in consequence enhances the bolic effects of PTH to take place (934).

Intermittent Chronic
PTH
PTH1R
OPG
RANKL RANK
Osteoclast
Osteoblast differentiation
proliferation
H+
Osteoblast Osteoclast

V-ATPase
FIGURE 7. The effects of PTH on bone. PTH has a dual effect on bone. Intermittent PTH exposure causes
osteoblast proliferation, leading to an increase in bone mass. Continuous PTH exposure results in RANKL
upregulation and concomitant OPG suppression (OPG serves as a decoy receptor for RANKL and prevents its
interaction with osteoclast RANK). The stimulated RANKL-RANK interaction leads to osteoclast proliferation
and increased bone turnover.
Continuous PTH exposure, on the other hand, mainly af- 4. PTH fragments
fects osteoclast numbers and activation, thereby increasing
bone turnover. Since osteoclasts are canonically thought to It should be noted that full-length PTH(1– 84) is not the
not express PTH1R (although this view has recently been only circulating form of the hormone in the body. Various
challenged, Ref. 260), the catabolic effects of PTH are re- PTH fragments can be found in the circulation, which par-
layed through osteoblast signaling. The PTH-induced tially originate directly from the parathyroid gland and par-
crosstalk between osteoblasts and osteoclast is mainly me- tially represent products of peripheral cleavage. The para-
diated by receptor activator of nuclear factor ␬B (RANK), thyroid itself releases COOH- and NH2-terminal hormone
osteoprotegrin (OPG), and RANK ligand (RANKL). Both fragments, which are generated by cysteine proteases (ca-
RANKL and OPG are expressed by osteoblasts and exert thepsin B and H) in distinct secretory vesicles of the gland
opposing actions on osteoclasts. RANKL promotes oste- (418, 427, 693). Interestingly, the fraction of secreted hor-
oclastogenesis by binding to RANK on osteoclasts. Con- mone fragments changes with extracellular calcium condi-
versely, OPG serves as a soluble decoy receptor for RANKL tions. It has been reported that more fragments are released
and thus inhibits its interaction with RANK, thereby sup- under conditions of hypercalcemia, when secretion of full-
pressing osteoclastogenesis. In accordance with this model, length PTH is suppressed (417, 418, 605, 726). Peripheral
RANKL-deficient animals develop osteopetrosis because of proteolysis represents the second source of PTH fragments.
insufficient osteoclasts activation (592). Sustained PTH ex- This process occurs predominantly in liver and the kidney
posure affects RANK-RANKL signaling by downregulat- (127, 234, 989). The group of fragments that have received
ing antiresorptive OPG, while simultaneously stimulat- the most amount of scientific attention is the large NH2-
ing production of RANKL by osteoblasts (FIGURE 7) terminally truncated non-PTH(1– 84) fragments. PTH(7–
(350, 497, 679, 689). The enhanced RANK-RANKL sig- 84) is the quantitatively major member of this group, which
naling induces formation of osteoclasts, which in turn is secreted by the parathyroids (233). The group of non-
leads to enhanced bone resorption and elevates serum PTH(1– 84) fragments can represent up to 20% of circulat-
calcium levels. ing PTH, but can increase in patients with renal failure
dramatically to up to 50% because of impaired renal clear-
In the intestine, several observations suggest that PTH may ance (130, 131, 444, 648). This is of particular interest, as it
have a direct, i.e., non-1,25(OH)2-vitamin-D mediated, ef- has become recently apparent that the non-PTH(1– 84)
fect on intestinal calcium absorption. Both isolated entero- fragments exert biological activity. In general, non-PTH(1–
cytes and intestinal loops demonstrated an increase in cal- 84) fragments antagonize the effects of PTH in its primary
cium uptake following acute PTH exposure (781, 783, target tissues, bone and the kidney but also the parathyroid
784). However, more investigations are needed to clearly gland directly. It has been shown that PTH(7– 84) can in-
establish a direct regulatory role of PTH in the context of hibit PTH release from the parathyroid, presumably in an
intestinal calcium uptake. autocrine fashion, despite low serum calcium concentra-

tions (493). In bone, PTH(7– 84) blocks the effects of PTH 2. The calcitonin receptor
on calcium mobilization in thyroparathyroidectomized rats
(786). More detailed investigations revealed that PTH(7– Calcitonin exerts its physiological functions via activation
84) reduces calcium release from bone in vivo and inhibits of the calcitonin receptor. The calcitonin receptor is a seven-
the formation of osteoclast-like cells in murine primary transmembrane domain GPCR. In particular, it is a member
marrow cultures (272). In the kidney, PTH(7– 84) can in- of the family B subfamily of GPCRs (669). It shares signif-
hibit the formation of 1,25(OH)2-vitamin D, presumably icant homology with other receptors of the family, which
via a posttranscriptional mechanism (768, 1102). include the PTH, GHRH, PACAP, VIP, secretin, glucagon,
and glucagon-like peptide receptors.
Since activation of PTH1R requires an intact NH2-terminal
domain of PTH, it has been speculated that non-PTH(1– The calcitonin receptor is expressed in the two most exten-
84) fragments exert their function through a pathway dis- sively described calcitonin target tissues, i.e., osteoclasts
tinct of PTH1R. The existence of a COOH-terminal PTH and the kidney, but also in other adult tissues, such as the
receptor has thus been postulated (270 –272, 786). The mo- prostate, CNS, skeletal muscle, and placenta (17, 329, 428,
lecular identity of this receptor is, however, not yet re- 790, 878, 1174). Multiple isoforms of the calcitonin recep-

solved. Another mechanism through which non-PTH(1– tor occur in the body, which results from different RNA
84) fragments may exert their biological activity is down- splicing directed by tissue-specific promoters (17, 30, 389,
regulation of PTH1R. It has been demonstrated that 606). Activation of the calcitonin receptor mostly translates
PTH(7– 84) causes internalization of PTH1R, thus offset- into a rise of intracellular cAMP levels via Gs-dependent
ting the effects of PTH by decreasing the number of avail- activation of adenylate cyclase (167, 332, 435, 669). Al-
able receptors at the cell surface (1022). though the cAMP/PKA pathway appears to be dominant,
activation of both PLC and PLD have also been reported
In conclusion, non-PTH(1– 84) fragments act as PTH an- (167, 332, 776).
tagonists and are secreted by the parathyroid in response to
hypercalcemia. 3. Cellular effects
A) OSTEOCLASTS. Shortly after the discovery of calcitonin and

C. Calcitonin its hypocalcemic effects, investigators set out to identify its
physiological site of action. First evidence for an effect of
Calcitonin is a peptide hormone that has been discovered by calcitonin on bone metabolism came from experiments on
Copp et al. in 1962 as a factor that reduces serum calcium rat embryonic bone in tissue culture. It was observed that
concentrations (160, 227). Calcitonin production was ini- calcitonin caused a decreased basal release of calcium from
tially falsely ascribed to the parathyroid glands, and it was these preparations (343). These observations served as the
only later that the thyroid gland had been established as the first evidence of how calcitonin lowers serum calcium levels.
source of calcitonin (463). The primary sites of calcitonin Furthermore, calcitonin blocked the resorptive actions of
production are the parafollicular cells (C-cells) of the thy- PTH on bone, albeit only temporarily (342, 343). After 4 – 6
roid gland. Calcitonin exerts its hypocalcemic effects pri- days of combined treatment (calcitonin ⫹ PTH), calcium
marily by inhibition of osteoclast activity. It should be release rose again (342). This desensitization to the effects
noted that the importance of calcitonin in day-to-day cal- of calcitonin has been coined as the calcitonin “escape”
cium homeostasis in humans is rather negligible (see sect. phenomenon (342). Today we know that the transient ef-
IVC4). For this reason, it will only be reviewed concisely. fect of calcitonin on osteoclasts is attributable to a down-
regulation of surface calcitonin receptors and their synthe-
1. Production and secretion sis (882, 1061, 1129, 1130).
Calcitonin is encoded by the CALCA gene and is initially As alluded to before, calcitonin directly inhibits the action
synthesized as a 141-amino acid precursor (preprocalci- of osteoclasts, causing the balance between bone absorp-
tonin), which is later processed to the mature 32-amino acid tion and formation to shift towards anabolism. Calcitonin
hormone (637). The same gene also encodes the neuropep- exerts its inhibitory effects on osteoclasts via activation of
tide CGRP. Production of either peptide is dependent on its receptor, which is expressed in abundance on their sur-
tissue-specific RNA splicing. Although encoded by a differ- face (428, 790, 878). Exposure to calcitonin triggers dis-
ent gene, amylin also belongs to the calcitonin peptide fam- tinct morphological changes in the osteoclast. Osteoclasts
ily. All three peptides, i.e., calcitonin, CGRP, and amylin, are highly motile cells that resorb bone via formation of
share some overlapping functions with regard to osteoclast so-called resorptive pits, which are membrane invagina-
suppression (16, 229, 1199). Calcitonin is released from the tions that are luminally acidified by active proton secretion.
C-cells in response to rising concentrations of plasma cal- Calcitonin has been shown to inhibit the formation of these
cium. The CaSR is responsible for the molecular process of resorptive bays in vitro (487, 1057). Furthermore, oste-
calcium sensing on the parafollicular cells (351, 367, 728). oclast motility is markedly decreased, causing the cell to

enter a state of functional quiescence (169). Apart from duced in HEK-293 cells following calcitonin exposure,
directly altering osteoclast function, calcitonin also affects suggesting a regulatory role of calcitonin in vitamin D
osteoclast differentiation. Calcitonin inhibits the formation catabolism (361). In addition to its putative direct effect
of multinucleated mature osteoclasts by arresting their dif- on calcium reabsorption, calcitonin may thus affect nor-
ferentiation in more immature stages (1060). mal calcium metabolism indirectly by modulating the
levels of circulating 1,25(OH)2-vitamin D.
B) KIDNEY. Renal calcium handling is the second organ
function that is influenced by calcitonin. However, it is 4. The relevance of calcitonin for
not entirely clear whether calcitonin causes calciuria or calcium homeostasis
enhances calcium reabsorption from the urine. The con-
flicting results may be to some extent attributable to spe- The relevance of calcitonin for day-to-day calcium balance
cies differences. In humans, calcitonin likely increases the is highly debatable. This is corroborated by fundamental
excretion calcium through the urine and thereby acts in observations during conditions of decreased or increased
concert with its inhibitory action on osteoclasts to lower calcitonin levels, neither of which result in an appreciable
serum calcium levels (31, 32, 143, 215, 819, 1016). Con- phenotype in terms of calcium balance. For example, pa-

versely, most studies demonstrating an increase in the tients with medullary carcinomas of the thyroid (MTC), a
renal reabsorption of calcium and magnesium were con- tumor of the thyroid C-cells resulting in the hypersecretion
ducted in rats, rabbits, or mice (84, 158, 159, 265, 304, of calcitonin, were shown to have normal bone mineral
877, 883, 1225). A single investigation established a cal- densities (1176). Animal studies further substantiate this
cium-conserving effect of calcitonin in human (160). The conundrum. A reduction in serum calcitonin levels by thy-
primary site of action for calcitonin in the rat is the thick roidectomy in rats did not impact serum calcium levels
ascending limb (TAL) of the loop of Henle, where calci- (223, 1064). In light of this evidence, the question arises as
tonin has been demonstrated to bind its receptor, in- to what the physiological role of calcitonin is.
crease local adenylate cyclase activity, and promote cal-
cium reabsorption (166, 168). Apart from enhancing the It has been suggested that calcitonin is an evolutionary rem-
reabsorption of calcium, calcitonin also promotes the nant (462). This is substantiated by the fact that calcitonin
vectorial transport of NaCl in the rat TAL, thereby am- from other species is more potent than human calcitonin.
plifying the corticomedullary concentration gradient, Teleost calcitonin has the highest biological activity in hu-
which is a prerequisite for the subsequent concentration mans, which may be a result of their higher dependence on
of urine in the collecting duct (265, 304). In the rabbit, the hormone. For example, salmon calcitonin has an ap-
the calcium-conserving effects of calcitonin seem to be proximately sixfold higher affinity to calcitonin receptor
mediated by the distal tubule (1225). than human calcitonin (28, 328). Furthermore, it is less
effectively eliminated by the kidney, resulting in a longer
It has also been speculated that calcitonin may act di- plasma half-life (405). The differences in the biological ac-
rectly on the collecting duct in a similar fashion to anti- tivity between calcitonin forms led to the introduction of
salmon calcitonin as a treatment for skeletal disorders, such
diuretic hormone (ADH or vasopressin), i.e., to concen-
as osteoporosis or Paget’s disease (1077).
trate the urine by increasing the reabsorption of water
from the primary urine (251). Indeed, calcitonin was
Given its ambiguous role in regular calcium homeostasis, it
shown to increase the apical expression of aquaporin 2
has been postulated that calcitonin may be of importance
(AQP2) in principal cells of the collecting duct (119).
during states of high calcium demand, such as during lac-
Apical insertion of AQP2 and subsequent transepithelial
tation (1170). It has been demonstrated that calcitonin and
water movement is the primary mechanism by which
CGRP (⫺/⫺) mice show greater loss of skeletal mass during
ADH causes concentration of the urine to lower plasma
lactation than wt animals (1170). Since calcitonin and
osmolarity.
CGRP are encoded by the same gene, animals were con-
trolled by CGRP substitution, which was without effect
In conclusion, the direct impact of calcitonin on renal
(1170). Another mechanism by which calcitonin may be
calcium handling is quite vague and may be of minor osteoprotective during lactation or pregnancy is by induc-
importance. However, calcitonin also has another, indi- ing the renal synthesis of 1,25(OH)2-vitamin D (1217).
rect effect on calcium homeostasis. Calcitonin was
shown to be an important regulator of the expression of
CYP27B1, the renal enzyme responsible for the conver- D. The CaSR
sion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D
(1009, 1217). In normocalcemic rats, CYP27B1 mRNA The CaSR is a G protein-coupled membrane-bound recep-
levels were inducible by calcitonin administration, lead- tor that is the primary sensor for calcium and is the first link
ing to an increase in the production of 1,25(OH)2-vita- in the regulatory chain of calcium homeostasis. By regulat-
min D (1009, 1217). Furthermore, CYP24A1 was in- ing the release of PTH from the parathyroid to modulate

current serum calcium levels, it presides over the subsequent On the cell surface, the CaSR resides in caveolin-1-rich
hierarchical cascade of vitamin D synthesis and calcium plasma membrane domains, which also contain associated
handling in the vitamin D target organs, such as the intes- signaling proteins (571). These signaling complexes are
tine, kidney, and bone. More recent investigations have formed with the help of scaffolding proteins. The COOH-
demonstrated that the CaSR is not exclusively expressed in terminal tail of CaSR binds to filamin A, an actin binding
the parathyroid gland, but is also present locally in the protein (48, 467). Silencing of filamin A with siRNAs re-
vitamin D target organs. This diverse expression suggests sults in the attenuation of MAPK signaling by the receptor
that CaSR can modulate organ function locally and outside (496) (see below).
of the strict PTH-vitamin D-organ axis. Thus a short and
local feedback loop is created, which allows the organs to In lack of a crystal structure of CaSR, the exact binding sites
respond rapidly to the local calcium environment. A de- of calcium on the extracellular domain remain subject of
tailed description of the receptor’s role in each tissue is speculation. So far, applicable structural data has only been
beyond the scope of this article, but an attempt will be made obtained from the metabotropic glutamate receptor type I
to identify the key features of CaSR in these local sites in a (mGluR1), which belongs to the same family of type C
subsequent section (FIGURE 8). For excellent in-depth re- GPCRs. In this model, glutamate binds to key residues

views, please refer to Refs. 372, 711, 906. which are located in a cavity, embedded in between two
lobular domains (LB1 and LB2) of the extracellular tail
The importance of CaSR as a regulator of calcium balance (611). This structural hallmark has been aptly coined the
is underlined by clinical pathologies that are caused by its receptor’s Venus fly trap module. This motif is conserved
mutation. Loss-of-function mutations cause familial hy- among other GPCRs of the same family. Multiple attempts
pocalciuric hypercalcaemia (FHH; OMIM 145980) and to identify the calcium binding sites have been undertaken
neonatal severe hyperparathyroidism (NSHPT; OMIM using computational homology modeling (499, 500, 1014).
239200), whereas activating mutations cause autosomal These models have postulated between one and five calcium
dominant hypocalcemia (OMIM 601198). These muta- binding sites (499, 500, 1014). With the employment of
tions mostly change the threshold of receptor activation in mutational analysis, it has been possible to validate func-
either direction. Currently, ⬃300 different mutations are tionality of some of these putative binding sites (500). Mon-
reported, two-thirds of which represent inactivating muta- itoring of the intracellular calcium response to increasing
tions (241). Given its broad expression pattern, the de- extracellular calcium levels in CaSR transfected HEK cells
ranged sensing of blood calcium levels in these disorders not had indicated previously that the Hill coefficient for this
only affects the secretion of PTH from the parathyroid response was ⬃3.1, suggesting that multiple calcium bind-
glands, but also causes local dysfunction in other organs, ing sites may exist (834).
such as the kidney where calcium absorption is perturbed.
It should be noted that the CaSR can also be stimulated by
1. Structure and signaling other polyvalent cations (Mg2⫹, Pb2⫹, Cd2⫹, Fe2⫹, Ba2⫹,
Ni2⫹, Co2⫹, or Gd3⫹) and larger polycationic molecules,
The CaSR was first cloned by Brown et al. (134) in 1993 such as spermine, spermidine, putricine, protamine, and
from bovine parathyroid using a Xenopus oocyte expres- neomycin (134, 416, 880). Furthermore, several substances
sion cloning system. Cloning of the human CaSR followed can allosterically modify the receptor and potentiate its sen-
2 years later (366). The CaSR is a 1,028-amino acid protein sitivity to its direct agonists. These include pharmacological
that belongs to the superfamily of classic 7-transmembrane small molecule substances (calcimimetics) that are in clini-
domain G protein-coupled receptors (134, 366). It is mainly cal use for the treatment of conditions, such as secondary
expressed as a homodimer on the cell surface (55). The hyperparathyroidism, and L-type amino acids, which en-
dimerization process has been shown to take place in the ER able the CaSR to act as a nutrient sensor (220). Truncation
and is mediated by the formation of disulfide bonds be- studies have demonstrated that the Venus fly trap motif is
tween cysteine residues (C129, C131) and noncovalent in- necessary for allosteric modification by L-type amino acids
teractions of leucine residues (L112, L156) in the extracel- (759). The affinity of calcium to the CaSR can also be mod-
lular domain of the receptor (54, 529, 858, 888, 1213). ulated by changes in extracellular pH (279, 879). An acidic
Following assembly in the ER, the CaSR undergoes extracellular milieu has been shown to decrease the sensi-
N-linked glycosylation in the Golgi apparatus, some of tivity of CaSR to its agonists, whereas an increased extra-
which is pivotal for cell surface expression (887). The traf- cellular pH has converse effects (879).
ficking between ER and Golgi apparatus is regulated by the
small GTP-binding protein Rab1 (1221). Knockdown and The intracellular domain of CaSR contains five PKC phos-
mutations of Rab1 in HEK cells results in decreased num- phorylation sites (366). Mutational analysis demonstrated
bers of CaSR at the cell surface (1221). Conversely, the that PKC-mediated phosphorylation of the CaSR at Thr-
internalization of CaSR is thought to be mediated by ubiq- 888 blunts its response to extracellular calcium, as evi-
uitination by the E3 ligase dorfin (498). denced by inhibited calcium release from intracellular

Calcium-sensing receptor
Kidney
Proximal tubule Distal convoluted tubule Collecting duct
CaSR CaSR
CaSR
HPO42– CaSR CaSR

NaPi-IIa
Na+ H+
Ca2+
V-ATPase
TRPV5
25(OH)-vitamin D CaSR

CaSR
Mitochondria:
CYP27B1
H2O
1,25(OH)2-vitamin D
AQP2
Intestine
Thick ascending limb of
the loop of Henle Enterocyte
ROMK
1
K+ CaSR
CaSR
2
NKCC2
CaSR
Na+
CFTR
2Cl–
1
Cl–
K+
3
2
Ca2+
H2O
Stomach Bone
PPIs G-cell
CaSR CaSR CaSR
APAs
CaSR
H+
H,K-ATPase
K+ ? ?
RANKL RANK
Gastrin Differentiation
CaSR ?
and function H+
Osteoblast Osteoclast
ECL-cell +
parietal cell
activation Circulation V-ATPase
Parietal cell
FIGURE 8. CaSR in the gastrointestinal tract, kidney, and bone. Kidney: the effects of CaSR activation on ion
transport in various nephron segments are shown. In the proximal tubule, CaSR stimulates phosphate
absorption and 1,25(OH)2-vitamin D synthesis. In the thick ascending limb of the loop of Henle, CaSR inhibits
apical potassium channels (ROMK), thereby inhibiting NKCC2 (potassium recycling). The resulting changes in
the lumen-positive potential inhibit paracellular calcium uptake. In the distal convoluted tubule, CaSR presum-
ably stimulates apical calcium entry through TRPV5. In the collecting duct, CaSR stimulates proton extrusion
through the V-type ATPase and inhibits urine concentration through AQP2. Stomach: in the parietal cell, CaSR
induces acid secretion by activating H⫹-K⫹-ATPase. In the G-cell, CaSR activation results in gastrin secretion.
Of note, CaSR serves as a luminal nutrient and calcium sensor on the G-cell. Bone: CaSR on osteoblasts
presumably regulates their differentiation and RANKL expression. Intestine: in the intestine, CaSR activation
reduces water secretion by inhibiting chloride secretion through CFTR.

stores (56, 246). The phosphorylation occurs in response to was shown that increases in calcium can potentiate the in-
receptor activation and thus represents an autoinhibitory hibitory effects of 1,25(OH)2-vitamin D (930). This effect is
feedback mechanism (246). ␤-Arrestins are most likely in- most likely mediated by CaSR, whose activation can decrease
volved in the process of PKC-associated desensitization PTH transcription by augmenting the inhibitory effects of
(681, 853). Conversely, dephosphorylation of the Thr-888 1,25(OH)2-vitamin D. Molecularly this is achieved by upregu-
residue is carried out by a calyculin-sensitive phosphatase, lating the expression of the VDR (151, 162, 362, 653, 916).
thereby restoring the receptor’s initial sensitivity (246). An- The current working model states that activation of CaSR
other mechanism of desensitization is mediated by a G pro- causes an increase of arachidonic acid metabolites and activa-
tein receptor kinase (GRK), most likely by interfering with tion of the MAPK pathway, which in turn results in increased
G␣q regulated pathways (see below) (681, 853). VDR mRNA levels (FIGURE 6) (151). This allows the parathy-
roid to adjust its 1,25(OH)2-vitamin D sensitivity to the cur-
Once stimulated, the CaSR activates a variety of intracellu- rent plasma calcium levels.
lar signaling cascades. Being a GPCR, most of these pro-
cesses are mediated by G proteins. Specifically, G␣q/11, G␣i, The molecular mechanisms underlying the trophic effects of
and G␣12/13 have been shown to be coupled to the CaSR CaSR activation are less clear. Earlier observations had al-

(40, 175, 495, 849). The expression of all subunits was ready suggested that hypocalcemia is associated with para-
confirmed in bovine parathyroid (1115). G␣i mediates the thyroid cell proliferation (778). Currently, the CaSR spe-
suppression of cAMP levels by inhibiting adenylyl cyclase cific calcimimetics provide the most useful insight into the
and activates the ERK/MAPK pathway (175, 250, 375, regulation of parathyroid growth by CaSR. Calcimimetics
572). Activation of G␣q/11 results in increased intracellular administered in the context of both animal models and
calcium concentrations via activation of PLC and IP3 trig- clinical studies of hyperparathyroidism demonstrate that
gered calcium release (133, 1010). As demonstrated in HEK activation of CaSR leads to a reduction in gland size
cells, this cascade can also activate further downstream (510, 589, 746, 1128). Conversely, inactivating muta-
phospholipase A2 leading to production of arachidonic acid tions of CaSR result in parathyroid enlargement. Para-
metabolites (415). G␣12/13 is thought to regulate phospho- thyroid-selective genetic disruption of G␣q was further-
lipase D and phosphatidylinositol 4-kinase (PI 4-K); how- more shown to cause moderate hyperparathyroidism
ever, this interaction has only been demonstrated in heter- with increased plasma PTH levels and gland hyperplasia,
ologous cell culture system (494, 495). suggesting a role of G␣q in the regulation of parathyroid
cell growth (849). Similar findings were reported in
2. CaSR in the parathyroid G␣q/11 double KO animals (1159).
CaSR regulates parathyroid function at three levels: 1) the 3. CaSR in the kidney
release of PTH from secretory granules, 2) de novo synthe-
sis of PTH, and 3) parathyroid cell growth. The CaSR acts as an important regulator of ion and water
homeostasis in the kidney. It should be noted that it can
Activation of CaSR by increasing plasma calcium results in exert its effects on calcium transport independently of other
an inhibition of PTH release, thereby lowering calcium lev- hormonal regulators, such as PTH and 1,25(OH)2-vitamin
els. It is thought that this response is mediated by the gen- D. The CaSR is expressed along most of the nephron, albeit
eration of arachidonic acid metabolites via G␣q and PLA2 in varying subcellular localizations (FIGURE 8) (907, 908).
activation (FIGURE 6) (121, 152). Cultured porcine parathy- In the proximal tubule, CaSR is localized apically at the
roid cells demonstrated an increase in arachidonic acid pro- base of the brush border, where it has been implicated to
duction after CaSR stimulation while PTH release was in- play a role in phosphate transport (52, 907, 909). The pri-
hibited (121). Furthermore, exogenous administration of mary regulator of phosphate transport in the proximal tu-
arachidonic acid suppressed PTH release from the parathy- bule of the kidney is PTH. In brief, increased PTH levels
roid cells (121). Similar effects were demonstrated for the inhibit phosphate reabsorption from the lumen. Activation
arachidonic acid metabolites 12- and 15-hydroxyeicosatet- of the apical CaSR can partially reverse the effects of PTH
ranoic acid, suggesting that they represent the downstream and restore phosphate absorption (52). Conversely, PTH
effectors of arachidonic acid production (120). and high phosphate levels reduce CaSR expression (909).
Furthermore, it is likely that the CaSR mediates the inhibi-
Apart from directly controlling PTH release, CaSR also tory effects of calcium on 1,25(OH)2-vitamin D synthesis in
modulates PTH synthesis. PTH gene transcription is mainly the proximal tubule (109, 702).
regulated by 1,25(OH)2-vitamin D. Binding of 1,25(OH)2-
vitamin D to the VDR causes a decrease in pre-pro-PTH In the thick ascending limb of the loop of Henle, CaSR is
mRNA levels creating a negative-feedback loop (154, 930, located on the basolateral membrane (907). In this nephron
931). However, it was recognized before the identification segment, the receptor acts as a major modulator of mon-
of the CaSR that serum calcium can modulate the actions of ovalent and polyvalent ion absorption. Activation of CaSR
1,25(OH)2-vitamin D on PTH gene transcription (930). It leads to an inhibition of the apical renal outer medullary

potassium (ROMK; Kir1.1) channel, mainly through ara- of calcium kidney stones is dependent on luminal pH, it has
chidonic acid metabolites created by PLA2 (1147, 1148). been speculated that this may represent an autoprotective
Apical ROMK releases potassium ions into the lumen, mechanism that prevents nephrolithiasis (901). Further-
which in turn are needed to fuel apical ion uptake through more, stimulation of apical CaSR in the principal cells of the
the Na⫹-K⫹-2Cl⫺ (NKCC2) cotransporter. By decreasing collecting duct leads to decreased ADH (vasopressin)-stim-
apical potassium efflux, CaSR inhibits sodium and chloride ulated water reabsorption through AQP2 (FIGURE 8) (942,
uptake through NKCC2 (906). This correlation is reflected 943). Taken together, activation of CaSR has diuretic ef-
in much earlier observations, which report that calcium fects via inhibiting NKCC2 in the thick ascending limb of
infusions can decrease tubular sodium clearance (300, 718, the loop of Henle and by inhibiting AQP2-mediated water
1052). In addition, impairment of NKCC2 has also impli- reabsorption the collecting duct.
cations for calcium absorption. Reduced NKCC2 activity
decreases the lumen-positive potential and negatively af- 4. CaSR in the gastrointestinal tract
fects countercurrent multiplication, and in consequence the
nephron’s ability to concentrate urine (434). Both mecha- The CaSR is distributed along most of the gastrointestinal
nisms will lead to impaired calcium absorption (434). Cal- tract, ranging from the stomach to the large intestine (186,

cium absorption in the medullary portion of the thick as- 360, 744, 932, 998). We are now only slowly beginning to
cending limb is thought to occur predominantly as passive unravel its function in this diverse array of tissues. In the
uptake through the paracellular route (995). Similar obser- stomach, CaSR localizes to the basolateral membrane of
vations have been made when blocking NKCC2 pharmaco- the acid-secreting parietal cells and to all membranes of the
gastrin-secreting G-cells (FIGURE 8) (142, 182, 886). Pri-
logically with the loop diuretic furosemide (299). It has thus
mary cultures of G-cells were shown to release gastrin after
been proposed that activation of basolateral CaSR has
stimulation of the CaSR with calcium (142, 886). The re-
“loop diuretic-like” effects, reducing NaCl but also calcium
lease is mediated via calcium influx into the cytosol through
absorption in the kidney (434).
nonselective cation channels opening after CaSR stimula-
tion (142). These findings provide the molecular basis for
In contrast to the medullary section, the cortical portion of
the observation that rises in serum calcium can increase
the thick ascending limb has been proposed to have pre-
serum gastrin levels (see sect. IIB2). The apical expression of
dominantly active calcium uptake properties, which are un-
CaSR in G-cells theoretically enables it to act as a luminal
der the hormonal regulation of PTH and calcitonin (344,
nutrient sensor modulating gastric acid secretion and other
509). PTH increases calcium absorption in this segment,
parameters. In recent studies there is direct evidence show-
and it has been shown that, similarly to phosphate absorp- ing that gastrin levels increase in mice after calcium and
tion in the proximal tubule, activation of CaSR can sup- L-type amino acid ingestion (325). This effect was abol-
press the effects of PTH (264, 754). The absorption of NaCl ished in CaSR (⫺/⫺) animals (325). In healthy human test
does not seem to be affected by CaSR (264, 754). subjects, pharmacological stimulation of CaSR leads to a
concomitant increase in gastrin levels and gastric acid out-
The distal convoluted tubule and the connecting tubule are put (165). CaSR on G-cells was thus postulated to play an
responsible for the fine-tuning of calcium reabsorption in important role in the gastric phase of acid secretion by
the kidney. To achieve this goal, they are equipped with maintaining acid output by maintaining gastrin secretion
molecular machinery, similar to that in the duodenum (325).
(TRPV5, calbindin-D 28k, NCX1, and PMCA1b) to ab-
sorb calcium against its electrochemical gradient through Apart from being expressed on G-cells, CaSR is also local-
the transcellular pathway (680). In analogy to the proximal ized on the basolateral membrane of the acid-secreting pa-
small intestine, these transporters are predominantly regu- rietal cell, where it exerts effects that are independent of
lated through 1,25(OH)2-vitamin D, but also PTH. CaSR gastrin and other secretagogues. Activation of parietal cell
colocalizes with TRPV5 in this segment (1090). Its activa- CaSR has been reported to increase H⫹-K⫹-ATPase-medi-
tion causes increase calcium influx through TRPV5 and ated proton secretion, thereby acidifying the gastric lumen
may thereby locally and rapidly adapt active absorption to (FIGURE 8) (145, 291, 373). This stimulatory effect was
the urine calcium concentration (FIGURE 8) (1090). demonstrated for direct activators, such as calcium or
Gd3⫹, but also allosteric modifiers, such as L-type amino
Apart from regulating calcium and phosphate absorption in acids (145, 291, 373). In parallel to other tissues, the intra-
the kidney, CaSR modulates proton and water movement in cellular activation signal for H⫹-K⫹-ATPase is mediated by
the collecting duct. In the intercalated cells of the collecting rises in intracellular calcium, PLC, MAPK, and PKC (899).
duct, apical V-ATPase acidifies the urine in an effort to In conclusion, both rises in luminal and plasma calcium
maintain systemic acid-base homeostasis. It has been shown concentrations can induce gastric acid secretion either indi-
that luminal calcium and neomycin can induce V-ATPase rectly through gastrin release or directly through parietal
activity via activation of CaSR, thereby causing proton se- cell activation. The physiological significance of this obser-
cretion into the urine (FIGURE 8) (901). Since the formation vation remains the subject of speculation, but may be linked

to facilitating calcium uptake by increasing acid output. As comitant genetic ablation of the parathyroid gland or PTH
described in a subsequent section, it has been speculated secretion, however, revealed that the skeletal phenotype of
that gastric acid increases the bioavailability of ingested CaSR single mutation (⫺/⫺) could mostly be rescued, sug-
calcium (see sect. V). Alternatively, CaSR may primarily gesting that the skeletal abnormalities were due to high
function as a nutrient sensor in the stomach (amino acid circulating PTH levels rather than CaSR inactivation (598,
sensing), which maintains constant acid output in the gas- 1096). Furthermore, CaSR does not seem to be the exclu-
tric (apical G-cell sensing) and postprandial (basolateral sive calcium-sensing mechanism in osteoblasts, as changes
parietal cell) phase of digestion, when circulating levels of in extracellular calcium can still elicit functional responses
amino acids are high (325). in CaSR (⫺/⫺) osteoblasts (852). This observation has been
attributed to another GPCR with calcium-sensing capabil-
In the intestine, functional investigations on CaSR have ities, namely, GPRC6A (850, 851). Although GPRC6A has
mainly been conducted in colonic epithelia, where CaSR a higher activation threshold for calcium, it also responds to
localizes to both the basolateral and apical membranes of the CaSR allosteric activator R568 (851). GPRC6A activa-
the colonic crypt (173, 186, 360). Expression patterns vary tion may thus represent a confounding factor in most in
slightly in the small intestine, with general basolateral ex- vitro studies on osteoblasts and their modulation by CaSR.

pression and additional weak apical expression in the villus Also, GPRC6A knockout leads to osteopenia, further un-
(173, 360). Furthermore, CaSR is expressed in both the derlining the possibility of an alternate calcium-sensing
Meissner’s and Auberach’s plexuses. Early experiments on pathway in bone (850). Osteoblasts extracted from these
single perfused colonic crypts demonstrated that intracellu- GPRC6A-deficient animals show decreased sensitivity to
lar calcium concentrations could be increased when expos- extracellular calcium and in vitro mineralization defects
ing the crypts to classic CaSR agonists and that forskolin- (854).
stimulated fluid secretion could be inhibited (186). This and
subsequent investigations indicate that CaSR plays an im- Although these observations have profoundly questioned
portant role as a modulator of colonic fluid secretion (185, the physiological significance of CaSR in bone, closer ex-
186). Subsequently, attempts have been made to take ad- amination still favors a role of CaSR in bone turnover. With
vantage of the “constipatory” effects of CaSR activation in the recent advances in genetic methods, an osteoblast-spe-
pathophysiological settings. Activations of CaSR in the cific CaSR (⫺/⫺) model has been created (171). These ani-
course of diarrheagenic enterotoxin exposure was shown to mals have severely stunted growth and skeletal develop-
decrease fluid secretion via increased breakdown of cyclic ment, clearly suggesting an involvement of CaSR in normal
nucleotides (371). Although the potential clinical applica- osteoblast function (171). The previous conflicting evidence
tions of ameliorating the symptoms of secretory diarrhea gained from global CaSR (⫺/⫺) models with survival rescue
are promising, more efforts will have to be made to fully by elimination of PTH synthesis have been attributed to the
unravel the physiological role of CaSR in intestinal ion and possible expression of alternate CaSR splice variants, which
fluid transport. So far it is not clear whether intestinal CaSR may compensate for the deletion of full-length CaSR in
can modulate calcium absorption, as is the case in the kid- these animals (171, 915). In an attempt to further elucidate
ney. the function of CaSR in osteoblasts, the reverse approach
has been executed by specifically upregulating CaSR in os-
5. CaSR in bone teoblasts with use of a constitutively active receptor mutant
(296). Upregulation of CaSR results in bone loss, as evidenced
It is well established that CaSR is expressed in osteoblasts, by a decrease in bone volume and density, specifically of tra-
osteoclasts, and their respective precursors (172, 174, 542, becular bone (296). These findings are accompanied by an
1183–1185, 1192). The functional role of CaSR in these increased number of osteoclasts, whereas osteoblast parame-
cells is, however, less clear. Undoubtedly, both cell lines are ters were essentially unchanged (296). Activation of CaSR has
exposed to local fluctuations in calcium concentrations been speculated to promote RANKL production by osteo-
making an adaptive response to the calcium environment blasts, which serves as an osteoclastogenic signal (296). Osteo-
plausible. Indeed, changes in extracellular calcium concen- blasts may thus recruit osteoclasts and induce their maturation
tration have been shown to regulate various cell functions, via CaSR signaling and increased RANKL expression, which
mostly in in vitro models. Extracellular calcium can stimu- would explain the observed increase in bone turnover and
late the proliferation, migration, and differentiation of os- osteoclast numbers in the setting of constitutive CaSR activa-
teoblasts (174, 297, 1183, 1184, 1186). Similarly, calcium tion (241).
was proposed as a differentiation signal for osteoclasts
(542, 544, 734). Significant doubt about the in vivo impor-
tance of CaSR in bone has emerged with the generation of V. THE STOMACH AND CALCIUM
the CaSR (⫺/⫺) mice. Although CaSR knockout results in
rickets, these animals suffer from severe hyperparathyroid- Preceding parts of this review have independently summa-
ism, which did not allow a discrimination between the ef- rized the physiology of acid secretion, intestinal calcium
fects of high PTH and CaSR on bone turnover (365). Con- absorption, and their respective regulation. The following

section will attempt to illustrate the functional intersections tigations came to lower prevalence results of ⬃5–10%
between these seemingly unrelated fields. In particular, the (1091). The osteomalacia was also shown to translate into
question of whether acid is needed to absorb calcium effec- an increased incidence of fractures in these patients (795).
tively from the gut or whether the stomach contributes to Naturally, gastrectomy represents a radical intervention,
the regulation of calcium homeostasis by secretion of an and the reasons for this correlation may be multifactorial,
endocrine substance will be investigated. but reduced acid output may be of significance.
Back in the field of PPIs, the seminal epidemiologic investi-

A. Proton Pump Inhibitors and the Risk gation by Yang et al. was subsequently followed up by a
of Fracture number of studies, which also focused on other types of
fractures, other populations, and other drugs reducing gas-
In May 2010, the Food and Drug Administration (FDA) tric acid output, such as H2 receptor antagonists (202, 228,
released the following safety announcement: “Healthcare 252, 394, 400, 559, 868, 923). Although their conclusions
professionals and users of proton pump inhibitors should were somewhat controversial, a recent meta-analysis sup-
be aware of the possible increased risk of fractures of the ports the initial hypothesis that a correlation between PPI

hip, wrist, and spine with the use of proton pump inhibi- intake and fracture risk (hip, spine, and any-site fractures)
tors, and weigh the known benefits against the potential exists (1195). The meta-analysis considered 11 studies and
risks when deciding to use them” (319). identified an overall odds ratio of 1.30 for all fracture types
combined (1195). There was no association between H2
Proton pump inhibitors (PPIs, see sect. IIC1) are in wide- blocker intake and an increase in fracture risk, although
spread use for the treatment of acid-related disorders, such some single studies supported a link (228, 1195). Another
as gastroesophageal reflux disease (GERD) or gastric ulcer meta-analysis came to a comparable conclusion with regard
disease. They exert their curative effects by inhibiting the to an increased fracture risk under PPI exposure (616).
acid output of the stomach. Over the recent years, mostly
epidemiological evidence has accumulated which links the
intake of PPIs to an increased risk of sustaining fractures, B. Gastric Acid and Intestinal
especially in the elderly population. Yang et al. (1190) pub- Calcium Uptake
lished one of the earliest and largest studies investigating
this potential correlation in 2006. Examining a population A variety of reasons could theoretically account for the
of over 13,000 hip fracture cases and over 135,000 controls observation that PPIs increase the likelihood of fractures.
over the age of 50, the authors concluded that long-term The most prominent hypothesis assumes that the reduced
(over 1 year) PPI use was associated with an increase in hip acidity in the stomach impairs the intestinal absorption of
fractures (AOR ⫽ 1.44) (1190). Although the likelihood of dietary calcium. This assumption is based on both patient
sustaining a fracture following PPI intake may seem fairly observations and experimental animal data. Alas, the num-
low, the implications for public health are substantial. This ber of animal studies, which in contrast to investigations in
has multiple reasons: PPIs represent the third most com- humans per default allow more radical experimental de-
monly prescribed medication in the United States and are
signs and genetic manipulation, is very small.
also available as over-the-counter formulations. Further-
more, there is an ongoing debate whether PPIs are overpre-
scribed, putting certain populations at unnecessary risk of 1. Effects of gastrectomy, vagotomy, and PPIs on
side effects. In combination with the high incidence of os- mineral metabolism in humans
teoporotic fractures, the mean incidence of hip fractures
alone between 1986 and 2005 was 957 per 100,000 women Before discussing the reports that try to correlate PPI use
over the age of 65 per year, a small increase in risk suddenly with calcium uptake, it is worthwhile to examine older
has implications for a very large population (123). literature on patients that had undergone partial or total
gastrectomy. As discussed previously, these procedures are
The roots of this controversy may potentially be traced back known to be linked to bone disease. In contrast to PPIs,
to the 1940s and 1950s. Before the advent of PPIs, total and which eliminate the singular factor of acid secretion, gas-
partial gastrectomies or vagotomies were performed to con- trectomies also influence gastric emptying, the emulsifica-
trol acid-related disorders. It was soon apparent that pation of food stuffs, and food habits. It is thus more difficult
tients who underwent these radical surgical procedures de- to draw conclusions on the influence of acid secretion on
veloped osteoporosis/-malacia (58, 305, 732, 876). A study calcium absorption from gastrectomized patients than from
that assessed the prevalence of osteomalacia in gastrecto- individuals on PPI therapy. A further caveat lies in the type
mized patients concluded that up to 12% of patients (19% of gastrectomy, as different surgical procedures are and
of females) had histologically overt osteomalacia, although were in use. Some surgeries bypass the duodenum (Billroth
general disturbances in calcium metabolism were estimated II, Roux-en-Y, total gastrectomy), whereas some leave the
to occur in up to 28% of patients (208, 368). Other inves- duodenal passage intact (Billroth I).

A common finding among gastrectomized patients is their calcium uptake, albeit the number of studies on this cohort
low 25(OH)-vitamin D levels, while levels of 1,25(OH)2- is very limited. Vagotomy abolishes the parasympathetic
vitamin D seem to be increased (101, 244, 378, 511, 794, input to the stomach and thereby decreases the amount of
972, 1081). The pathophysiological reason for this is not secreted acid. Although the gross anatomy of the stomach
entirely clear. It has been argued that bone disease and low remains intact, other parameters, such as gastrin levels, are
25(OH)-vitamin D are a result of impaired vitamin D ab- also deranged given the important role of the vagus nerve in
sorption following surgery; however, the consensus seems the regulation of gastric acid secretion (see sect. IIB). While
to be that uptake rates of vitamin D is not impaired in these bone disease is generally not reported in these patients, low
patients (245, 378; contested by Ref. 1081). The vitamin D 25(OH)-vitamin D levels are common (514, 793). Similarly
insufficiency may also be a byproduct of improper nutrition to gastrectomy, the 1,25(OH)2-vitamin D levels are con-
(378). As fat and milk intolerance can develop, especially in comitantly elevated, suggesting adaptive upregulation po-
surgeries which exclude the duodenum (Billroth II), a tentially to compensate for decreased calcium absorption
change of dietary habits with insufficient intake of the fat- (793). As discussed previously, the decreased 25(OH)-vita-
soluble vitamin D may be an underlying cause. Indeed, min D could be indicative of augmented catabolism of the
long-term longitudinal studies suggest that maintaining vitamin (244). Serum calcium is commonly decreased or in

body weight reduces the risk of developing bone disease the lower normal range, while intestinal calcium absorption
after gastrectomy, which emphasizes the role of adequate is increased, presumably in response to elevated 1,25(OH)2-
nutrition (667, 668). On the other hand, Billroth I and II vitamin D (110, 974). Secondary hyperparathyroidism does
patients show the same loss in bone density, although Bill- not manifest (793, 974).
roth II surgery (bypassing of the duodenum) is associated
with a much higher degree of fat malabsorption (110, 651). In general, the disturbance in mineral metabolism is more
A different investigation even concluded that Billroth I pa- pronounced in gastrectomized patients than in vagoto-
tients have a higher loss in bone density than Billroth II mized patients, as evidenced by the higher incidence of bone
patients (794). A more recent report suggests that the prob- disease and secondary hyperparathyroidism. It is challeng-
lem underlying bone disease after gastrectomy may be im- ing to draw clear conclusions on the influence of gastric acid
paired calcium absorption, rather than dietary vitamin D on calcium absorption in either patient group. Yet, it is
deficiency (244). It has been shown that high 1,25(OH)2- apparent that compensatory mechanisms are in place in
vitamin D levels accelerate the breakdown of 25(OH)-vita- these patients, as evidenced by the increased 1,25(OH)2-
min D (210 –212, 244). The observed low 25(OH)-vitamin vitamin D and PTH levels. Less efficient calcium uptake due
D levels in gastrectomized patients may thus be a byproduct to decreased acid output may be one explanation for this,
of increased catabolism, and not insufficient intake, but without further analysis this conclusion remains specu-
whereas the high 1,25(OH)2-vitamin D levels may represent lative.
compensatory upregulation due to insufficient calcium ab-
sorption or intake (244). Calcium absorption in gastrecto- With the advent of PPIs and H2 blockers, the number of
mized patients (Billroth I ⫹ II) has been reported to be in the surgical interventions to control acid-related disorders de-
low-normal range, while 1,25(OH)2-vitamin D levels are creased massively. Given their high specificity, PPIs selec-
increased (794). In line with these findings, secondary hy- tively eliminate gastric acid output. Several investigations
perparathyroidism, an indicator of compensatory upregu- that try to tie PPI intake to a disturbance in mineral metab-
lation due to low serum calcium levels, is a known finding olism exist. Graziani et al. (396) observed in eight healthy
after gastrectomy (101, 244, 1171). Other investigations on volunteers that postprandial calcium concentrations did
intestinal calcium absorption in gastrectomized patients not increase in subjects on a PPI regime (omeprazole 20 mg
came to very contradictory results, ranging from increased 3⫻ daily), whereas control subjects demonstrated a clear
to impaired absorption (8, 34, 255, 398, 585, 794). Many spike in serum calcium levels. Urine calcium excretion was
of these reports failed to assess 1,25(OH)2-vitamin D and also reduced compared with the control group (396). A
PTH levels, which means that adaptive mechanisms may similar effect of PPIs was later observed by two independent
mask the insufficient baseline uptake of calcium in the in- groups in patients undergoing hemodialysis (395, 423). It
testine (8, 34, 255, 398, 585, 794). In conclusion, the exact should be noted that neither of these studies directly as-
pathogenesis of postgastrectomy osteopenia remains some- sessed intestinal calcium absorption, but rather measured
what unclear. The disorder may be attributable to vitamin serum calcium as an indirectly related parameter. More
D insufficiency, impaired calcium absorption, inappropri- recently, intestinal calcium absorption was measured by
ate diet, or a combination of all factors. O’Connell et al. (807) using a radiolabeled calcium isotope.
The investigators reported that 7 days of PPI (omeprazole
The intrusiveness of gastric surgery makes it difficult to 20 mg 1⫻ daily) intake significantly reduced calcium ab-
dissect the influence of gastric acid on these parameters. sorption in elderly women under fasting conditions com-
This is why vagotomized patients are a somewhat more apt pared with the placebo group. Although these studies sup-
patient population to study the effects of gastric acid on port a role of PPIs in reducing calcium uptake, conflicting

evidence exists. Several investigations that assessed calcium total gastrectomy causes massively reduced calcium uptake
absorption using radioactive tracers and a whole gut lavage and secondary hyperparathyroidism (700). In this study,
technique found no evidence for a decrease in absorption the duodenum was surgically bypassed by esophagojeju-
under short-term PPI treatment (421, 991, 1173). It is not nostomy, thereby eliminating the site of maximal active
clear why these discrepancies in the outcomes of the trials calcium absorption and limiting the conclusion that can be
exist. There is, however, variability in the experimental drawn (700).
technique to measure calcium uptake, the cohorts investi-
gated (young vs. postemenopausal women vs. dialysis pa- In addition, several reports of vagotomy in a rat model
tients) and the form of calcium administration (calcium are available to us (49, 307, 308, 928). It has been dem-
salts vs. whole meals), which may partially account for the onstrated that vagotomy alone has no effect on the rate of
divergent results. Indeed, different calcium salts are ab- intestinal absorption (307, 928). Secondary hyperpara-
sorbed with different effectiveness in acid suppressed indi- thyroidism was observed by one group, while PTH levels
viduals, which will be subject of later discussion (see sect. were reported to be unaffected by the other group (307,
VC). Furthermore, different populations may have different 928). 1,25(OH)2-vitamin D was not measured, which
capacities for endocrine compensation. would have provided further evidence of compensation

due to decreased calcium bioavailability. However, if va-
In summary, it is experimentally difficult to unmask the gotomy and parathyroidectomy are performed together,
potential correlation between a reduction in gastric acidity intestinal calcium absorption is significantly impaired
and calcium absorption, given our body’s high capacity for compared with vagotomy or parathyroidectomy alone
compensation. In addition, slight alterations in mineral ho- (307). This is in accordance with the low serum calcium
meostasis may take years to manifest themselves clinically, concentrations found in gastrectomized and parathyroid-
for example, in osteopenia or fractures. Without following ectomized rats (49).
up on test subjects on a long-term basis, snapshot measure-
ments which may still lie within clinically normal range can PPIs were also used to relate acid secretion to bone dis-
be misleading. ease in rats. Bone weight did not change in rats that were
treated for 4 wk with omeprazole (841). Alas, calcium
2. Effects of gastrectomy, vagotomy, and PPIs on absorption was not measured in these animals, and a
mineral metabolism in the animal model decrease in bone weight represents a very terminal and
long-term outcome. A more recent investigation by
To further elucidate the problem of osteopenia following Schinke et al. (963) demonstrates that mice which have
gastrectomy or PPI use, several animal studies tried to rep- been genetically manipulated to be achlorhydric (CCK2
licate and expand the observations made in human test ⫺/⫺) have decreased serum calcium levels as well as de-
subjects. velop osteoporosis and secondary hyperparathyroidism
in an effort to maintain calcium balance (963). This study
For example, Axelson et al. (49) measured serum calcium is especially noteworthy, as acid secretion is knocked out
concentrations in rats who had undergone parathyroidec- selectively in this mouse model while the stomach re-
tomy and various surgical procedures to reduce gastric acid mains intact (stomach morphology). Furthermore, a ge-
output (vagotomy, antrectomy, gastrectomy). While para- netic mutation that has been associated with osteopetro-
thyroidectomy alone predictably reduced serum calcium sis (a disease characterized by increased bone density)
levels, the gastric operations (with intact parathyroid due to osteoclast malfunction was also shown to cause
glands) had little to no effect on calcium concentrations decreased gastric acid secretion. These patients present
(49). Interestingly, intestinal calcium absorption was even with lower serum calcium values. Rather than being a
increased in the latter group. The authors attributed this product of impaired bone resorption (osteoclast defect),
observation to a compensatory upregulation of PTH secre- the hypocalcemia may thus be related to impaired intes-
tion and concomitant 1,25(OH)2-vitamin D production. To tinal calcium absorption (gastric acid secretory defect)
eliminate this factor, gastrectomy or fundectomy was con- (963).
ducted after parathyroidectomy, thereby depriving the ani-
mals of their compensatory machinery. This intervention C. Calcium Salts
resulted in massive hypocalcemia and death after a few
days, which led the authors to conclude that acid secretion Many investigators have employed calcium salts to de-
is important for the maintenance of calcium homeostasis termine the efficacy of intestinal calcium absorption. Fur-
(49). Another investigation in rats that had undergone thermore, calcium salts are in wide clinical use as a di-
antrectomy (Billroth I) observed a significantly decreased etary supplement. As will be discussed in this section,
absorption of calcium (345). Fundectomy did not affect calcium salts differ in their bioavailability, which not
calcium absorption (927). However, both studies employed only represents a potential source of error in experimen-
the balance method to calculate calcium absorption, which tal designs, but more importantly, has extensive clinical
is considered less accurate than using radiotracers. In pigs, implications.

Calcium salts represent the most common supplementation (520). The group reported that absorption of calcium car-
form of calcium for individuals who do not meet their ad- bonate was severely impaired in four male patients suffering
equate daily intake. The indications for supplementation from achlorhydria (520). Compared with five control sub-
can be diverse, but mostly include conditions such as osteo- jects, who absorbed between 9 and 18% of the ingested
porosis/-penia or preventative intake after menopause, dur- calcium carbonate, these patients only absorbed 0 –2%. In-
ing glucocorticoid intake or if lactose intolerant. In the year terestingly, when gastric acid secretion of one of these pa-
2000, the National Health Interview Survey concluded that tients was stimulated by administration of betazol hydro-
11% of Americans ingest calcium supplements on a daily chloride (a histamine analog), calcium carbonate absorp-
basis (739). Females account for 80% of this population, tion rose from 2 to 10% (520). This investigation somewhat
mostly to ensure supply after menopause (739). Calcium spawned the entire controversy of whether gastric acid is
salts exist in multiple formulations. The most commonly necessary to absorb calcium effectively from the intestine. A
used salts are calcium carbonate, calcium citrate, calcium similar investigation was conducted later by Recker
lactate, and calcium gluconate. Calcium carbonate is the (891) in a larger sample of achlorhydric patients. The
most widely used formulation, because it contains the high- investigator concluded that 1) control subjects absorb
est percentage of elemental calcium per weight (40%), calcium carbonate and calcium citrate equally well,

which equates to small tablet size and easier ingestion (997). 2) but that achlorhydric patients lose their capability to
In comparison, calcium citrate contains 21% elemental cal- absorb calcium carbonate, while calcium citrate absorp-
cium, calcium lactate 14%, and calcium gluconate 9% tion is increased (presumably through compensatory up-
(997). However, the calcium salts do not only differ in their regulation of the absorption via vitamin D) (891). It is
calcium fraction, but are massively divergent with regard to important to mention that these absorption assays were
their solubility in water. Calcium carbonate is the least wa- conducted in the fasting state. When the achlorhydric
ter-soluble salt at a neutral pH. For example, calcium citrate patients ingested the calcium carbonate salt together with
dissolves 17 times more readily in water than calcium car- a meal, their calcium uptake normalized. It cannot be
bonate (997). Very fundamental in vitro solubility experi- conclusively answered which factor of the meal was re-
ments have shown that after 1 h in 500 ml of water only 1% sponsible for the increase, as several food components,
of the initial 500 mg of calcium carbonate are dissolved at such as fiber and protein, are known to affect calcium
37°C (997). The solubility of calcium carbonate can be uptake. However, the authors speculated that the pH
greatly improved by an acidic environment (390, 997). Ad- (5.8) of the meal was sufficiently low to dissolve the
justing the pH to 5.5 in the same experiment dissolves 86% ingested calcium carbonate (891). Furthermore, a previ-
of the calcium carbonate; further lowering it to 2.5, a value ously cited study that demonstrated decreased calcium
that can be expected in the stomach, increases the dissolved absorption under PPI therapy employed calcium carbon-
fraction to 100%. Given these differences in solubility, a ate as source of calcium for the conducted measurements
plethora of studies have investigated the bioavailability of (807). Patients with gastric bypass surgery also absorb
the various calcium salts, mostly focusing on the difference calcium carbonate less effectively than calcium citrate
between calcium carbonate and calcium citrate. Again, the (1089). The importance of acid for the absorption of
conclusions are heterogenic. Several studies suggest that calcium carbonate was also demonstrated in the previ-
calcium carbonate is absorbed less effectively than the more ously discussed achlorhydric CCK2 (⫺/⫺) mouse model
soluble calcium citrate (422, 438, 439, 789), while others (963). The osteoporotic phenotype and secondary hyper-
conclude that there is no difference in bioavailability (432, parathyroidism in these achlorhydric mice could only be
433, 520, 547, 831, 832, 891, 997, 1038). A detailed anal- fully rescued by a high-calcium gluconate (2%) diet, but
ysis of the individual trials is beyond the scope of this re- not by a high-calcium carbonate (2%) diet (963). In the
view. It suffices to say that there is strong variability in the light of these reports, it is evident that although the bio-
experimental methods (direct absorption measurements vs. availability of calcium salts in the healthy individual may
measurement of postprandial serum calcium vs. urine ex- be equal, an impairment of acid secretion has a negative
cretion) and design of the studies (populations; administra- effect on the bioavailability of calcium carbonate, pre-
tion in the fasting state vs. with a meal). A confounding sumably because of decreased solubility. Given the fact
factor to the results of these studies may be the gastric pH at that calcium carbonate is the most commonly used for-
the time of the measurement. As discussed earlier, calcium mulation for calcium substitution therapy, these findings
carbonate is not very soluble at more alkali pH values, may partially account for the statistical correlation be-
which may have implications for patients using these sup- tween PPI use and the increased risk of sustaining frac-
plements while on PPI therapy (997). Furthermore, meals tures.
dramatically affect gastric pH and may change the bioavail-
ability of the supplements. Indeed, there seems to be a cor- Another factor that needs to be taken into consideration
relation between gastric pH and the absorbability of cal- when assessing solubility of calcium salts is the PCO2
cium carbonate. The first observation indicative of this as- (390). In the local milieu of the duodenum, the PCO2 can
sociation was made by Ivanovich et al. in the late 1960s reach values of up to 300 mmHg, resulting from the

pancreatic secretion of bicarbonate (929). Solubility ex- bone mineral density (BMD) in rat and murine models (261,
periments of calcium carbonate have shown that a high 357). Ghrelin also promotes the formation of new bone
PCO2 negatively affects its solubility, as the carbonate following injury (261). For example, mice that received a
enters equilibrium with CO2 (390). Compared with other standardized bone injury demonstrated 1.6 times more new
calcium salts, the particularly low bioavailability of cal- bone surface if treated with ghrelin compared with control
cium carbonate in acid suppressed patients may thus be a animals (261).
compounded effect of reduced acid secretion and a high
duodenal PCO2. Several studies aimed to identify a link between serum ghre-
lin levels and BMD in human populations. The most recent,
and one of the largest (n ⫽ 707 subjects), investigation
D. The Endocrine Stomach and
assessed BMD with peripheral quantitative computed to-
Calcium Homeostasis mography (pQCT). This technique allows for separate
analysis of trabecular and cortical bone. The results showed
Apart from being a mere acid secretory organ, the stomach
a positive correlation between ghrelin and trabecular BMD
also plays an important role as an endocrine organ. It
in elderly men and women (775). A different large-scale

should be noted that all of the aforementioned surgical or
study, investigating a similar cohort (n ⫽ 977) found no
pharmacological interventions, i.e., gastrectomies, vagoto-
association using dual-energy X-ray and single-photon ab-
mies, or pharmacological acid suppression therapy, will in-
sorptiometry (1157). These techniques, however, do not
evitably impact the endocrine functions of the stomach. It is
permit a discrimination between cortical and trabecular
therefore plausible that not only the changes in intragastric
bone. Other small-scale studies also came to contradictory
pH affect the absorption of calcium, but that the dysregu-
conclusions (388, 811). The reason for these discrepancies
lation of the endocrine stomach is responsible for changes in
is elusive. Since the formation of trabecular bone represents
calcium homeostasis. The following section will address
a more dynamic process, its direct measurement may be
how hormones that are secreted by the stomach may impact
calcium and bone homeostasis. more sensitive to subtle changes than overall bone density
measurement (775). Baseline plasma ghrelin levels were
also shown to be inversely correlated to type 1 collagen ␤
1. Ghrelin
C-telopeptide (␤CTX), a marker for bone resorption (501).
Ghrelin has been discovered fairly recently (1999) by Ko-
The source of ghrelin represents another potential caveat. In
jima and colleagues and is mainly implicated in regulating
vitro studies suggest that osteoblasts can also synthesize
food intake in the hypothalamus (588, 777). Ghrelin levels
ghrelin (254, 357). Ghrelin was identified on the mRNA
are inversely correlated with body mass and elevated in
conditions of fasting, such as anorexia nervosa (377). Ghre- and protein level by two investigations (254, 357). A differ-
lin is mainly synthesized and secreted in a pulsatile manner ent group did not find evidence for ghrelin in osteoblasts
by special neuroendocrine cells (P/D1 cells) in the fundic (214). This has important implications, as ghrelin may be
region of the stomach (242, 777). The influence of ghrelin secreted in an auto-/paracrine fashion, which would make
on gastric acid secretion is discussed in a separate section plasma ghrelin levels less significant for osteoblast activa-
(see section IIB5E). A few years after its discovery, it was tion. On the other hand, (partial) gastrectomy significantly
shown that ghrelin can also directly affect osteoblasts (254, decreases plasma ghrelin concentrations, which could con-
357, 576, 691). Ghrelin induces osteoblast proliferation tribute to postgastrectomy osteopenia, although these may
and differentiation and inhibits their apoptosis (357, 576, just be two independent factors. Total gastrectomy causes a
691, 1141). It is not entirely clear whether this effect is drop in plasma ghrelin levels by as much as 70% (528).
mediated via the ghrelin surface receptor, the growth hor- Partial gastrectomy also severely decreases plasma ghrelin;
mone secretagogue receptor 1a (GHS-R1a), or not. While however, levels normalize depending on the type of resec-
the receptor is expressed in rat and murine osteoblasts and tion to 48 – 88% of the preoperative levels due to compen-
its pharmacological inhibition abolishes the effects of ghre- satory production in the remaining gastric mucosa (528).
lin on differentiation and proliferation, no GHS-R1a This recovery already occurs after 7days. It thus remains to
mRNA could be detected in a human osteoblast cell line be elucidated if the slightly decreased ghrelin levels after
(254, 357, 691). It should be noted that this effect is inde- small gastric resections can account for the long-term phe-
pendent of growth hormone (GH). Ghrelin serves as a po- nomenon of postgastrectomy osteopenia. Furthermore, in
tent stimulator of GH secretion from the pituitary gland, mice, the reduction of bone mass after gastrectomy cannot
which in turn acts as an activator of osteoblasts through the be rescued by exogenous administration of ghrelin (277).
GH/IGF-I axis. However, the observations that 1) pharma- Ghrelin administration did also not affect markers of bone
cological inhibition of GHS-R1a attenuates the effects of resorption in gastrectomized patients, although these pa-
ghrelin and that 2) GH-deficient rats are still sensitive to rameters were only measured very acutely 4 h after ghrelin
ghrelin, suggest a direct effect on osteoblasts (357). In vivo, infusion (501). So far, no data on the effect of chronic
the activation of osteoblasts translates to an increase in ghrelin treatment on BMD are available.

Although decreased ghrelin levels could in theory be a con- replicated in chicken (842). The unknown hormone was
tributing factor to the reduction of bone mass following tentatively named ”gastrocalcin“ (844). When ghrelin was
gastrectomy, it is unknown if PPIs can directly affect ghrelin discovered, it was speculated that it might represent a can-
levels. A potential link between PPI-related fractures and didate hormone for gastrocalcin. However, unlike gastro-
ghrelin levels remains to be investigated. An indirect asso- calcin, ghrelin is not under gastrin control, making this
ciation may be present in patients with Helicobacter pylori proposition unlikely (276). Subsequent investigations sug-
infections. These infections represent a common indication gested that the origin of gastrocalcin were the gastric ECL
for PPI intake and were suggested to coincide with reduced cells. ECL extracts can indeed trigger a calcium second mes-
ghrelin in plasma and the gastric mucosa (527). Given the senger response in osteoblast (629, 630). Yet, functional
recent discovery of ghrelin’s impact on osteoblast function, evidence for gastrocalcin-mediated osteoblast activation is
many questions still remain to be answered. It is, however, still lacking. A recent report postulates that parathyroid
clear that our view of the stomach as a mere acid secretory hormone-like hormone (PTHLH) may in fact be gastrocal-
pouch needs to be expanded to a new level. cin (676). PTHLH exerts similar physiological effects as
PTH by sharing a common receptor and is commonly ele-
2. Gastrin vated in paraneoplastic syndromes (1056). PTHLH has

been identified in ECL cells, and its transcription has been
Gastrin represents one of the main acid secretagogues (see shown to be inducible by gastrin in parietal cells (523, 676).
sect. IIB2). It is secreted by specialized G-cells in the antrum Of note, PTH causes effects opposite to those assigned to
of the stomach and the duodenum. The released gastrin gastrin and gastrocalcin, namely, hypercalcemia. Further
enters the circulation and induces acid secretion in gastric studies will thus be needed to corroborate this hypothesis.
parietal cells via the CCK2 receptor. It has been hypothe-
sized fairly early that plasma gastrin may have an impact on Whatever the exact effector hormone of gastrin may be,
bone metabolism. Injection of gastrin and its synthetic an- changes in gastrin levels cannot entirely explain the clinical
alog pentagastrin was shown to decrease plasma calcium phenomenon of postgastrectomy osteopenia and PPI-re-
levels in pigs and rats in the 1970s (222, 980). This effect lated fractures. Although vagotomy and PPIs undoubtedly
was attributed to gastrin-stimulated release of calcitonin increase serum gastrin levels through a negative-feedback
from the thyroid gland. Indeed, pentagastrin was shown to mechanism, most partial and all total gastrectomies result
be a potent stimulator of calcitonin secretion in various in hypogastrinemia. Yet both hyper- and hypogastrinemic
species and is still in clinical use to evaluate thyroid C-cell conditions have similar outcomes, i.e., osteopenia and in-
hyperplasia and medullary carcinomas (155, 156, 226, 441, creased risks of fractures. It is, of course, plausible that
829). Although a clinical correlation between plasma gas- different factors contribute to this outcome in each individ-
trin levels and plasma calcitonin has been demonstrated by ual group. Gastrin may be involved in certain pathologies,
one study in patients with Zollinger-Ellison syndrome (hy- but given that its true impact on bone metabolism is some-
pergastrinemic patients) and in pigs, it is unclear if native what elusive, this assumption remains speculative.
gastrin, i.e., not pentagastrin, acts as an important secreta-
gogue for calcitonin in humans (224, 1020). In fact, other
investigations found no association between gastrin and
calcitonin levels in other cohorts (122, 454). Acid suppression
At least in the rat, the hypothesis of the gastrin-calcitonin

axis has been severely challenged. Although gastrin de-
creases plasma calcium levels in rats, the same effect occurs
Calcium solubility Gastrin
in (para)thyroidectomized animals, suggesting that calci-
tonin is not involved in this process (980). Furthermore,
cultured rat thyroid cells could not be stimulated to release ?
calcitonin if incubated with gastrin (225). Fundectomy- and
omeprazole-induced hypergastrinemia also did not affect
calcitonin levels in rats (843, 927). Interestingly, hypocal- Calcitonin
Intestinal absorption Pancreastatin
cemia after gastrin injection could not be induced in rats
that had been (para)thyroidectomized and gastrectomized
(844, 981). This observation led to the conclusion that gas-
trin may stimulate the release of an unknown substance
from the rat stomach, which in turn exerts calcitropic ac-
tivity. In accordance with this hypothesis, mucosal extracts PTH
from rat stomachs were shown to have the same hypocal-
cemic effects as gastrin and to stimulate uptake of radiola- FIGURE 9. Model summarizing the potential impact of acid sup-
beled calcium into the bone (844). These findings were also pression on calcium homeostasis.

3. Pancreastatin review we have focused on the important role calcium plays

as a first and second messenger in the maintenance of bone
Pancreastatin is a cleavage product of chromogranin A that health. By relying on a complex series of receptors, chan-
was initially isolated from porcine pancreas (1072). Gastric nels, and transport proteins, calcium is tightly controlled at
ECL cells are also known to harbor significant amounts of the cellular and tissue level to ensure its bioavailability to
chromogranin A and pancreastatin. Pancreastatin is se- bone. Modulations to any of these pathways by disease,
creted together with histamine from ECL cells in response mutation, or pharmaceutical perturbation can lead to clin-
to their neuroendocrine stimulation (see sect. IIB3) (176). In ical changes in bone health.
rat, it has been shown that the serum pancreastatin levels
correlate with the secretory status of ECL cells. States that ACKNOWLEDGMENTS
enhance ECL cell secretion, such as gastrin infusion, re-
sulted in elevated serum pancreastatin levels (411). In ac-
cordance with this hypothesis, and of special relevance for S. Kopic is a Howard Hughes Medical Institute Interna-
the topic of this review, PPI therapy also resulted in in- tional Student Research Fellow. Special thanks to Sashka
creased serum pancreastatin levels (the ECL is stimulated by Dimitrievska for her untiring support and critical editing of

gastrin, which in turn is released in response to high gastric the manuscript.
pH) (411). These observations led the investigators to con-
clude that ECL cells are a major contributor to the serum Address for reprint requests and other correspondence: J. P.
levels of pancreastatin in the rat and that these levels change Geibel, Yale School of Medicine, 310 Cedar St., BML 238,
in parallel with ECL cell secretion (411). This is also cor- New Haven, CT 06510 (e-mail: John.geibel@yale.edu).
roborated by the observation that gastrectomy reduces pan-
creastatin levels in rats (644).
DISCLOSURES
Pancreastatin exerts a variety of metabolic effects. Apart
from influencing energy metabolism, pancreasstatin was No conflicts of interest, financial or otherwise, are declared
shown to affect the secretion of PTH from the parathyroid by the authors.
gland. In isolated bovine and porcine parathyroid cells,
pancreastatin has a clear inhibitory effect on PTH secretion
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Gastric Acid Calcium Absorbtion Bone Health J Geibel - 13

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Physiol Rev 93: 189 –268, 2013

GASTRIC ACID, CALCIUM ABSORPTION, AND

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I. INTRODUCTION 189 which primarily consists of the calcitropic hormones: 1,25-

0031-9333/13 Copyright © 2013 the American Physiological Society 189

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Oxyntic mucosa Antrum

Somatostatin CCK1 CCK

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5. Other substances D) NEUROTENSIN. Neurotensin is a 13-amino acid neuropep-

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Stimulates PTH secretion

Increases bone resorption

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Increases renal calcium absorption

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7-dehydrocholesterol Dietary vitamin D

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25(OH)-vitamin D DBP Mitochondria:

1,25(OH)2-vitamin D Target organs