ANNUAL

REVIEWS Further
Annu. Rev. Physioi. 1994. 56:711-39 Quick links to online content
Copyright © 1994 by Annual Reviews Inc. All rights reserved

HORMONAL SIGNALING AND

REGULATION OF SALT AND
WATER TRANSPORT IN THE
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

COLLECTING DUCT
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

Matthew D. Breyer and Yasuhiro Ando

Division of Nephrology and Departments of Medicine and Molecular Physiology
and Biophysics, Veterans Administration Medical Center and Vanderbilt
University, Nashville Tennessee, and Division of Nephrology, Jichi Medical
School, Kawachi-gun, Tochigi, Japan

KEY WORDS: protein kinase C, calcium, cyclic AMP, sodium, vasopressin

INTRODUCTION

The collecting duct is a major site of hormonally regulated water and ion
transport, It is the major intra-renal target for vasopressin action, as well
as an important site of action for catecholamines, atrial natriuretic peptide,
prostaglandin E2, and mineralocorticoids. The purpose of this review is to
summarize the current understanding of the hormonal signaling mechanisms
that regulate water and ion transport in the c ol lecting du ct .

Cellular Components of the Collecting Duct

Collecting ducts are classified by their location within the kidney: cortical,
outer medullary (outer stripe and inner stripe), and inner medullary segments.
The collecting duct is a heterogeneous epithelium consisting of three cell
types: principle cells, and a and 13 intercalated cells (107, 118). Principal
cells are thought to be primarily responsible for water and cation transport,
while intercalated cells play roles in acid-base, K+, and anion transport
(35, 56, 140). The water transport effect of vasopressin is thought to be
primarily mediated by principal cells (33, 98), although it remains possible
711

0066-4278/94/0315-0711$05.00
 712 BREYER & ANDO

that intercalated cells also participate (99, 194). The reader is referred to
the previous year's Annual Review of Physiology for a review of intercalated
cell function (172). Of relevance to the present considerations is the recent
observation that, in cell culture, the /3 intercalated cell may convert to a
principal cell (57). These studies suggest that the functional distinction
between these cells may not be static. This review focuses on the coupling
between signaling and water and cation transport in the principal cell. Before
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

discussing the cellular signaling mechanisms that modulate water and salt
transport in the collecting duct, we briefly discuss the transporters that are
thought to be the major targets for these signaling mechanisms.
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

WATER CHANNELS It is well established that vasopressin-stimulated water

absorption involves the exocytic insertion of water-selective channels into
the apical membrane of the collecting duct (32, 74, 77). This process is
accompanied by the reorganization of an apical actin web (82). Inhibitors
of microtubule and microfilament formation, such as colchicine or cyto­
chalasin B, block vasopressin-stimulated water flow (147, 210). In contrast
to other exocytic processes such as peptide hormone secretion, where release
of the vesicular contents is important, the salient feature of vasopressin­
stimulated water permeability is the insertion of the limiting vesicle mem­
brane (which contains water channels) into the cell membrane.
A recently cloned 28 kd erythrocyte-membrane protein (channel-forming
integral membrane protein; CHIP28) has been demonstrated to be a water
channel (149, 150). Another water channel, designated WCH-CD, has now
been isolated from the rat kidney by homology with CHIP28 (63). WCH-CD
consists of 270 amino acids and has six putative transmembrane domains.
There is 42% amino acid sequence homology to CHIP28. Expression of
WCH-CD in Xenopus oocytes increases osmotic water permeability. This
was inhibited by HgClz, a characteristic of water-permeable endosomes from
the collecting duct (74).
In the kidney, CHIP28 is expressed mainly in the proximal tubule and
the thin descending limb of loop of Henle, whereas WCH-CD mRNA is
exclusively expressed in the collecting duct, especially in the inner medullary
portion (63, 162, 164). WCH-CD is localized predominantly in the apical
membrane. WCH-CD mRNA expression, but not that of CHIP28, is en­
hanced by dehydration (164). These data suggest that WCH-CD is the water
channel responsible for vasopressin-stimulated water transport. The water
and urea permeability pathways appear to be distinct, since in the cortical
collecting duct, vasopressin exclusively stimulates water transport without
changing urea permeability. Furthermore, although vasopressin increases
both water and urea permeabilities, phloretin has been shown to selectively
inhibit urea transport without affecting water transport (102).
 COLLECTING DUCT SIGNALING 713

Ion Transporters
Na CHANNELS Amiloride-inhibitable Na + channels mediate the electrogenic
transport of Na+ across the apical cortical collecting duct (CCD) membrane,
into the cell, and down its electrochemical gradient. Patch-clamp studies of the
collecting duct document the existence of at least three functionally different
amiloride-inhibitable Na+ channels (142). These include a 4-5 pS channel that
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

is highly selective for Na:K> 10, a 7-10 pS channel that is three to four times
more selective for Na>K, and a 28 pS channel that is non-selective for Na+
and K+ (142). Since most evidence suggests that electrogenic Na + absorption
is highly Na+ selective, the 4-5 pS channel is the most likely candidate for
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

mediating electrogenic Na+ absorption in the CCD.

The mechanisms regulating Na + channel activity appear to be diverse
and include modulation of channel density by exocytic insertion (120), as
well as altered channel gating, influenced by G proteins (38), protein kinase
C (PKC), (114), protein kinase G, cGMP (110), and modulation by the
actin filament polymerization (39). An amiloride-binding protein has been
purified from A6 cells and bovine kidney (17, 100). In the absence of
reducing agents, this protein migrates as a single broad band of approxi­
mately 700 kd. When treated with reducing agents, the protein separates
into five distinct bands of 315, 150,95, 70,and 55 kd. The 315 kd subunit
has been found to be phosphorylated in response to vasopressin (17, 143,
163, 166). Recently a cDNA has been cloned from rat colon that expresses
an amiloride-sensitive Na + conductance in oocytes (37, 115). The predicted
molecular weight of this protein is 79 K and in vitro translation yields a
protein that migrates at 75 kd and after glycosylation, at 92 kd. Interestingly,
the predicted amino-acid sequence of this protein includes consensus phos­
phorylation sites for PKA, PKC, and casein kinase II. It remains unclear
exactly how this cloned protein corresponds to the multimeric protein purified
from bovine kidney. Both proteins are candidates for mediating electrogenic
Na + absorption in the collecting duct.

+ CHANNELS +
K Vasopressin stimulates K secretion in the distal tubule and
collecting duct (60). In the collecting duct, K + is secreted via an apical
conductive pathway. Patch-clamp studies have identified several functionally
distinct apical K+ channels in this nephron segment (214) These include a
80-140 pS K+ channel that is Ca2+-dependent, a small, outward rectifying
K+ channel observed in cultured CCDs (113), and an inward rectifying 35
pS K + channel that is regulated by ATP (81,214). It has been suggested
that this latter channel provides the major route for K+ secretion in the
collecting duct (214).
The open probability of the 35 pS apical K + channel is markedly increased
 714 BREYER & ANDO

by PKA and ATP in excised patches (212). In agreement with these

+
observations, the predicted amino acid sequence of an ATP-regulated K
channel recently cloned from rat renal medulla contains two consensus
sequences for PKA phosphorylation (8 1). These results suggest that vaso­
+
pressin and cAMP, through PKA phosphorylation, could activate K se­
cretion via this channel.
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

NaCl SYMPORT It remains unclear whether electroneutral NaCI transport

exists in the CCD. While there is evidence that a thiazide-sensitive NaCI
symport mechanism is present in the rat CCD (201), this has not been
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

uniformly observed (161). Thiazide-sensitive NaCI symport appears to be

absent from the rabbit CCD, but present upstream in the connecting segment
( 179). A cDNA encoding a thiazide-inhibited NaCI symporter has recently
been cloned from the urinary bladder of the winter flounder (64). This 1 12
kd protein possess 12 putative membrane-spanning regions and has several
potential protein kinase phosphorylation sites. It remains to be determined
whether a homologue is expressed along the mammalian nephron.

NalK ATPASE The favorable electrochemical gradients mediating Na + ab­

sorption and K + secretion by the collecting duct are generated by the
NaJK-ATPase. Immunohistochemical studies of the CCD demonstrate that
NaJK-ATPase selectively localizes to the basolateral domain of principal
cells. No labeling of intercalated cells was seen (94). This ATPase exists
as a heterodimer with the a.-subunit possessing the catalytic activity and
oubain binding site. The j3-subunit is a glycoprotein required for enzymatic
activity. The NaJK ATPase a.-subunit is a substrate for both protein kinase
A and protein kinase C (43), and phosphorylation of the a.-subunit inhibits
NaJK-ATPase activity (21). There are three isoforms of the a.-subunit and
possibly two isoforms of the j3-subunit (195). Most evidence suggests a. 1
i s the major isoform i n the kidney; however, variable renal expression of
a.2 and a.3 isoforms has also been reported (54). These isozymes display
different affinities for ouabain, Na +, and K + ( 195), and it is thought that
different isozymes may be subject to differential regulation both at the level
of gene expression and by protein kinases (51 , 195).

V 2 /CYCLIC AMP-MEDIATED SIGNALING

Arginine vasopressin (AVP) is the single most important hormone regulating

urine volume. The primary physiologic action of AVP, antidiuresis, is
mediated through the V2 receptor located in the collecting duct (and in some
rodents in medullary thick ascending limb) ( 125). AVP not only enhances
water reabsorption in the collecting duct, but also enhances Na reabsorption
 COLLECTING DUCT SIGNALING 715

and K secretion. This section reviews how the Vrmediated signal modulates
water and salt transport in the collecting duct.

Water Transport
It is generally accepted that AVP stimulates osmotic water permeability in
collecting ducts through the V2 receptor, which stimulates adenylate cyclase
and cyclic AMP (cAMP) generation and results in the activation of cAMP­
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

dependent protein kinase (PKA) ( 1 , 77, 1 63, 1 85). This activation causes
increased water permeability of the apical epithelial membrane of the
collecting duct (Figure 1 ). Each element of this process is discussed below.
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

'

The V2 Receptor
The complementary DNA and the predicted amino acid sequence for the
renal V2 receptor and hepatic VIa receptor have recently been reported (22,
1 16, 124). The rat liver V 1a and renal V2 receptors are 394 (44 kd) and
370 amino acid proteins (40.5 kd), respectively. Like other G protein-coupled
receptors, these receptor proteins display three intra- and three extracellular
loops with seven transmembrane domains. The V 1a and the V2 receptors
are 60% homologous,
While the VIa receptor mRNA is expressed in multiple organs including
liver, spleen, brain, and kidney, V2 receptor mRNA is almost exclusively
expressed in the kidney. In situ hybridization demonstrates V2 expression
in the cortical and medullary collecting duct and the medullary thick

BLOOD

PKA

�k'
H20
H20
URINE
microtubule.
 716 BREYER & ANDO

ascending limb (116). In the collecting duct, V 2 receptors are thought to

reside on the basolateral membrane. Apical V2 receptors may also exist in
cultured rat inner medullary collecting duct cells (219), which produce
cAMP in response to apical nanomolar AVP. Nevertheless, in the native
rabbit cortical collecting duct perfused in vitro, luminal AVP, even in
nanomolar concentrations, did not increase water permeability (l0, 70).
Thus functional V2 receptors, whieh mediate the stimulation of water
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

transport, are restricted to the basolateral side of the collecting duct.

G Proteins
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

STIMULATORY G PROTEINS Binding of AVP to the V2 receptor leads to

activation of adenylyl cyclase via a stimulatory heterotrimeric G protein,
Gs (as and 13,),-subunits) (22, 123). Immunohistochemical studies of rat
kidney show a distinct basolateral localization of Gas within the collecting
duct (in contrast to the proximal tubule where apical localization is seen)
(193). AVP and \3-adrenergic agonists are the major stimulators of basolateral
adenylyl cyclase activity in the collecting duct (125). Association of these
hormones with their respective receptors favors Gas dissociation from 13')',
frees Gas, interacts with, and stimulates adenylyl cyclase (19). Free 13')'­
subunits are also capable of regulating adenylyl cyclase. For instance, Gas
activation of purified type I adenylyl cyclase (a brain-specific isoform) was
inhibited by (3),-subunits, while (3)' augmented the Gas activation of purified
type II adenylyl cyclase (197). Other adenylyl cyclase isoforms appear to
be insensitive to the effects of 13')'.

INHIBITORY G PROTEINS Inhibitory G proteins (GiS) counteract the stimu­

latory effects of Gs on cAMP production (123, 180). Gai2 appears to be
the major isoform present in the rat collecting duct and displays basolateral
and cytoplasmic localization (34, 193). While the inhibitory effects of Gi
·
on cAMP generation are clear, the molecular mechanisms whereby this
effect occurs is somewhat controversial. Evidence exists for direct inhibitory
effects of the ai-subunit, as well as inhibitory effects of free \3')' (123). The
inhibitory effects of 13')' may be mediated by their association with free as
thereby decreasing the amount of as available to stimulate adenylyl cyclase
(123).
Whatever the precise mechanism, OJ activation appears to be an important
target for several hormones and autacoids that antagonize the Gs-coupled
effects of vasopressin. A hallmark of OJ-mediated inhibition of adenylyl
cyclase is that it can be experimentally blocked by pertussis toxin (see
Figure 2), which irreversibly ADP ribosylates Gaj (129). Furthermore,
inhibitory effects mediated by OJ can be experimentally bypassed by ad-
 COLLECTING DUCT SIGNALING 717

ministration of cell-permeable cAMP analogues. Based on these criteria,

several hormones and autacoids, including PGE2 (79, 187. 188), epinephrine
(67, 155), acetylcholine (67), and endothelin (130), have been shown to
antagonize the G,-coupled effect of vasopressin via Gj-dependent mecha­
nisms. Adenylyl cyclase-independent effects of Gaj on ion channels in the
collecting duct have also been proposed (38).
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

Adenylyl Cyclase
Hormone-stimulated adenylyl cy clase regulates the intracellular level of
3' ,5' -cAMP by catalyzing its generation from ATP. Adenylyl cyclases are
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

now known to comprise a family of eight proteins, each characterized by

twelve putative membrane-spanning regions and approximate molecular mass
of 120-150 kd (-1200 amino acid residues). Of the eight isoforms of
adenylyl cyclase, seven were detected in rat kidney (104). Not only may
specific G proteins couple to distinct adenylyl cyclase isoforms (68), but it
has also been demonstrated that some adenylyl cyclase isoforms are mod­
2
ulated by 13'Y-subunits of heterotrimeric G proteins (see above), and by Ca +
2+
and/or Ca /calmodulin (75). The adenylyl cyclase isoforms present in the
collecting duct have not been characterized. However, both type V and type
VI appear to be highly expressed in rat kidney (148). Of interest, both
2
adenylyl cyclase isoforms are directly inhibited by submicromolar Ca + in
2+
a calmodulin-independent fashion (95, 104, 221). If these Ca -sensitive
isoforms are present in the collecting duct, it would provide a potentially
2
important site for cross-talk between the Ca +-coupled V 1 and cAMP-coupled
V2 systems.

cAMP Phosphodiesterase
Cytosolic cAMP levels are also regulated by cAMP-phosphodiesterase
(cAMP-PDE), which hydrolyzes 3' ,5'-cAMP to 5'-AMP. PDE isozymes
have been tentatively classified according to their affinity for cyclic nucle­
otides (cAMP and cGMP), dependence on calmodulin, and sensitivity to
selective inhibitors, such as rolipram and cilostamide (15). The primary
structures of several PDE isozymes have been deduced (15, 18, 92, 153)
and reveal an amino-terminal regulatory domain and a mid-molecule catalytic
domain (18, 92). The cAMP-binding region of the catalytic domain is
homologous to that of the regulatory subunit of protein kinase A, although
the mode of cAMP binding may be distinct (92).
Although the intra-nephron distribution of PDE isozymes is largely un­
known, rolipram-sensitive PDE and calmodulin-dependent PDE, which are
low Km phosphodiesterases, appear to play significant roles in mouse and
rat collecting duct (18, 84). Enhanced activity of a specific rolipram-sensitive
cAMP-PDE in the collecting duct is known to cause hereditary nephrogenic
 718 BREYER & ANDO

diabetes insipidus in mice (45 , 84, 196). This highlights the importance of
P DE as a regulator of the antidiuretic action of AVP. Recent studies also
suggest that PDE activity might be regulated by a receptor G protein-coupled
mechanism in hepatocytes (119).

cAMP-dependent Protein Kinase (PKA)

There is evolving evidence that vasopressin and cAMP-stimulated water
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

flow are mediated, in part, by PKA. PKA exists as a heterotetramer

comprised of two catalytic (C) subunits and two regulatory (R) subunits.
Each R subunit possesses two cAMP-binding sites (site A and site B) (Figure
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

1). Dissociation of Rand C subunits occurs when cAMP binds to both the
A and B sites on the regulatory subunit (16). The free C subunit is released
from tonic inhibition by R. Two major holoenzyme isoforms of PKA exist
and are distinguished by their regulatory subunits (RI and RII). RII is larger
than RI (monomer molecular weight = 54-59 K vs 49 K). RII exists as a
dimer formed by a disulfide bridge and contains an autophosphorylation site
(16, 173). The type I isoform of PKA is primarily cytosolic, while the type
II isoform is associated with the cytoskeleton and appears to specifically
bind to acidic amphipathic helical protein sequences (41, 173, 174). These
protein kinase anchoring sequences undoubtedly play an important role in
targeting PKA activity to specific protein substrates. While equal amounts
of PKA type I and II exist in the rat medullary thick ascending limb, the
rat medullary collecting duct predominantly contains type I PKA (65). The
selective, expression of the type II isozyme, coupled with its specific
intracellular localization, may serve as a mechanism for generating tissue­
selective effects of cAMP. There are also u and � isoforms of RI and RII
regulatory subunits and at least three isoforms of the catalytic subunit (Cu,
CI3, and Coy) (173). This heterogeneity allows for further selectivity of
action.
Although it has been assumed that PKA is essential for the induction of
water permeability (1, 52), a direct relationship between PKA activation
and the exocytic insertion of water channels into the apical membrane
remains only partially established. Some studies have suggested a discrep­
ancy between PKA activation and the hydroosmotic effect of AVP. For
example, we have observed that several inhibitors of protein kinase A (H-8,
K252a, KT5720) enhanced rather than inhibited the hydroosmotic effect of
AVP (6). More recently Snyder et al suggested an integral role of PKA in
mediating the hydroosmotic effect of AVP (185). In this study, site A- and
site B-selective cAMP analogues synergistically stimulated water transport
in the isolated perfused rabbit CCD. Also, two different PKA inhibitors
(Rp-cAMPS, H-89) inhibited the AVP and cAMP-induced water transport,
 COLLECTING DUCT SIGNALING 71 9

Vasopressin-stimulated PKA-induced phosphorylation of intrinsic protein

substrates has been demonstrated in the collecting duct, although the substrate
protein has not been specified (53, 85). Therefore, despite the inconsistent
actions of several kinase inhibitors, PKA appears to be involved in stimu­
lating water transport. It remains unclear whether different PKA isoforms
are more-or-less susceptible to these different inhibitors, which accounts for
these apparently discrepant results.
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

It is conceivable that there are also direct effects of the R subunit of

PKA distinct from kinase activity. In prokaryotes such as E. coli, cAMP
exerts its actions through binding to cAMP receptor protein (CRP), which
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

lacks protein kinase activity ( 1 3 1 ). Considerable structural homology exists

between CRP and R subunit of PKA. In addition, the cAMP-regulatory
subunit complex, but not the catalytic subunit, appears to be a potent
inhibitor of a phosphoprotein phosphatase ( 1 76) and to induce protein
synthesis in SV40-3T3 fibroblasts (135). cAMP may also directly bind to
other proteins such as the cation channel observed in olfactory epithelium,
which is directly gated by cAMP ( 1 1 7, 1 32). Thus kinase-independent
effects of cAMP either via the PKA R subunit or binding to other acceptor
proteins could participate in collecting duct signal transduction.

Modulation of Water Permeability at the Apical Membrane

The final step of V2-mediated signaling is insertion of water channels into
the apical plasma membrane. In toad urinary bladder, particle aggregates,
which contain water channels, are arrayed linearly in the membrane of a
cylindrical organelle termed the aggrephore (77). Upon vasopressin stimu­
lation, aggrephores fuse with the apical plasma membrane and the integral
membrane proteins aggregate in clusters. In the mammalian collecting duct,
intracellular aggrephores are observed less frequently (48). In this tissue, a
SUb-popUlation of endosomal vesicles is assumed to deliver the water
channels. Once inserted into the apical membrane, water channels localize
in clathrin-coated pits (33). With AVP removal, endocytic retrieval of the
water channel from the apical surface is observed and water permeability
declines (32, 74,77, 209).
Cytoskeleton elements are presumed to play critical roles in the movement
of vesicles and water channels (1 98). Roles for microtubules and actin
filaments in aggrephore movement and insertion of water channels into
apical membrane, respectively, have been suggested ( 1 28, 1 47,2 10). Upon
AVP-stimulation, disruption of actin filament network appears to precede
the delivery of water channels (48, 82). However, the precise mechanism
is not yet defined. It is also unknown whether the AVP-sensitive water
channels display gating similar to ion channels.
 720 BREYER & ANDO

V2 Effects on Cation Transport

+ + + +
Na AND K Vasopressin stimulates both Na absorption and K secretion
(61 , 83, 1 66, 2 14). These effects may be species-dependent, since in the
rabbit, this stimulation is transient, whereas in the rat, the stimulatory effect
of vasopressin is persistent. Most evidence suggests that vasopressin and
cAMP stimulate Na + absorption by increasing the density of Na+ channels
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

in the apical membrane of the collecting duct ( 1 20, 1 66, 1 67). While cAMP
+
has been shown to inhibit Na + IK ATPase in broken cells (2 1 , 1 65), the
+
major effect of vasopressin and cAMP appears to be stimulation of Na
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

absorption. Following treatment with vasopressin or cAMP, intracellular

+
sodium increases through enhanced luminal Na entry (30, 1 56). Patch­
clamp studies fail to demonstrate an effect of vasopressin or cAMP on open
probability or channel conductance; however, channel number appears to
increase following vasopressin treatment ( 1 20). By analogy with the process
of vasopressin-stimulated water permeability, it may be that stimulation of
+
Na + absorption occurs via the exocytic insertion of amiloride-sensitive Na
channels ( 1 66).
In contrast to its effects on sodium absorption, the cellular mechanisms
+
by which vasopressin stimulates K secretion is less firmly established.
+
cAMP and PKA increase the open probability (Po) of a 35 pS K channel
(2 1 2) (in contrast to the lack of effect of cAMP on Po of the amiloride­
sensitive sodium channel). It remains uncertain whether the stimulation of
+
K + secretion results secondarily from increased apical K conductance, or
+
simply arises from an enhanced electrochemical gradient for K secretion,
the result of the primary effects on Na+ transport (1 68). A role for exocytic
+
insertion of K channels in response to cAMP remains purely speculative.

cAMP STIMULATION OF BASOLATERAL Na + Icl+ EXCHANGEAlthough it has

2+
been suggested that vasopressin increases CCD intracellular Ca via a VI
2+
receptor, there is also evidence that vasopressin may increase [Ca ]j via
a V2/cAMP-dependent mechanism (28) . This effect appears to involve
+ 2+
activation of a basolateral Na /Ca exchanger. As vasopressin or cAMP
+
activates apical Na + entry, intracellular Na concentration increases (above
+ + 2+
approximately 15 mM), and ci can then enter the cell via the Na /Ca
2+
exchanger (27, 28, 183). The Ca increase results in feedback inhibition
of vasopressin-stimulated Na + permeability, possibly contributing to the
+
sustained inhibition of Na transport produced by vasopressin in the rabbit
(28, 83). It is also evident that as luminal Na+ delivery falls, the absolute
+ 2+
increase in cell Na and intracellular Ca falls. In this manner, decreased
luminal Na + delivery could convert the net effect of vasopressin in the
rabbit CCD from inhibition of Na + absorption to stimulation.
 COLLECTING DUCT SIGNALING 721

2+
V 1/Ca -COUPLED SIGNALING

S everal hormones and autacoids including vasopressin, PGE2, acetylcholine,

and endothelin have been reported to modulate the AVP-induced water
transport in the collecting duct via a signaling mechanism coupled to
2+
phospholipid turnover and increased cell Ca (1, 29) (Figure 2). While
2+
cooperative effects of the Vz!cAMP and Ca -coupled pathways remain an
2+
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

attractive possibility, the majority of studies suggest that the Ca -coupled

pathway inhibits vasopressin action.
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

Vasopressin Receptor-Stimulated Phospholipid Breakdown

V I RECEPTOR AND G PROTEIN COUPLING The cDNA for the V la receptor has
been cloned from rat liver. The message encodes a 394 amino acid protein. The
expressed protein preferentially binds AVP>oxytocin = dDAVP (a V2-selec­
tive analogue) (124). Genomic southern hybridization suggests the existence of
'
y
multi le members of this receptor family. There is accumulating evidence for
a Ca + -coupled vasopressin receptor in the collecting duct; however, the
precise subtype is not well defined (3, 5, 28, 36, 190, 191). There is evidence
supporting roles for VI and V2 receptors (3, 28, 190). In the case of the V2
receptor, it is conceivable that high concentrations of A VP release enough G
protein 13'Y subunits to activate phospholipase C and phosphatidylinositol
hydrolysis (22a). In contrast, Get subunits may mediate the effects of the Via
receptor. Typically, as in hepatocytes, the Via receptor (124) couples to a

Figure 2 2+
Interaction between cAMP and Ca /phospholipase-coupled signaling systems in the
collecting duct.
 722 BREYER & ANDO

phosphoinositide-specific phospholipase C (PLC) through a pertussis toxin-in­

sensitive, heterotrimeric GTP-binding protein designated Gq (46, 182, 199).
Three other G proteins, Gal l , Ga14, and GalS (or cd6 in human) also fall
into the Gq family (2 16). Gq, Gal l , and Ga14 are present in mouse kidney
(2 16), and a preliminary report suggests both Gal l and Ga14 are present in the
rat collecting duct (1 75) Other pertussis toxin-sensitive G proteins such as Go
may also participate in phosphatidylinositol hydrolysis (1 26); however, in the
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

2+
collecting duct, agonist-stimulated Ca transients are typically pertussis
toxin-insensitive (79, 130).
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

PHOSPHATIDYLINOSITOL BREAKDOWN Vasopressin increases collecting duct

2+
cell Ca by releasing calcium from intracellular stores, an effect dependent
upon IP3 generation (28, 36). G protein-coupled receptors typically activate
P LC - (3 , whereas PLC--y is activated by tyrosine kinase-coupled receptors
(154). PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2), a minor
constituent of cell membrane phospholipids, thereby initiating two major
intracellular signal transduction events: the activation of protein kinase C
2+
(PKC) and the mobilization of Ca from an intracellular store (20, 136).
Two PIP2 breakdown products, diacylglycerol (DAG) and inositol-l ,4,5-tri­
phosphate (IP3), are responsible for these signals (20, 136). Diacylglycerols
in the fresence of Ca
H
directly bind to and activate PKC. The increase
2 +
in Ca may also lead to activation of ci Icalmodulin-dependent protein
2+
kinases or other Ca -dependent protein kinases. Phosphorylation of sub­
strate proteins by these activated protein kinases is believed to be essential
to complete signal transduction. As is the case with PKA-mediated signaling,
the PKC substrate proteins and their functional roles have not been clearly
identified in the collecting duct; however, cytoskeletal elements are candidate
targets for PKC or PKC-activated kinases (76, 1 7 7).

PHOSPHATIDYLCHOLlNE TURNOVER Although phospholipase-mediated PIP2

breakdown is a major initial pathway for DAG formation in intact cells, it
is transient even in the continued presence of agonist, and other p hos­
pholipases may be responsible for sustained DAG formation (55, 136).
Numerous studies have documented the importance of phosphatidylcholine
as a source for DAG formation (24, 55). A phospholipase C activity that
hydrolyzes phosphatidylcholine to diacylglycerol and phosphocholine has
been observed in cultured MDCK cells (146). It remains unclear whether
a similar activity is present in the collecting duct.
Vasopressin may activate not only phospholipase C, but also phos­
pholipase D (1 2, 24, 55). Phospholipase D (PLD) hydrolyzes phos­
phatidylcholine (PC), the major component of membrane phospholipid,
which yields phosphatidic acid and choline (24, 87). Phosphatidic acids
 COLLECTING DUCT SIGNALING 723

may be converted to DAG by the action of phosphatidic acid phosphatase

(23). In the rabbit CCD, we have demonstrated that exogenous phosphatidic
acids inhibit AVP-induced water transport through a protein kinase-dependent
mechanism (9). DAG production via PLD is more sustained than the transient
increase in DAG that results from PIP2 breakdown and could be responsible
for prolonged activation of PKC in the continued presence of hormone
(136). Indeed, there is good evidence that PKC itself may activate PLD
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

(136) thereby perpetuating its own activation.

PROTEIN KINASE C The ultimate consequence of DAG formation is to

Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

activate PKC. There are at least ten different PKC isoforms (136). To date,
three isoforms, IX, 13, and " have been detected in the kidney (50, 103).
2+
In the case of IX, 13, and "y isoforms, both micromolar Ca and diacyl­
glycerols are required to activate protein kinase C (PKC). Other PKC
2+
isoforms including � exhibit Ca -independent activation (136). The specific
and hormonally activated PKC isoforms in the collecting duct have not yet
been identified. There is also the possibility that diacylglycerol action is
mediated by PKC-independent mechanisms related to alterations in actin
structure (177).

INOSITOL PHOSPHATES Nanomolar concentrations of vasopressin, PGE2 ,

muscarinic cholinergic agonists, and endothelin all produce a prompt biphasic
increase in collecting duct calcium (28, 67, 79, 130, 190). After reaching a peak
(in the range of 1 fJ.M), ci falls to new but persistently elevated values. This
+
. 2+ 2+
Iatter phase ·IS aSSOCIated Wit 'h'Increased Ca ·InflUX. The InltIa
' ··I C a: ·Increase
2+
results from release of Ca from intracellular stores and influx of extracellular
2+
Ca ( 2 0). It is well established that V I receptor activation generates IP3
formation from PIP2 hydrolysis (2 , 36). Increased cytosolic IP3 binds to its
receptor located in the endoplasmic reticulum. The IP3 receptors comprise a
2+ 2+
family ofCa channels, which upon binding IP3, open and release Ca from
intracellular stores (20,59). IP3 may not only participate in the initial increase
2+
in [Ca )j, but it has been suggested that some inositol phosphate-sensitive
calcium channels mal also reside in the plasma membrane and mediate
+
agonist-stimulated Ca influx (20, 96). It has been proposed that inositol-
�
1 ,3,4,5-tetrakisphosphate IP4)' which is generated from 1 ,4,5-IP3 in response
+ 2+
to AVP, may promote Ca influx through such a Ca channel (109). The
+
existence of voltage or ligand-operated c i channels in the collecting duct
2+
remains speculative. Alternatively, [ Ca ]i influx may also be increased by
2+
modulation of the basolateral Na + I Ca exchanger (28).

Phospholipase A2 and Prostaglandin Synthesis

In addition to stimulating phosphatidylinositol (PI) breakdown, vasopressin
and several other agonists (including endothelin, bradykinin, and epidermal
 724 BREYER & ANDO

growth factor) stimulate arachidonic acid release and prostaglandin synthesis

in the collecting duct. PGE2 is the major cyclooxygenase product of
arachidonate metabolism in the collecting duct. and it is a major inhibitor
of water and sodium absorption in this segment (25). Stimulation of PGE2
production by vasopressin appears to constitute a feedback regulatory system.
Arachidonic acid release may also participate in PKC-dependent signalin,g
since many cis-unsaturated fatty acids, including arachidonate, may activate
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

PKC either by themselves, or in cooperation with diacyclglycerols (136).

The major route of arachidonate release is via the action of cytosolic
phospholipase A2 (PLA2 ) (88) . These enzymes hydrolyze phospholipids
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

(including phosphatidylcholine, phosphatidylethanolaminc, and phosphati­

dylserine, as well as phosphatidylinositol) at the sn-2 position, which
selectively releases arachidonic acid (14, 26). While an arachidonate-selec­
tive cytosolic PLA2 has recently been cloned (44), there are many types of
PLA2 including some that are not arachidonate-selective. It remains uncertain
which PLA2 is relevant for hormone action in the collecting duct.
EGF, bradykinin, vasopressin, and endothelin activate PLA2 and arachido­
nic acid release in the collecting duct (11, 91, 170, 178, 200, 222). Several
of these agents also activate PIP2 hydrolysis and PKC, which stimulates
prostaglandin synthesis in A VP-sensitive cells (139, 169). While agonists
2+
that signal via Ca IPKC have been demonstrated to stimulate PLA2, MAP
2+
kinase appears to be the primary activator and may mediate the Ca IPKC
activation of PLA2 (111, 134).
G protein-coupled receptors also stimulate cPLAz, although the precise
molecular mechanism remains unclear (14, 26, 71, 218). There is evidence
that a G protein-coupled mechanism, distinct from that involved in phos­
pholipase C activation, is involved (71, 1 81). Of relevance to this review
are the observations that bradykinin-stimulated PGE2 production was blocked
by pertussis toxin, and bradykinin inhibited A VP-stimulated water flow via
a pertussis toxin-sensitive, cyclooxygenase-dependent process (171, 178).
However, bradykinin does not increase intracellular calcium or act through
PKC (80), which suggests that, at least in the collecting duct, the bradykinin
receptor is selectively coupled to PLA2 activation.

Functional Consequences of Phospholipid Hydrolysis in the

Collecting Duct
Schlondorff & Levine first demonstrated that PKC was present in toad
bladder and that its activation inhibited AVP-sensitive water transport (169).
Subsequently, PKC activity has been demonstrated in primary cultured rabbit
cortical-collecting duct cells (49). PKCu has also been detected in situ in
2
the collecting duct (50). As mentioned above, vasopressin-stimulated [Ca +L
 COLLECTING DUCT SIGNALING 725

and PIP2 hydrolysis have also been demonstrated in the mammalian-collect­

ing duct (36).
The functional role of PIP2 breakdown in modulating AVP-sensitive water
transport in the collecting duct has also been examined (9). PKC activators
such as phorbol myristate acetate (PMA) and dioctanoylglycerol inhibit
AVP-induced water transport in rabbit CCD (8, 169). This inhibition was
independent of cyclooxygenase metabolites. �eritubular PMA (10 -9 to 10-7)
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

potently blocked the hydroosmotic effect of AVP or a cell-permeable cAMP

analogue in an equivalent and concentration-dependent fashion (7). This
suggests that PKC primarily interferes with AVP-stimulated water flow at
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

post-cAMP step(s). In cultured rabbit CCD cells, PMA was also reported
to inhibit AVP-sensitive adenylate cyclase (pre-cAMP inhibition) (49). The
mechanisms of both pre- and post-cAMP inhibition of A VP-induced water
transport by PKC are undetermined.
Maneuvers that increase cytosolic Ca2+ also modulate AVP action.
However, conflicting results have been reported depending on the experi­
mental condition, the procedure used to increase [Ca2+L, and the animal
species. In toad urinary bladder, simultaneous administration of the Ca2+­
ionophore A23187 together with AVP enhanced the AVP-induced water
transport, while A23187 pretreatment suppressed AVP action (73). The
effect of [Ca2+ Ji on vasopressin action may also be temperature-dependent
(8). At 37°C, 10 nM A23187 inhibits AVP-stimulated water permeability
in the CCO, while at 25°C, it stimulates water permeability. The primary
site of the inhibitory effect appears to be at a pre-cAMP site, although
significant inhibition of cAMP-stimulated water flow was observed when
A23187 concentration was increased to 1 fA-M (8, 93). This difference may
reflect differences in the magnitude of the [Ca2 + ]i increase.
There are several potential mechanisms by which increased cytosolic Ca2+
might inhibit AVP-stimulated water flow. As discussed above, a Ca2+-in­
hibited adenylyl cyclase is present in rat kidney (95, 104, 221). Ca2+ has
also been shown to stimulate PDE activity in the collecting duct, consistent
with the presence of Ca-calmodulin-stimulated PDE (105). Preliminary
studies in the rat medullary collecting duct suggest that either AVP itself
or PKC activators can stimulate POE activity (86, 204). Increased POE
activity has also been suggested to mediate the inhibitory effect of PGE2
on cAMP generation in the rat collecting duct (205).
Increased Ca2+ also stimulates formation of endogenous cycIooxygenase
products (44, 170), an effect that may be functionally relevant since
cyclooxygenase inhibitors reverse the inhibitory effect of A23187 (8). In
contrast, indomethacin had no effect on phorbol ester inhibition of water
flow, while a PKC inhibitor, staurosporine, blocked the PMA inhibition,
 726 BREYER & ANDO

+
but not that observed with 10 nM A21387. Synergy between the Ca2 and
protein kinase C-mediated pathways was also observed (8).
2+
Ca /PKC Effects on Cati(Jn Transport
+
There is good evidence that Ca2 /PKC-coupled signaling not only inhibits
+ +
water flow, but also modulates transepithelial Na absorption and K
secretion. Exogenous diacylglycerols and phorbol esters potently inhibit both
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

+
Na + absorption and K secretion in the collecting duct (78, 220). Cell
attached patch-clamp studies suggest PKC activation decreases the open
+
probability of a 4 pS amiloride-sensitive Na channel in the apical membrane
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

of cultured rabbit-collecting ducts (114). Similarly, maneuvers that increase

+
intracellular Ca2 inhibit sodium absorption in the collecting duct, apparently
+
by reducing Na permeability of the apical membrane (62). Cell attached
+
patch-clamp studies demonstrate increased cell calcium inhibits Na channel
activity in the rat cortical collecting duct (144). In contrast, increasing bath
+
[Ca2 ] had no effect on channel activity when added to cell-excised inside­
2+
out patches, which suggests that the effect of increased Ca was indirect
and dependent on some intracellular effector (144). PKC activation has also
+
been shown to reduce the open probability of the 35 pS ATP-sensitive K
channel in the apical membrane of the rat cortical collecting duct (213).
+
Increasing bath [Ci ] in cell-excised patches enhanced PKC-induced re­
duction of channel open probability. Thus PKC-induced phosphorylation
reduces the open probability of apical cation channels in the collecting duct.
The above results suggest that agonists that stimulate PIP2 hydrolysis in
the collecting duct should inhibit cation transport in this segment. In support
+
of this, it has been demonstrated that the inhibitory effect of PGEQ on Na
2 +
transport is coupled to the release of Ca from intracellular stores, and
2+ 2+
that reducing bath [Ca ] prevents this Ca increase and the inhibition of
+ +
Na transport (79). The mechanism of PGE 2-mediated inhibition of Na
+
transport may involve both inhibition of apical Na conductance and
+ +
inhibition of the basolateral Na /K ATPase (90,114,215). Similarly,
+
muscarinic receptor activation appears to activate PKC , release Ca2 from
intracellular stores, and depolarize transepithelial voltage in the cortical
+
collecting duct, which suggests that it may also inhibit Na transport via
enhanced PIP2 hydrolysis (184). These data are in agreement with a pre­
dominant inhibitory role for PIP2 hydrolysis in the collecting duct, with
respect to cation transport.

Basolateral VI and V2 Receptors

2+
Vasopressin increases collecting duct [Ca ]j, which suggests the presence
of basolateral VI receptors (28, 190). Receptor binding assays also suggest
the presence of collecting duct V 1 receptors , especially in the cortical portion
 COLLECTING DUCT SIGNALING 727

(3). Since stimulation of the major V I signaling pathways , PLC and PLAz,
appear to inhibit AVP-stimulated water flow , A VP might inhibit its own
Vrmediated hydroosmotic effect via V I receptors. This would be consistent,
at least in part, with prostaglandin-mediated regulation of antidiuresis ob­
served in the whole kidney (4, 211). We evaluated the functional role of
basolateral VI receptors in the rabbit CCD (6). The dose-response relation­
ship of the AVP-stimulated hydraulic conductivity (Lp) showed that between
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

I and 230 pM A VP progressively increased Lp, while increasing the

concentration to 23 nM produced a significant decline in the Lp(vs 230 pM
A VP). The water permeability response to 23 nM AVP was enhanced by
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

pretreatment with either a PKC inhibitor or indomethacin. Staurosporine or

indomethacin did not augment the water flow response to 23 or 230 pM
AVP. These observations are consistent with studies showing that nanomolar
+
AVP is required to release Ca2 from intracellular stores or for stimulation
of PGEQ synthesis (27, 39, 107, 182, 202). The results suggest that
V I -mediated autoinhibition is only activated at nanomolar vasopressin con­
centrations .
Autoinhibition of water transport by nanomolar AVP has been recently
reported in anuran urinary bladder and rat CCD (133, 152). Interestingly ,
recent reports from the same laboratory suggest that neither prostaglandins,
+
phorbol esters , nor maneuvers that increase Ca2 inhibit A VP-stimulated
+
Na and water transport in the rat cortical collecting duct (42 , 160). In
contrast, Han et al reported similar self-inhibition of the water transport by
nanomolar A VP in the rat inner medullary collecting duct via V rlike
receptors (72). The VI-receptor subtypes in the collecting duct could be
+
unique since the spike-like Ca2 response can be induced not only by A VP,
but also by the V2-selective agonist dDAVP (30, 72, 190). Alternatively,
as discussed above, V 2 -mediated release of G 13'Y could account for these
effects (22a).
Circulating AVP, the major determinant of distal nephron water reabsorp­
tion in vivo, is 1 pM in euhydrated mammals (47, 157). Severe dehydration
�

or hypovolemia only raises circulating AVP level to 50-100 pM. Never­

theless, no evidence for VI activation (including PGE2 synthesis) can be
demonstrated using picomolar vasopressin in the isolated collecting duct.
While this might seem inconsistent with the established role of endogenous
prostaglandins in regulating AVP antidiuresis in vivo (4, 211), these studies
did not address the site of prostaglandin production in response to physio­
logical concentrations of AVP. Picomolar A VP might stimulate renal pros­
taglandin synthesis at some other site than the collecting duct (e.g. interstitial
cells). Alternatively, picomolar AVP might induce the release of other
autacoids such as kinins (58), which in tum stimulate collecting duct
prostaglandin synthesis. These considerations raise the question of what
 728 BREYER & ANDO

physiological role the Ca2+-coupled vasopressin receptor(s) play in the

collecting duct.
2
In addition to the inhibitory action of increased [Ca2 + 1i, lowering [Ca +l;
below a certain level interferes with the hydroosmotic effect of AVP (13,
2
89, 105, 108). It has been suggested that an optimum range of [Ca +]i is
required for the full development of water transport in response to A VP.
Similarly a facilitory role for protein kinase C in the movement of water
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

channels has been suggested (121). In this study, while the hydroosmotic
effect of AVP was inhibited by apical PMA pretreatment, apical PMA alone
induced exocytosis and endocytosis, which appeared to be associated with
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

a slow and slight increase in osmotic water permeability. This suggested

that localized activation of PKC might mediate the movement of water
channels. However, generalized activation is inhibitory to AVP-induced
water transport.

LUMINAL ACTION OF AVP AVP stimulates water and Na transport from the
basolateral, but not the apical, side (70, 106, 141). However, some studies
suggest that AVP may act from the apical side as well. It is of note that
urine contains much higher concentrations of intact AVP than plasma (97,
127, 151). Apical AVP stimulated prostaglandin synthesis in primary cul­
tured canine CCD cells (66). Furthermore, it is evident that A VP exerts
non-classical Ca2+-coupled effects, and the activation of these effects by
luminal AVP has recently been examined (5, 10). Luminal nanomolar AVP
hyperpolarized transepithelial voltage without a significant change in Na or
K transport. This hyperpolarization is inhibited by acetazolamide, but not
by ouabain. The luminal action of AVP appears to be mediated by an apical
VI receptor, but not by a V2 or an oxytocin receptor (5). While luminal
AVP does not enhance osmotic permeability, it inhibits the hydroosmotic
effect of basolateral AVP. The cellular mechanism of the apical VI receptor
remains to be elucidated. It is of interest that while luminal dDAVP had
no effect, basolateral dDAVP was roughly equipotent with A VP in raising
intracellular calcium (5, 28), which suggests that basolateral and luminal
V I receptors may be different subtypes. Although self-inhibition of basolate­
ral AVP-induced water transport is not experimentally demonstrable, even
at the maximal concentration of plasma AVP, luminal AVP-induced inhi­
bition is demonstrable and could be significant in view of high urinary AVP
concentrations. While the physiological significance of luminal and basolate­
ral AVP receptors is unknown, one possibility is that luminal AVP may
prevent excessive antidiuresis when A VP is inappropriately high, as in
SIADH (122) or physical stress.
 COLLECTING DUCT SIGNALING 729

TYROSINE KINASES

Epidermal growth factor (EGF) potently inhibits both vasopressin-stimulated

water permeability and Na + transport in the rabbit cortical collecting duct
(3 1 , 207). The EGF receptor is a tyrosine kinase that has been shown to
phosphorylate several critical signal transduction proteins including phos­
pholipase C 'Y (40). The activation of PIP2 hydrolysis by PLC-'Y may display
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

delayed kinetics as compare with PLC-(3 (20). It has also been suggested
that activation of phosphatidylcholine-specific PLC requires tyrosine phos­
phorylation by growth factor-like receptors ( 1 36). Tyrosine kinase-coupled
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

receptors also initiate a complex phosphorylation cascade leading to the

activation of MAP kinases ( 14S) which, as discussed above , activate PLA2
and gene transcription ( 14S). Although the precise mechanism by which
EGF inhibits water and salt transport is not well established, it appears that
the inhibition of water permeability is at a post-cAMP step that involves
protein kinase (possibly PKC) activation (31). EGF also inhibits apical Na+
entry in the cortical collecting duct via a mechanism that requires calcium
(208 , 21S), but unlike PGEz, it may not inhibit the Na/K ATPase . The
basis for these unique effects is unknown, but it is tempting to speculate
that re-organization of the apical actin web could play an important role
(69, 82).

cGMP Multiple forms of guanylyl cyclase exist (217), and recent interest
in the role of cGMP in the regulation of Na+ and water transport has
surged. At least two general forms of guanylyl cyclase exist in the collecting
duct: a particulate form that is an ANP receptor (202), and a soluble form
that is stimulated by nitric oxide (203 , 206). Important roles for cGMP
stimulation of pathways in regulating collecting duct water and salt transport
have been suggested.
ANP inhibits Na+ absorption and vasopressin-stimulated water permeabil­
ity in the collecting duct; however, the mechanism of these effects remains
unclear. Given the existence of a cGMP-activated cyclic nucleotide phos­
phodiesterase in rat renal medulla ( 1 86), it seems plausible that at least one
mechanism by which ANP inhibits water permeability is via increased cAMP
catabolism. If this were the operative mechanism, then cGMP should not
inhibit the effects of cAMP analogues on transport. However, two studies
provide apparently conflicting results with respect to the mechanism of ANP;
one demonstrating inhibition ( 1 37) and one a lack of inhibition ( 1 S9) of
cAMP-stimulated water flow. Alternative molecular mechanisms of cGMP
action are only beginning to be defined (see review in this volume by S
Francis & J Corbin) .
 730 BREYER & ANDO

Most data suggest that the ANP receptor is predominantly expressed in

the inner medullary rather than the cortical collecting duct (138, 202).
However, effects in both portions of the collecting duct have been
reported. ANP may inhibit electroneutral, but not electrogenic , NaCl
transport in the rat CCD ( 10 1). ANP also inhibits Na+ absorption in the
rat inner medullary collecting duct (158). Possible mechanisms include
direct inhibitory effects of cGMP or PKG on open probability of an apical
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.

amiloride-sensitive cation channel (110, 189). ANP has also been dem­
onstrated to stimulate NaCl secretion in the rat IMCD, an effect mimicked
by cGMP and one that is opposite of the cAMP-mediated effects of
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org

vasopressin (158). It is intriguing that the effect is accompanied by an

enhanced lumen-negative voltage, which suggests that electrogenic CI­
secretion may be the primary event. Protein kinase G may activate a 10
pS Cl- channel that resembles the cystic fibrosis transmembrane conduc­
tance regulator, as has been observed in T-84 cells, a colonic epithelial
cell line that secretes Cl- (112). It is conceivable that a similar mechanism
operates in the collecting duct.
Recently it was suggested that nitric oxide may stimulate cGMP accu­
mulation and inhibition of Na+ absorption in the collecting duct in a manner
similar to ANP (192). In co-culture experiments, pulmonary endothelial
cells were required for bradykinin-stimulated NO synthesis and for stimu­
lation of cGMP generation and inhibition of sodium transport in co-cultured
mouse collecting duct cells ( 192). The recent identification of both NO
synthase and soluble guanylyl cyclase in rat cortical and medullary collecting
duct (203, 206) supports the possibility that this cGMP-generating pathway
plays an important role in modulating collecting duct transport.

SUMMARY

The regulation of transport in the collecting duct is under multi-hormonal

control . Vasopressin stimulates water and cation transport, primarly through
a V 2 /Gs-coupled receptor that activates adenylyl cyclase, which raises cAMP.
These stimulatory effects are damped by the action of several hormones,
including vasopressin itself, which activate inhibitory G proteins, stimulate
phospholipid breakdown, increase prostaglandin production, raise intracel­
2+
lular Ca , activate protein kinase C, stimulate tyrosine kinases, and raise
cGMP. These inhibitory signals interact with the stimulatory, cAMP-coupled
signaling pathway at multiple levels. The balance between these pathways
controls net salt and water transport in the collecting duct.
 COLLECTING DUCT SIGNALING
Literature Cited
1. Abramow M, Beauwens R, Cogan E .
1987. Cellular events in vasopressin
action. Kidney Int. 32:S56-66
2. Aiyar N, Nambi P, Stassen FL, Crooke
ST. 1986. Vascular vasopressin recep­
tors mediate phosphatidylinositol turn­
over and calcium efflux in an estab­
lished smooth muscle cell line. Life
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
Sci. 39:37-45
3. Ammar A, Roseau S, Butlen D. 1992.
Pharmacological characterization of
V i a vasopressin receptors in the cor­
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
tical collecting duct. Am . J. Physiol.
262:F546-53
4. Anderson R J , Berl T, McDonald KM,
Schrier RW. 1975. Evidence for an in
vitro antagonism between vasopressin
and prostaglandin in the mammalian
kidney. 1. Clin . Invest. 56:420-26
5. Ando Y, Asano Y. 1993. Functional
evidence for an apical V 1 receptor in
the rabbit cortical collecting duct. Am.
1. Physiol. 264:F467-7 1
6. Ando Y, Jacobson H, Breyer M. 1989.
Does cyclic AMP-dependent protein
kinase (PKA) mediate the hydroosmotic
effect of vasopressin (AVP) in rabbit
cortical collecting duct (CCD)? Kidney
Int. 37:576 (Abstr.)
7. Ando Y, Jacobson HR, Breyer MD.
1987. Phorbol myristate acetate, di­
octanoylglycerol, and phosphatidic
acid inhibit the hydroosmotic effect
of vasopressin on rabbit cortical col­
lecting tubule. J. Clin. Invest. 80 :
590-93
8. Ando Y, Jacobson HR , Breyer MD.
1988. Phorbol ester and A23 1 87 have
additive but mechanistically separate
effects on vasopressin action in rabbit
cortical collecting tubule. 1. CUn. In­
vest. 8 1 : 1 578-84
9. Ando Y, Jacobson HR , Breyer MD.
1989. Phosphatidic acids inhibit vaso­
pressin-induced water transport via
protein kinase C activation. Am. 1.
Physioi. 257:F524--30
10. Ando Y, Tabei K, Asano. Y. 1991 .
Luminal vasopressin modulates trans­
port in the rabbit cortical collecting
duct. 1. Clin. Invest. 88:952-59
1 1. Aramori I, Nakani shi S. 1992. Cou­
pling of two endothelin receptor sub­
types to differing signal transduction
in transfected Chinese hamster ovary
cells. 1. Bioi. Chem. 267( 1 8): 1 2468-
74
12. Augert G, Bocckino SB, Blackmore
PF, Exton JH . 1989. Hormonal stim­
ulation of diacylglycerol formation in
731
hepatocytes: evidence for phospha­
tidylcholine breakdown. 1. BioI. Chern.
264(36):21689-98
13. Ausiello DA, Hall D. 198 1 . Regulation
of vasopressin sensitive adenylate cy­
clase by calmodulin. J. Bioi. Chem.
256:979�98
14. Axelrod J. 1990. Receptor-mediated
activation of phospholipase A2 and
arachidonic acid release in signal trans­
duction. Biochem. Soc. Trans. 1 8(4):
503-7
15. Beavo JA, Reifsnyder DH. 1990. Pri­
mary sequence of cyclic nucleotide
phosphodiesterase isozymes and the
design of selective inhibitors. Trends
Pharmacal. Sci. 1 1 : 1 50-55
16. Beebe SJ, Blackmore BF, Chrisman
TD, Corbin ID. 1988. Use of syner­
gistic pairs of site-selective cAMP an­
alogs in intact cells. In Methods in
Enzymology: Initiation and Termination
of Cyclic Nucleotide Action. ed. ID
Corbin, RA Johnson, pp. 1 1 8-39. New
York: Academic
17 . Benos DJ, Saccomani G, Sariban­
Sohraby S. 1987. The epithelial sodium
channel: subunit number and location
of amiloride binding site. J. Bioi.
Chern. 262: 1 06 1 3- 1 8
18. Bentley JK, Kadlecek A , Sherbert C H ,
Seger D, Sonnenburg W K , e t a l . 1 992.
Molecular cloning of cDNA encoding
a "63-kOa calmodulin-stimulated phos­
phodiesterase from bovine brain. J.
Bioi. Chem. 267: l 867�82
19. Berlot CH , Bourne HR. 1992. Identi­
fication of effector-activating residues
of Gs". Cell 68:91 1-22
20. Berridge MI. 1993. Inositol trisphosph­
ate and calcium signalling. Nature 361 :
3 1 5-25
21. Bertorello AM, Aperia A , Walaas SI,
Nairn A , Greengard P. 1 99 1 . Phos­
phorylation of the catalytic subunit of
Na+ , K+-ATPase inhibits the activity
of the enzyme. Proc. Natl. Acad. Sci.
USA 88: 1 1 359-62
22. Birnbaumer M, Seibold A , Gilbert S ,
Ishido M , Barberis C, e t al. 1992.
Molecular cloni ng of the receptor for
human antidiuretic hormone. Nature
357:333-35
22a. Bimbaumer L. 1992. Receptor-to-ef­
fector signaling through G proteins:
Roles for (3'1 dimers as well as a
subunits. Cell 7 1 : 1069-72
23. Bishop WR, Bell RM. 1 988. Assembly
of phospholipids into cellular mem­
branes: biosynthesis, transmembrane
 732 BREYER & ANDO
movement and intracellular transloca­
tion. Annu. Rev. Cell Bioi. 4:579-6 1 0
24. Bocckino SB, B lakemore PF, Wilson
PB, Exton JH. 1 987. Phosphatidate
accumulation in hormone-treated hepa­
tocytes via a phospholipase 0 mech­
. anism. 1. Bioi. Chem. 262: 1 5309- 1 5
25. Bonvalet JP, Pradelles P, Farman N .
1 987. Segmental synthesis and actions
of prostaglandins along the nephron.
Am. 1. Physiol. 253:F377-87
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
26. Bonventre JV. 1 992. Phospholipase A2
and signal transduction. 1. Am . Soc.
Nephrol. 3(2) : 1 28- 1 50
27. Bourdeau JE, Lau K. 1 990. Basolateral
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
cell membrane Ca-Na exchange in
single rabbit connecting tubules. Am.
1. Physiol. 258:FI497-1503
28. Breyer M. 1 99 1 . Feedback inhibition
of cyclic adenosine monophosphate
stimulated Na transport in the rabbit
cortical collecting duct via Na + de­
pendent basolateral Ca + entry. J. CUn.
2
Invest. 88: 1 502- 1 0
29. Breyer M D . 1 99 1 . Regulation o f water
and salt transport in collecting duct
through calcium-dependent signaling
mechanisms. Am . 1. Physiol. 260:FI­
Fll
30. Breyer MD, Fredin D . 1 99 1 . Cyclic
AMP regulates intracellular sodium
concentration ([Na +)) in the rabbit
cortical collecting duct (CCD). J. Am.
Soc. Nephrol. 2(3):732 (abstract)
31 . Breyer MD, Jacobson HR, Breyer JA.
1 98 8. Epidermal growth factor inhibits
the hydroosmotic effect of vasopressin
in the isolated perfused rabbit cortical
collecting tubule. 1. Clin. Invest.
82: 1 3 1 3-20
32. Brown D. 1 989. Membrane recycling
and epithelial cell function. Am. 1.
Physiol. 256:F I - 1 2
33. Brown 0, Orci L. 1 9 8 3 . Vasopressin
stimulates formation of coated pits in
rat kidney collecting ducts. Nature
302:253-55
34. Brunskill N, Bastani B, Hayes C,
Morrissey J, Klahr S. 1 99 1 . Localiza­
tion and polar distribution of several
G-protein subunits along nephron seg­
ments. Kidney Int. 40:997-1 006
35. Burnatowska-Hledin M A . Spielman
WS. 1 988. Immunodissection of mi­
tochondria-rich cells from rabbit outer
medullary collecting tubule. A m . 1.
Physiol. 254:F907- 1 1
36. Burnatowska-Hledin MA, Spielman
WS. 1 989. Vasopressin VI receptors
on the principal cells of the rabbit
cortical collecting tubule: stimulation
of cytosolic free calcium and inositol
phosphate production via coupling to
a pertussis toxin substrate. 1. Clin.
InvesT. 83 :84-89
37. Canessa CM, Horisberger J-D, Rossier
BC. 1 993. Epithelial sodium channel
related to proteins involved in ncu­
rodegeneration. Nature 361 :467-70
38. Cantiello HF, Patenaude CR, Codina
J, Birnbaumer L. 1 990. G alpha i-3
regulates epithelial Na + channels by
activation of phospholipase A2 and
lipoxygenase pathways. 1. Bioi. Chem.
265:21 624-28
39. Cantiello HF, Stow JL, Prat AG,
Ausiello DA. 1 99 1 . Actin filaments
regulate epithelial Na + channel activ­
ity. A m . 1. Physiol. 261 :C882-88
40. Carpenter G, Cohen S. 1 990. Epider­
mal growth factor. J. Bioi. Chem.
265( 14):7709- 1 2
41. Carr OW, Stofko-Hahn RE, Fraser
IDC, Cone RD, Scott ID. 1 992. Lo­
calization of the cAMP-dependent pro­
tein kinase to the postsynaptic densities
by A-Kinase anchoring proteins: char­
acterization of AKAP 79. 1. Bioi.
Chem. 267: 1 68 1 6-23
42. Chen L, Reif MC, Schafer JA. 1 99 1 .
Clonidine and PGE2 have different
effects on Na + and water transport in
rat and rabbit CCD. Am. 1. Physiol.
26 1 :F I 26- 1 36
43. Chilablin AV, Vasilates LA, Hennekes
H, Pra10ng 0, Geering K. 1 992. Phos­
phorylation of Na,K-ATPase a-sub­
units in microsomes and in homog­
enates of Xenopus oocytes resuting
from the stimulation of protein kinase
A and protein kinase C. J. Biol. Chern.
267(3 1 ):22378-84
44. Cl ark ID, Lin L-L, Kriz RW, Ramesha
CS, Su1tzman LA, et al. 1 99 1 . A
novel arachidonic acid-selective cytoso­
2+
lie PLA2 contains a Ca -dependent
translocation domain with homology
to PKC and GAP . Cell 65: 1 043-5 1
45 . Coffey AK, O'Sullivan OJ, Homma
S, Dousa TP, Valtin H. 1 99 1 . in­
duction of intramembranous particle
c1ustcrs in mice with ncphrogenic
diabetes insipiduS. Am. J. Physiol.
26 1 :F640-46
46. Conklin BR, Chabre 0, Wong YH,
Federman AD, Bourne HR. 1992.
Recombinant Gqa. 1. Bioi. Chern.
267: 3 1 -34
47. Cort J H . , Schlick 0, Stribma J, Skop­
kova J, Jost K, Mulder JL. 1 97 5 . Role
of the disulfide bridge and the C-ter­
minal tripeptide in the antidiuretic ac­
tion of vasopressin in man and the
rat. Kidney Int. 8:292-302
48. Ding G, McGovern B, Singhal P,
Hays RM. 1 989. Aggrephores have
 COLLECTING DUCT SIGNALING
little, if any role In water channel
delivery in rat collecting duct. Kidney
Int. 35:305
49. Dixon B S , Breckon R, Burke C , An­
derson RJ. 1988 . Phorbol esters inhibit
adenylate cyclase activity in cultured
collecting tubular cells. Am. J. Physiol.
254:C I 83-91
SO. Dong L , Stevens JL, Jaken S. 1 99 1 .
Biochemical and immunological char­
acterization of renal protein kinase C.
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
Am. J. Physiol. 261 :F678-87
5I . Doucet A, Barlet C. 1986. Evidence
for differences in the sensitivity to
ouabain of Na/K-ATPase along the
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
nephrons of rabbit kidney. J. Bioi.
Chem. 261 :993-95
52. Dousa TP, Valtin H. 1 976. Cellular
actions of vasopressin in the mamma­
lian kidney. Kidney Int. 1 0:46--63
53. Edwards RM, Jackson BA, Dousa TP.
1980. Protein kinase activity in isolated
tubules of rat medulla. Am. J. Physiol.
238:F269-78
54. Emanuel lR, Garetz S, Sone L, leven­
son R. 1 987. Differential expression
of Na-K-ATPase alpha and beta subunit
mRNAs in rat tissues and cell lines.
Proc. Natl. Acal. Sci. USA 84:9030--34
55. Exton JH. 1 990. Signaling through
phosphatidylcholine breakdown. J.
Bioi. Chem . 265 ( 1 ) : 1-4
56. Fejes-T6th G, Naray-Fejes-T6th A.
1 987. Differentiated transport func­
tions in primary cultures of rabbit
collecting ducts. Am. J. Physiol. 253:
F 1 302-7
57. Fejes-Toth G, Naray-fejes-Toth A .
1 992. Differentiation o f l3-intercalated
cells (!3-ICC) in culture into a-ICC
and principal cells (PC) via asymmetric
cell division. J. Am. Soc. Nephrol.
3:838 (Abstr.)
58. Fejes-Toth G , Zahajszky T, Filep J.
1 980. Effect of vasopressin on kalli­
krein excretion. Am. J. Physiol. 239:
F388-92
59. Ferris CD, Huganir RL, Supattapone
S, Snyder SH. 1 989. Purified inositol
1 ,4,5-trisphosphate receptor mediates
calcium flux in reconstituted lipid ves­
icles. Nature 342:87-89
60. Field MF, Stanton BA, Giebisch GH.
1 984. Influence of AIJH on renal
potassium handling: a micropuncture
and microperfusion study. Kidney Int.
25:502- 1 1
61. Frindt G , Burg M B . 1 972. Effect of
vasopressin on sodium transport in renal
cortical collecting tubules. Kidney Int.
1 :224--3 1
62. Frindt G, Windhager EE. 1 990. Ca2-t _
dependent inhibition of sodium trans-
733
port in rabbit cortical collecting tubules.
Am. J. Physiol. 258:F568-82
63. Fushimi K, Uchuda S, Hara Y, Hirata
Y , Marumo F, Sasaki S. 1 993 . Cloning
and expression of apical membrane
water channel of rat kidney collecting
tubule. Nature 361 :549--52
64. Gamba G, Saltzberg SN, Lombardi M ,
Miyanoshita A, Lytton J , e t al. 1993.
Primary structure and functional ex­
pression of a eDNA encoding the
thiazide-sensitive, electroneutral so­
dium-chloride cotransporter. Proc.
Natl. Acad. Sci. USA 90:2749--53
65. Gapstur SM, Homma S, Dousa TP.
1988. cAMP-binding proteins in med­
ullary tubules from rat kidney: effect
of ADH. Am. J. Physiol. 255:F292-
300
66. Garcia-Perez A, Smith WL. 1 984.
Apical-basolateral membrane asymme­
try in canine cortical collecting tubule
cells. J. CUn. Invest. 74:63-74
67. Garg LC. 1992. Actions of adren­
ergic and cholinergic drugs on renal
tubular cells. Pharmacol. Rev. 44( 1 ):
8 1 - 1 02
68. Glatt CE, Snyder SH. 1 993. Cloning
and expression of an adenylyl cyclase
localized to the corpus striatum. Nature
361 :536-38
69. Goldschmidt-Clermont P, Kim JW,
Machesky LM, Rhee SG, Pollard TD.
1 99 1 . Regulation of phospholipase C­
'Y I by profilin and tyrosine phosphor­
ylation. Science 25 1 : 1 23 1-33
70. Grantham JJ, Burg MB. 1 966. Effect
of vasopressin and cyclic AMP on
permeability of isolated collecting tu­
bules. A m . J. Physiol. 2 1 1 :255-59
71. Gupta SK, Diez E, Heasley LE, Osawa
S, Johnson GL. 1990. A G protein
mutant that inhibits thrombin and pu­
rinergic receptor activation of phos­
pholipase A2. Science 249:662-66
72. Han IS , Maeda Y, Knepper MA. 1 992.
High concentration of vasopressin in­
hibit vasopressin-stimulated water
transport in rat terminal IMCD. J. Am .
Soc. Nephrol. 3:793 (Abstr.)
73. Hardy MA. 1 978. Intracellular calcium
as a modulator of transepithelial per­
meability to water in frog urinary
bladder. J. Cell Bioi. 76:787-9 1
74. Harris HW, Strange K, Zeidel ML.
1 99 1 . Current understanding of the
cellular biology and molecular structure
of the antidiuretic hormone-stimulated
water transport pathway. J. CUn. In­
vest. 88: 1-8
75. Harrison JK, Hewlett KGH, Gnegy
ME. 1989. Regulation of calmodulin­
sensitive adenylate cyclase by the stim-
 734 BREYER & ANOO
ulatory G-protein, Gsa. J. 8iol. Chem .
264: 1 5880-85
76. Hartwig JH, Thelen M, Rosen A,
Janmey PA, Nairn AC, Aderem A.
1992. MARCKS is an actin filament
crosslinking protein regulated by pro­
tein kinase C and calcium-calmodulin.
Nature 356:61 8-22
77. Hays RM. 1 99 1 . Cell biology of va­
sopress in . In The Kidney , ed. BM
Brenner, FC Rector, pp. 424--44. Phil­
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
adelphia: Saunders
78. Hays SR, Baum M, Kokko JP. 1987.
Effects of protein kinase C activation
on sodium , potassium, chloride , and
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
total CO2 transport in the rabbit cortical
collecting tubule. J. CUn. Invest. 80:
1 561-70
79. Hebert RL, Jacobson HR, Breyer MD.
1 99 1 . Prostaglandin E2 inhibits sodium
transport in the rabbit CCD by raising
intracellular calcium. J. CUn. Invest.
87: 1992-98
80. Hebert RL, Jukic D, Regoli D. 1992 .
Mediation of bradykinin (BDK) actions
in rabbit cortical collecting duct (CCD)
via a specific BDK-B2 receptor. J.
Am. Soc. Nephrol. 3(3):493
81. Ho K, Nichols CG, Lederer WJ, Lytton
J, Vassilev PM, et al. 1993. Cloning
and expression of an inwardly rectify­
ing ATP-regulated potassium channel.
Nature 362:3 1-38
82. Holmgren K, Mugnusson K-E, Franki
N, Hays RM. 1992. ADH-induced
depolymerization of F-actin in the toad
bladder granular cell: a confocal mi­
croscope study. Am. J. Physiol. 262:
C672-77
83. Holt WF, LeChene C. 1 98 1 . ADH­
PGE2 interactions in cortical collecting
tubule. I . Depression of sodium trans­
port. Am. J. Physiol. 241 :F452-60
84. Homma S , Gapstur SM, Coffey A ,
Valtin H, Dousa TP. 1 99 1 . Role of
cAMP-phosphodiesterase isozymes in
pathogenesis of murine nephrogenic
diabetes insipidUS. Am. J. Physiol.
261 :F345-53
85. Homma S, Gapstur SM, Yusufi ANK,
Dousa TP. 1 988. In situ phosphoryla­
tion of proteins in MCTs micro­
dissected from rat kidney: effect of
AVP. Am. J. Physiol. 254:F5 1 2-20
86. Homma S , Takeda S , Tetsuka T,
Kusano E, Asano Y. 1 99 1 . Vasopressin
(AVP) stimulates low-Km cAMP phos­
phodiesterase (PDE) in medullary col­
lecting ducts (MCD). J. Am. Soc.
Nephrol. 2:723
87. Huang C , Cabot Me. 1 990. Vasopres­
sin-induced polyphosphoinositide and
phosphatidylcholine degradation in fi-
broblasts. J. 8iol. Chem . 265 : 1 7468-
73
88. Irvine RF. 1 982. How is the level of
free arachidonic acid controlled in
mammalian cells? B iochem . J. 204:3-
16
89. Ishikawa S , S aito T. 1 990. Optimal
concentration of cellular free calcium
for A VP-induced cAMP in collecting
tubules. Kidney Int. 37: 1 060-66
90. Jabs K , Zeidel ML, Silva P. 1989.
Prostaglandin E2 inhibits Na +-K+ -
ATPase activity in the inner medullary
collecting duct. Am. J. Physiol. (257):
P424-F430
91. Jassier P, Bugeon L, Blot-Chabaud M ,
Bonvalet JP, Farman N . 1989. Effects
of AVP and dDA VP on PGE2 synthesis
in superfused cortical collecting tu­
bules. Am. J. Physiol. 256:FI044-50
92. Jin S-LC, Swinnen JV, Conti M . 1 992.
Characterization of the structure of a
low Km rolipram-sensitive cAMP phos­
phodiesterase . J. Bioi. Chem. 267:
1 8929--39
93 . Jones SM, Frindt G, Windhager EE.
1988. Effect of peritubular [Cal or
ionomycin on hydrosmotic response of
CCTs to ADH or cAMP. Am. 1.
Physiol. 254:F240-53
94. Kashgarian M, Diemsderfer D, Caplan
M, Forbush B . 1985. Monoclonal an­
tibody to Na,K-ATPase: immunocyto­
chemical localization along nephron
segements. Kidney Int. 28:899--9 1 3
95. Katsushika S , Chen L , Kawabe J-I,
Nilakantan R , Halnon NJ, et al. 1 992.
Cloning and characterization of a sixth
adenylyl cyclase isoform: Types V and
VI constitute a subgroup within the
mammalian adenylyl cyclase family.
Proc. Natl. Acad. Sci. USA 89:8774-
78
96. Khan AA, Steiner JP, Klein MG,
Schneider MF, Snyder SH. 1 992. IP3
receptor: localization to plasma mem­
brane of T cells and cocapping with
the T cell receptor. Science 257 : 8 1 5-18
97. Kimura T, Share L. 1 98 1 . Character­
ization of the renal handling of vaso­
pressin in the dog by stop-flow
analysis. Endocrinology. 109:2089--94
98. Kirk KL. 1988. Binding and internal­
ization of a fluorescent vasopressin
analogue by collecting duct cells. Am.
J. Physiol. 255 :C622-32
99. Kirk KL. 1988. Origin of ADH-in­
duced vacuoles in rabbit cortical col­
lecting tubule . Am. J. Physiol. 254:
F7 1 9--33
100. Kleyman TR, Kraehenbuhl I-P, Ernst
SA. 199 1 . Characterization and cellular
localization of the epithelial Na + chan-
 COLLECTING DUCT SIGNALING
nel: studies using an anti-Na + channel
antibody raised by an antiidiotypic
route. J. BioI. Chem. 266(6):3907-1 5
1 0 1 . Knepper MA, Lankford SP, Tereda Y.
1 99 1 . Renal tubular actions of ANF.
Can. J. Physiol. Pharmacol. 69: 1 537-
45
\02. Knepper MA, Star RA. 1 990. The
vasopressin-regulated urea transporter
in renal inner medullary collecting duct.
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
Am. J. Physiol. 259:F393-401
\ 03 . Kosaka Y, Ogita K, Ase K, Nomura
H , Kikkawa U , Nishizuka Y . 1988.
The heterogeneity of protein kinase C
in various rat tissues. Biochem . Bio­
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
phys. Res. Comm. 1 5 1 :973-8 1
\04. Krupinski J, Lehman TC, Frankenfield
CD, Zwaagstra JC, Watson PA. 1992.
Molecular diversity in the adenyly-cy­
cIase family: evidence for eight forms
of the enzyme and cloning of type VI.
J. Bioi. Chern. 267(34):24858-62
105. Kusano E, Murayama N, Werness JL,
Christensen S, Homma S, et al. 1985.
Effects of calcium on the vasopressin­
sensitive cAMP metabolism in medul­
lary tubules. Am. J. Physiol. 249:
F956-66
\06. Leaf A, Anderson J, Page LB. 1958.
Active sodium transport by the isolated
toad bladder. J. Gen. Physiol. 4 1 :657-
68
\07. Lefurgey A, Tisher CC. 1979. Mor­
phology of the rabbit collecting tubule.
Am. J. Anal. 1 55: 1 1 1-24
108. Leite JM, Rouse D, Lederer E,
Abramowitz J , Suki WN. 1 99 1 . TMB-8
prevents the hydroosmotic response to
ADH in rabbit cortical collecting tu­
bules. Kidney Int. 40:434-40
109. Li G, Pralong W-F, Pittet D, Mayr
GW, Schlegel W, Wollheim CB. 1992.
Inositol tetrakisphosphate isomers and
elevation of cytosolic Ca2+ in vaso­
pressin-stimulated insulin-secreting
RINm5F cells. J. Bioi. Chem . 267:
4349-56
1 10. Light DB, Corbin JD, Stanton BA.
1990. Dual ion-channel regulation by
cyclic GMP and cyclic-GMP dependent
protein kinase. Nature 344:336--39
111. Lin L-L, Wartmann M, Lin AY, Knopf
JL, Seth A, Davis RJ. 1993. cPLA2
is phosphorylated and activated by
MAP kinase. Cell 72:269-78
1 1 2. Lin M, Nairn AC, Guggino SE. 1992.
cGMP-dependent protein kinase regu­
lation of a chloride channel in T -84
cells. Am. J. Physiol. 262:CI 304- 1 2
1 13. Ling B N , Hinton CF, Eaton DC. 1 99 1 .
Potassium permeable channels i n pri­
mary cultures of rabbit cortical collect­
ing tubule. Kidney Int. 40:441-52
735
1 14. Ling BN, Kokko KE, Eaton DC. 1992.
Inhibition of apical Na+ channels in
rabbit cortical collecting tubules by
basolateral prostaglandin E2 is modu­
lated by protein kinase C. J. Clin.
Invest. 90:1 328-34
1 15. Lingueglia E, VoilJey N, Waldmann
R, Lazdunski M, B arbry P. 1993.
Expression cloning of an epithelial
amiloride-sensitive Na+ channel. FEBS
Lett. 3 1 8:95-99
1 1 6. Lolait S1, 0'Carrol A-M, McBride
OW, Konig M, Morel A, Brownstein
MJ. 1992. Cloning and characterization
of a vasopressin V2 receptor and pos­
sible link to nephrogenic diabetes in­
sipidUS. Nature 357:336--39
1 17. Ludwig J, Margalit T, Eismann E,
Lancet D, Kaupp UB . 1990. Primary
structure of cAMP-gated channel from
bovine olfactory epithelium. FEBS
Lett. 270:24-29
1 1 8. Madsen KM, Tisher CC. 1986. Struc­
ture function relationships along the
distal nephron. Am. J. Physiol. 250
( l 9): F 1 - l 5
1 19. Manganiello VC , Smith CJ, Degerman
E, Belfrage P. 1990. Cyclic GMP-in­
hibited cyclic nucleotide phospho­
dieterases. In Cyclic Nucleotide Phos­
phodiesterases: Structure, Regulation
and Drug Action. ed. J Beavo. MD
Houslay, pp. 87- 1 1 6 . New York:
Wiley & Sons
120. Marunaka Y, Eaton DC. 1 99 1 . Effects
of vasopressin and cAMP on single
amiloride-blockable Na channels. Am .
J. Physiol. 260:C\ o71-84
121. Masur SK, Sapirstein V, Rivero D .
1 985 . Phorbol myristate acetate in­
duces endocytosis as well as exocyto­
sis and hydroosmusis in toad urinary
bladder. Biochem . Biophys. Acta. 82 1 :
286-96
1 22 . Miller M, Moses AM. 1972. Urinary
antidiuretic hormone in polyuric dis­
orders and in inappropriate ADH
syndrome. Ann. Intern . Med. 77: 7 1 5-
21
1 23 . Miller RT. 1 99 1 . Transmembrane sig­
nalling through G proteins. Kidney Int.
39:421-29
124. Morel A, O'Carroll A-M, Brownstein
MJ, Lolait SJ. 1992. Molecular cloning
and expression of a rat V I a arginine
vasopressin receptor. Nature 356:523-
26
1 25 . Morel F, Doucet A. 1986. Hormonal
control of kidney functions at the cell
level . Physiol. Rev. 66:377-468
1 26. Moriarty TM, Padrell E, Carty DJ,
Omri G, Landau EM, Iyengar R .
1990. G o protein as signal transducer
 736 BREYER & ANDO
in the pertussis toxin-sensitive phos­
phatidylinositol pathway. Nature 343:
79-82
1 27 . Moses A, Steciak E. 1 986. Urinary
and metabolic clearances of arginine
vasopressin in normal subjects. Am.
J. Physiol. 25 1 :R365-70
1 28. Muller J, Kachadorian W A, DiScala
VA. 1980. Evidence that ADH-stim­
ulated intramembranous particle ag­
gregates are transfered from cyto­
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
plasmic to luminal membranes in toad
bladder epithelial cells. J. Cell Bioi.
85:83-95
1 29. Murayama T, Ui M. 1983. Loss of
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
the inhibitory function of the guanine
nucleotide regulatory component of ad­
enylate cyclase due to its ADP ribosyla­
tion by islet-activating protein, per­
tussis toxin, in adipocyte membranes.
J. Bioi. Chern. 258:33 1 9-26
1 30. Nadler SP, Zimpelmann JA, Hebert
RL. 1992. Endothelin inhibits vas­
orpessin-stimulated water permeability
in rat terminal inner medullary collect­
ing duct. J. Clin . Invest. 90: 1458-66
1 3 1 . Nagamine Y, Reich E. 1985. Gene
expression and cAMP. Proc. Natl.
Acad. Sci. USA 82:4606-1 0
1 32. Nakamura T, Gold G H . 1987. A cyclic
nucleotide-gated conductance in ulfac­
tory receptor cilia. Nature 325:442-44
1 3 3 . Natochin YV, Shakhmatova EL 1992.
Vasopressin V I -antagonist increases
the hydroosmotic response to arginine
vasopressin in frog urinary bladder.
Pfliigers Arch. 42 1 :406-8
1 34. Nemenoff RA, Sinitz S , Qian N-X,
Van Putten V, Johnson GL, Heasley
LE. 1 993. Phosphorylation and acti­
vation of a high molecular weight form
of phuspholipase A2 by p42 microtu­
bule-associated protein 2 kinase and
protein kinase C. J. Bioi. Chern .
268(3): 1960-64
1 3 5 . Nesterova MV, Glukhov AI, Severin
ES. 1982. Effect of regulatory subunit
of cAMP-dependent protein kinase on
the genetic activity of eukaryotic cells.
Mol. Cell. Biochem . 49:53-61
1 36. Nishizuka Y. 1992. Intracellular sig­
naling by hydrolysis of phospholipids
and activation of protein kinase C.
Science 258:607- 1 4
1 37 . Nonoguchi H , Sands J M , Knepper
MA. 1988. Atrial natriuretic factor
inhibits vasopressin-stimulated osmotic
water permeability in rat inner med­
ullary collecting duct. J. Clin. Invest.
82: 1 383-90
1 38. Nonoguchi HM, Knepper MA, Man­
ganiellu Vc. 1987. Effects uf atrial
natriuretic factor on cyclic guanosine
monophosphate and cyclic adenosine
monophosphate accumulation in micro­
dissected nephron segments from rats.
J. Clin. Invest. 79:500-7
139. Ohuchi K , levIne L. 1978. Stimulation
of prostaglandin synthesis by tumor
promoting phorbol- 1 2 , 1 3-diesters in ca­
nine kidney (MDCK) cells. J. Bioi.
Chern. 253 :4783-90
140. O'Neil RG, Hayhurst RH. 1 985. Func­
tional differentiatiun uf cell types of
the cortical collecting duct. Am . J.
Physiol. 248:F449-53
141 . Orloff J, Handler JS. 1962. The sim­
ilarity of effects of vasopressin, aden­
osine-3' ,5' -phosphate (cyclic AMP) and
theophylline on the toad bladder. J .
Clin. Invest. 41 :702-9
142. Palmer LG. 1992. Epithelial Na chan­
nels: function and diversity. Annu. Rev.
Physiol. 54:5 1-66
143. Palmer LG, Frindt G. 1986. Amilor­
ide-sensitive Na channels from thc
apical membrane of the rat cortical
collecting tubule. Proc . Natl. Acad.
Sci. USA 83:2767-70
144. Palmer LG, Frindt G. 1987. Effects
of cell Ca and pH on Na channels
from rat cortical collecting tubule. Am .
J. Physiol. 253:F333-39
145. Pelech SL, Sanghera JS. 1992. MAP
kinases: charting the regulatory path­
ways. Science 257: 1 355-56)
146. Peterson MW, Walter ME. 1992. Cal­
cium-activated phosphatidylcholine­
specific phospholipase C and D in
MDCK epithelial cells. Am . J. Physiol.
263:C I 2 1 6-24
147. Phillips ME, Taylor A. 1989. Effect
of nocodazole on the water permeabil­
ity response to vasopressin in rabbit
collecting tubules perfused in vitro. J.
Physiol. 4 1 1 :529-44
148. Premont RT, Chen J , Ma H-W, Pon­
napalli M, Iyengar R. 1992. Two
members of a widely expressed sub­
family of hormone-stimulated adenylyl
cyclases. Proc . Natl. Acad. Sci. USA
89:9809- 1 3
149. Preston B M , Agre P. 1 99 1 . Isolation
of the eDNA for erythrocyte integral
membrane protein of 28 kilodaltons:
member of an ancient channel family.
Proc. Natl. Acad. Sci. USA 88: 1 1 1 10-
14
150. Preston BM, Carroll TP, Guggino WB ,
Agre P. 1992. Appearance of water
channels in Xenopus oocytes expressing
red cell CHIP28 protein. Science 256:
385-87
151. Rabkin R, Share L, Payne PA, Young
J, Crofton J. 1979. The handling of
immunoreactive vasopressin by the iso-
 COLLECTING DUCT SIGNALING
lated perfused rat kidney. 1. Clin.
Invest. 63:6-13
1 52. Reif MC, Troutman SL, Schafer JA.
1 984. Sustained response to vasopressin
in isolated rat cortical collecting tubule .
Kidney Int. 26:725-32
1 53 . Repaske DR, Swinncn JV, Jin S-LC,
Van Wyk 11, Conti M. 1992. A
polymerase chain reaction strategy to
identify and clone cyclic nucleotide
phosphodiesterase cDNAs. 1. Bioi.
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
Chern . 267 : 1 8683-88
154. Rhee SG, Choi KD. 1992. Regulation
of inositol phospholipid-specific phos­
pholipase C isozymes. J. Bioi. Chem.
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
267( 1 8): 12393-96
1 55 . Ribeiro C-P, Ribeiro-Neto F, Field JB,
Suki WN. 1987. Prevention of a2-ad­
renergic inhibition on ADH action by
pertussis toxin in rabbit CCT. Am. 1.
Physioi. 253:CI05-12
1 56. Rick R. Spancken G . Dorge A. 1 988.
Differential effects of aldosterone and
ADH on intracellular electrolytes in
the toad urinary bladder epithelium. J.
Membr. Bioi. 1 0 1 :275-82
1 57 . Robertson GL. 1977. The regulation
of vasopressin function in health and
disease. Recent Prog. Harm. Res. 33:
333-85
1 58. Rocha AS, Kudo LH. 1990. Atrial
peptide and eGMP effects on NaCI
transport in inner medullary collecting
duct. Am. J. Physiol. 259:F258--68
1 59. Rocha AS, Kudo LH. 1990. Effect of
atrial natriuretic factor and cyclic
guanosine monophosphate on water and
urea transport in the inner medullary
collecting duct. Pfliigers Arch. 4 1 7:84-
90
160. Rouch AJ, Chen L, Kudo L, Corbitt
BD, Schafer lA. J 99 1 . Changes in
intracellular Ca2 + or PKC activity do
not alter AVP-dependent Na + or H 20
transport in the rat cortical collecting
duct (CCD) . J. A m . Soc. Nephrol.
2:740 (Abslr.)
161. Rouch AJ, Chen L, Troutman SL,
Schafer JA. 1 99 1 . Na+ transport in
isolated Tat CCD: effects of bradykinin,
ANP. c1onidine. and hydrochlorothia­
zide. Am. J. Physiol. 260:F86-95
162. Sabolic I, Valenti G, Verbavatz J-M,
Van Hoek AN, Verkman AS, et al.
1992. Localization of the CHIP28 water
channel in rat kidney. Am. J. Physiol.
263:CI 225-33
163. Sariban-Sohraby S, Sorscher EJ, Bren­
ner BM, Benos DJ. 1988. Phosphor­
ylation of a single subunit of the
epithelial Na channel protein following
vasopressin treatment of A6 cells. J.
Bioi. Chern . 263: 1 3875-79
737
164. Sasaki S. Fushimi K. Uchida S ,
Mammo F. 1992. Regulation and lo­
calization of two types of water channel
in the rat kidney. J. Am. Soc. Nephrol.
3:798 (Abstr.)
165. Satoh T, Cohen HT, Kats AI. 1992.
Intracellular signaling in the regulation
of renal Na-K-ATPase. I. role of cyclic
AMP and phospholipase A2 . J. Clin .
Invest. 89: 1 496-1 500
166. Schafer JA, Hawk CT. 1992. Regula­
tion of Na + channels in the cortical
collecting duct by AVP and min­
eralocorticoids. Kidney Int. 4 1 :255-68
167. Schafer JA, Troutman SL. 1 990. cAMP
mediates the increase in apical mem­
brane Na + conductance produced in
rat CCD by vasopressin. Am. J . Phys­
iol. 259(28):F823-3 1
168. Schafer JA, Troutman SL, Schlatter
E. 1990. Vasopressin and mineral­
ocorticoid increase apical membrane
driving force for K+ secretion in rat
CCD. Am. J. Physiol. 258:FI99-2 1 0
169. Schlondorff D. Levine S D . 1985. In­
hibition of vasopressin stimulated water
flow in toad bladder by phorbol my­
ristate acetate, dioctanoylglycerol, and
RHC- 80267 . 1. Clin . Invest. 76: 1071-
78
170. Schlondorff 0, Satriano JA, Schwartz
GJ. 1985. Synthesis of prostaglandin
E2 in different segments of isolated
collecting tubules from adult and neo­
natal rabbits. Am. 1. Physiol. 248:
F 1 34-44
171. Schuster VL. 1985. Mechanism of
bradykinin, ADH, and cAMP interac­
tion in rabbit cortical collecting duct.
Am. J. Physial. 249:F645-53
172. Schuster VL. 1993. Function and reg­
ulation of collecting duct intercalated
cells. Annu. Rev. Physiol. 55:267-88
173. Scott 10. 1 99 1 . Cyclic nucleotide-de­
pendent protein kinases. Pharmacal.
Ther. 50: 1 23-45
174. Scott JD, Stofko RE, McDonalds JR,
Comer JD, Vitalis EA, Mangili JA.
1990. Type II regulatory subunit di­
merization determines the subcellular
localization of the cAMP-dependent
protein kinase. J. Bioi. Chern. 265:
2 1 56 1-66
1 75 . Senkfor 51, Johnson GL, Berl T. 1993.
Molecular map of G protein a chains
in microdissected rat nephron segments.
J. Clin. Invest. 92:786-90
1 76 . Shacter E, Stadtman ER, Jurgensen
SR, Chock PB . 1988. Role of cAMP
in cyclic cascade regulation. See Ref.
16, pp. 3-19
177. Shariff A, Luna E. 1992. Diacyl­
glycerol-stimulated formation of actin
 738 BREYER & ANDO
nucleation sites at plasma membranes.
Science 256(256):24�7
178. Shayman JA, Morrissey n, Morrison
AR. 1987. Islet activating protein in­
hibits kinin-stimulated inositol phos­
phate production, calcium mobil­
ization, and prostaglandin E2 synthesis
in renal papillary collecting tubule cells
independent of cyclic AMP. J. Bioi.
Chem. 262 : 1 7083--87
Shimizu T, Yoshitomi K, Nakamura
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
1 79.
M, Imai M. 1 988. Site and mechanism
of action of trichlormethiazide in rabbit
distal nephron segments perfused in
vitro. J. Clin. Invest. 82:721-30
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
1 80. Skorecki KL, Verkman AS , Ausiello
DA. 1987. Cross talk between stimu­
latory and inhibitory guanosine 5' -tri­
phosphate binding proteins: role in
activation and desensitization of the
adenylate cyclase response to vasopres­
sin. Biochemistry. 26:639-45
1 8 1 . Slivka SR, Insel PA. 1987. c d -Ad­
renergic receptor-mediated phospho­
inositide hydrolysis and prostaglandin
E2 formation in Madin-Darby canine
kidney cells: possible parallel activation
of phospholipase C and phospholipase
A2. J. Bioi. Chem. 262(9):4200-7
1 82 . Smrck AV, Hepler JR, Brown KO,
Sternweis PC. 1 99 1 . Regulation of
polyphosphoinositide-specific phospho­
lipase C activity by purified Gq. Sci­
ence 804:804-7
1 83 . Snowdowne KW, Borle AB. 1985 .
Effect of low extracellular sodium on
cytosolic ionized calcium:Na + -ca2+
exchange as a major calcium influx
pathway in kidney cells. J. Bioi. Chem .
260: 14998-5007
1 84 . Snyder HM, Fredin OM, Breyer MD.
1 99 1 . Muscarinic receptor activation
inhibits AVP-induced water flow in
rabbit cortical collecting ducts. Am. J.
Physiol. 260:F283--3 6
185. Snyder HM, Noland TO, Breyer MD.
1992. cAMP-dependent kinase medi­
ates hydroosmotic effect of vasopressin
in collecting duct. Am. J. Physiol.
263:CI47-53
1 86. Sonnenburg WK, Mullaney PJ, Beavo
JA. 1 99 1 . Molecular cloning of a cyclic
GMP-stimulated cyclic nucleotide
phosphodiesterase cDNA: identification
and distribution of isozyme variants .
J. Bioi. Chem. 266(26) : 1 7655-61
1 87 . Sonnenburg WK, Smith WL. 1988.
Regulation of cyclic AMP metabolism
in rabbit cortical collecting tubule cells
by prostaglandins. J. Bioi. Chem . 263:
6 1 55-60
1 88. Sonnenburg WK, Zhu J, Smith WL.
1990. A prostglandin E receptor cou-
pled to a pertussis toxin-sensitive gua­
nine nucleotide regulatory protein in
rabbit cortical collecting tubule cells .
J. Bioi. Chem. 265:8479-83
1 89. Stanton BA. 1 99 1 . Molecular mecha­
nisms of ANP inhibition of renal
sodium transport. Can. J. Physiol.
Pharmacal. 69: 1 546--52
190. Star RA, Nonoguchi H, Balaban RB ,
Knepper MA. 1988. Calcium and cy­
clic adenosine monophosphate as sec­
ond messengers for vasopressin in the
rat inner medullary collecting duct. J.
Clin. Invest. 8 1 : 1 879-88
Stassen FL, Heckman G, Schmidt 0 ,
191.
Papadopoulos MT, Nambi P, et al.
1988. Oxytocin induced a transient
increase in cytosolic free [Ca2 +] in
renal tubular epithelial cells: evidence
for oxytocin receptors on LLC-PKI
cells. Mol. Pharmacol. 33:21 8-24
192. Stoos BA, Carretero OA, Farhy RD,
Scicili G , Garvin JL. 1992. Endothe­
lium-derived relaxing factor inhibits
transport and increases cGMP content
in cultured mouse cortical collecting
duct cells. J. Clin. Invest . 89 : 761-65
193. Stow JL, Sabolic I, Brown D. 1 99 1 .
Heterogeneous localization of G protein
a-subunits in rat kidney. Am. J. Phys­
iol. 1 99 1 :F83 1-40
194. Strange K, Spring KR. 1 987. Cell
membrane water permeability of rabbit
cortical collecting duct. J. Membr.
BioI. 96:27-43
195. Sweadner KJ. 1989. Isozymes of the
Na+/K+-ATPase . Biochem. Biophys.
Acta 988: 1 85-220
196. Takeda S, Lin C-T, Morgano PG,
Mcintyre SJ, Dousa TP. 1 99 1 . High
activity of low-Michaelis-Menten con­
stant 3' ,5' -cyclic adenosine monophos­
phate-phosphodiesterase isozymes in
renal inner medula of mice with he­
reditary nephrogenic diabetes insipidus.
Endocrinology. 1 29:287-94
197. Taussig R, Qaurmby LM, Gilman AG.
1993. Regulation of purified type I
and type II adenylyIcyciases by G
protein bg subunits. J. Bioi. Chem.
268:9- 1 2
198. Taylor A , Mamelak M , Reaven E ,
Maffly R. 1973 . Vasopressin: possible
role of microtubules and microfilaments
in its action. Science 1 8 1 : 347-50
199. Taylor SJ, Chae HZ, Rhee SG, Exton
JH. 1 99 1 . Activation of the 13 1 isozyme
of phospholipase C by a subunits of
the Gq class of G proteins. Nature
350: 5 1 6- 1 8
200. Teitelbaum I . 1990. The epidermal
growth factor receptor is coupled to a
phospholipase A2-specific. pertussis
 COLLECTING DUCT SIGNALING
toxin inhibitable guanine nucleotide­
binding regulatory protein in cultured
rat inner medullary collecting tubule
cells. J. Bioi. Chem. 265:42 1 8-22
20 1 . Tereda Y, Knepper MA. 1990. Thia­
zide sensitive NaCI absorption in rat
cortical collecting duct. A m . J. Physiol.
259:F5 1 9-28
202. Tereda Y, Moriyama T, Martin BM,
Knepper MA, Garcia PA. 1 99 1 . RT­
PCR microlocalization of mRNA [or
Access provided by University of California - San Francisco UCSF on 01/31/15. For personal use only.
guanyly1 cyclase-coupled ANF receptor
in rat kidney. Am. J. Physiol. 26 1 :
F 1 080-87
203. Tereda Y, Tomita K, Nonoguchi H ,
Annu. Rev. Physiol. 1994.56:711-739. Downloaded from www.annualreviews.org
Marumo F. 1992. Polymerase chain
reaction localization of constitutive ni­
tric oxide synthase and soluble guanyl­
ate cyclase messenger RNAs in micro
dissected rat nephron segments. J. Ciin.
Invest. 90:659-65
204. Tetsuka T, Kusano E, Takeda S ,
Homma S , Ando Y , Asano Y . 1 992.
Phorbol myristate acetate (PMA) acti­
vates rolipram sensitive cyclic AMP
phosphodiesterase (POlE) in medullary
collecting tubules (MCT) of the rat
kidney. J. Am. Soc. Nephrol. 3 : 5 1 0
205. Torikai S , Kurokawa K . 1 98 3 . Effect
of PGE2 on vasopressin-dependent cell
cAMP in isolated single nephron seg­
ments. Am. J. Physiol. 249:F58-F66
206 . Ujiie K, Drewett JG, Yuen ST, Star
RA. 1 993. Differential expression of
mRNA for guanylyl cyclase-linked en­
dothelium derived relaxing factor re­
ceptor subunits in rat kidney. J. CUn.
Invest. 9 1 :730-34
207. Vehaskari VM, Hering-Smith KS,
Moskowitz DW, Weiner ID, Hamm
LL. 1 989. Effect of epidermal growth
factor on sodium transport in the cor­
tical collecting tubule. A m . J. Physioi.
256:F803-9
208. Vehaskari VM, Herndon J, Hamm LL.
1 99 1 . Mechanism of sodium transport
inhibition by epidermal growth factor
in cortical collecting ducts. Am. J.
Physiol. 26 1 :F896-903
209 . Verkman A S , Lencer WI, Brown D ,
Ausiello DA. 1 988. Endosomes from
kidney collecting tubule cells contain
the vasopressin-sensitive water channel.
Nature 333:268-69
210. Wade JB , Kachadorian WA. 1 98 8 .
Cytochalasin B inhibition of toad blad­
der apical membrane responses to
ADH. Am. J. Physiol. 255:C526
739
21 J . Walker LA, Whorton AR, Smigel M ,
France R , Frolich JC. 1 978. Antidi­
uretic hormone increases renal prosta­
glandin synthesis in vivo. Am. J.
Physiol. 234:F1 80-85 .
212. Wang W, Giebisch G. 1 99 1 . Dual
effect of adenosine triphosphate on the
apical small conductance K+ channel
of the rat cortical collecting duct. J.
Gen. Physioi. 98:35-61
213. Wang W , Giebisch G . 1 99 1 . Dual
modulation of renal ATP-sensitive K +
channel b y protein kinases A and C .
Proc. Natl. Acad. Sci. USA 88 :9722-25
214. Wang W, Sackin H , Giebisch G. 1 992.
Renal potassium channels and their
regulation. Annu. Rev. Physioi. 54:8 1 -
96
215. Warden D H , Stokes JB . 1 993 . EGF
and PGE2 inhibit rabbit CCD Na+
transport by different mechanisms:
PGE2 inhibits the Na+jK+-ATPase .
Am. J. Physioi. 264:F670-77
2 1 6. Wilke TM, Scherle PA, Strathmann
MP, Slepak VZ, Simon Ml. 1 99 1 .
Characterization of G-protein ex sub­
units in the Gq class: Expression in
murine tissues and in stromal and
'hematopoietic cell lines. Proc. Natl.
Acad. Sci. USA 8 8 : 10049-53
217. Wong S-K-F, Garbers DL. 1 992. Re­
ceptor guanylyl cyclases. J. Clin. In­
vest. 90:299-305
218. Xing M, Mattera R. 1992. Phosphor­
ylation-dependent regulation of phos­
2
pholipase A2 by G-proteins and Ca +
in HL-60 granulocytes. 1. Bioi. Chem .
267(36):25966-75
219. Yagil Y. 1 992. Differential effect of
basolatera1 and apical adenosine on
A VP-stimulated cAMP formation in
primary culture of IMCD. A m . J.
Physioi. 263: F268-76
220. Yanese M, Handler JS. 1 986. Activa­
tors of protein kinase C inhibit sodium
transport in A6 epithelia. Am. J. Phys­
iol. 250:C5 1 7-22
22 1 . Yoshimura M, Cooper DMF. 1 992.
2
Cloning and expression of a Ca +
inhibitable adenylyl cyclase from NeB-
20 cells. Proc. Nat!. Acad. Sci. USA
89:67 1 6-20
222. Zeide1 ML, Brady HR, Kone B C ,
Gullans SR, Brenner B M . 1 989. En­
dothelin, a peptide inhibitor of Na+­
K+ -ATPase in intact renal tubular
epithelial cells. A m . J. Physiol. 257:
C I I O I -07