opening? Another question is whether the coupling of DHPR 2. Fruen BR, Bardy JM, and Louis CF.
Bardy JM, and Louis CF. Calmodulin activation of skeletal mus-
to RYR1 alters the ability of the DHPR to bind CaM. As men-
tioned previously, there is a difference in apoCaM modulation
of RYR1 and RYR2, in that apoCaM does not appear to mod-
ulate the latter. This raises a question as to what differences in
primary structure between RYR1 and RYR2 account for differ-
ences in activation of the two RYRs by apoCaM.
In summary, it seems likely that CaM binding to the DHPR
and RYR must, in some way, modulate E-C coupling in both
cardiac and skeletal muscle. Its role may be to regulate the
Ca2+-dependent enhancement and inhibition of activity or,
possibly, to prevent or enhance coupling between the DHPR
and RYR1. Since CaM plays a wide variety of roles in both
development and cell function, it would be difficult to create
a CaM knockout animal model to determine the functional
role of CaM in regulation of either cardiac or skeletal muscle
E-C coupling. Instead, the most likely approach will be to
mutate its binding sites on RYR1 and/or the DHPR, express
these mutated channels in cells that are deficient in one of
these proteins, and assess the functional consequences. This
approach will require the further identification of the molec-
ular determinants on RYR and the DHPR involved in both
apoCaM and Ca2+CaM binding. If the amino acids needed
for apoCaM binding are different from those for Ca2+CaM
binding, it may be possible to selectively destroy the binding
of one form of CaM without greatly altering the interaction of
the other form. This would allow the assessment of the func-
tional contributions of the different forms of CaM.
References
1. Franzini-Armstrong C and Protasi F. Ryanodine receptors of striated mus-
cles: a complex channel capable of multiple interactions. Physiol Rev 77:
699–729, 1997.
GABA in the Mammalian Enteric Nervous System
Anthony Krantis
γ-Aminobutyric acid (GABA) is a transmitter of enteric interneurons, targeting excitatory GABAA or
inhibitory GABAB receptors that modulate motility and mucosal function. Enteric GABA may also
subserve hormonal and paracrine signaling. Disruption in gastrointestinal function following
perturbation of enteric GABA receptors presents potential new target sites for drug development.
S ince 1980, a considerable body of literature has accu-
mulated on the occurrence, distribution, and actions of
γ-aminobutyric acid (GABA) in the mammalian gastrointesti-
nal tract. Although these reports convincingly show that
GABA meets the criteria to be considered a transmitter of
enteric neurons, it has received little attention from researchers
studying the neurochemistry of the enteric nervous system
A. Krantis is a Professor in the Department of Cellular and Molecular Med-
icine, Digestive Diseases Research Group, University of Ottawa, Ottawa,
ON, Canada K1H 8M5.
284 News Physiol. Sci. • Volume 15 • December 2000
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cle (but not cardiac) ryanodine receptors: modulation by effectors of cal-
cium-induced calcium release (Abstract). Biophys J 74: A61, 1998.
3. Houdusse A, Silver M, and Cohen C. A model of Ca2+-free calmodulin
binding to unconventional myosins reveals how calmodulin acts as a
regulatory switch. Structure 4: 1475–1490, 1996.
4. Ikura M, Clore GM, Gronenborn AM, Zhu G, Klee CB, and Bax A. Solu-
tion structure of a calmodulin-target peptide complex by multidimen-
sional NMR. Science 256: 632–638, 1992.
5. Kuboniwa H, Tjandra N, Grzesiek S, Ren H, Klee CB, and Bax A. Solution
structure of calcium-free calmodulin. Nat Struct Biol 2: 768–776, 1995.
6. Moore CP, Rodney G, Zhang JZ, Santacruz-Toloza L, Strasburg G, and
Hamilton SL. Apocalmodulin and Ca2+ calmodulin bind to the same
region on the skeletal muscle Ca2+ release channel. Biochemistry 38:
8532–8537, 1999.
7. Moore CP, Zhang JZ, and Hamilton SL. A role for cysteine 3635 of RYR1
in redox modulation and calmodulin binding. J Biol Chem 274:
36831–36834, 1999.
8. Peterson BZ, DeMaria CD, Adelman JP, and Yue DT. Calmodulin is the
Ca2+ sensor for Ca2+-dependent inactivation of L-type calcium channels.
Neuron 22: 549–558, 1999.
9. Rhoads AR and Friedberg F. Sequence motifs for calmodulin recognition.
FASEB J 11: 331–340, 1997.
10. Rodney GG, Williams BY, Strasburg GM, Beckingham K, and Hamilton
SL. Regulation of RYR1 activity by Ca2+ and calmodulin. Biochemistry 39:
7807–7812, 2000.
11. Tripathy A, Xu L, Mann G, and Meissner G. Calmodulin activation and
inhibition of skeletal muscle Ca2+ release channel (ryanodine receptor).
Biophys J 69: 106–119, 1995.
12. Wagenknecht T, Berkowitz J, Grassucci R, Timerman A, and Fleischer S.
Localization of calmodulin binding sites on the ryanodine receptor from
skeletal muscle by electron microscopy. Biophys J 67: 2286–2295, 1994.
13. Xu L, Tripathy A, Pasek DA, and Meissner G. Potential for pharmacology
of ryanodine receptor/calcium release channels. Ann NY Acad Sci 853:
130–148, 1998.
14. Zhang JZ, Wu Y, Williams BY, Rodney G, Mandel F, Strasburg GM, and
Hamilton SL. Oxidation of the skeletal muscle Ca2+ release channel alters
calmodulin binding. Am J Physiol Cell Physiol 276: C46–C53, 1999.
15. Zuhlke RD, Pitt GS, Deisseroth K, Tsien RW, and Reuter H. Calmodulin
supports both inactivation and facilitation of L-type calcium channels.
Nature 399: 59–62, 1999.
(ENS). The presence of GABA neurons in enteric ganglia of a
variety of species has been reported. In the rat and human
intestine, enteric GABAergic neurons comprise at least three
distinct neurochemical populations and two morphological
cell types. Enteric GABAergic fibers are profuse, ramifying
throughout the ganglionated and nonganglionated enteric
nerve networks of the gut wall. The enteric GABAergic system
is in many respects identical to that of the central nervous
system (CNS), with some exceptions. Enteric GABAergic neu-
rons appear to be exclusively interneurons that release GABA
as an excitatory neurotransmitter, in contrast to its inhibitory
0886-1714/99 5.00 © 2000 Int. Union Physiol. Sci./Am.Physiol. Soc.
role in the CNS. In addition to GABAergic nerve fibers, the
mucosa of the rodent and human gut contains GABA in
endocrine-like cells in the gastric antrum through to the dis-
tal colon. This neural and endocrine cell localization for
GABA in the gut wall is a feature of other enteric transmitters,
including 5-hydroxytryptamine (5-HT), enkephalin, vasoac-
tive intestinal peptide (VIP), somatostatin, and substance P.
There are a number of reviews on GABA as a transmitter in
enteric nerves that have focused on GABA, its enzymes, and
its mechanisms of action in the ENS. The aim of this review
is to show the distribution of the GABAergic system within
the mammalian gut wall and how this system fits into a
model for GABAergic transmission with multiple signaling
pathways. In addition, GABAergic interneurons will be
shown to be involved in enteric neural circuits controlling
spontaneous and reflex motor and secretomotor activity.
When viewed in the context of the extensive pharmacologi-
cal data on GABA actions in the gastrointestinal tract, the
major neuronal and minor endocrine distribution of GABA,
and the presence of GABA receptor subunits in the mam-
malian gut wall, GABAergic neurotransmission must be a
major component in the control of gastrointestinal function.
It will become evident in the following discussion that
GABAergic interneurons represent the ideal candidate for the
integration of circuits controlling gut motility and secretion.
GABA in the gut
Neural. Like the CNS, the primary synthesis reaction for
enteric GABA is catalyzed by L-glutamate decarboxylase using
the substrate glutamate (3). Enteric GABA can also be derived
from putrescine via the actions of diamine oxidase/aldehyde
dehydrogenase. The highest L-glutamate decarboxylase activ-
ity in the gut wall is found in the myenteric plexus. Autoradi-
ographic and immunohistochemical (7) studies collectively
demonstrate GABAergic neurons with Dogiel type I and type II
morphology in myenteric ganglia. GABAergic neurons have
also been visualized in cultures of the myenteric plexus by
studies showing the high-affinity uptake, localization, and
release of GABA (7). GABAergic nerve fibers are typically vari-
cose and often form a rich arbor around ganglion cells. In the
rat, GABAergic neurons account for >5–8% of the total num-
ber of myenteric neurons in the large intestine. Examples of the
localization and distribution of GABAergic elements in the
gastrointestinal tract are shown in Fig. 1.
GABAergic myenteric interneurons in the human and rat
colon fall into three neurochemically distinct, nonoverlapping
subpopulations: 1) neurons with somatostatin, which account
for ~40% of the GABA population; 2) neurons with enkephalin,
which account for ~10 % of the GABA population; and 3) neu-
rons with NADPH diaphorase-related nitric oxide synthase
(NOS) activity, which account for ~20% of the GABA popu-
lation (Fig. 2). Neither somatostatin- nor enkephalin-positive
cells show NOS activity. GABAergic neurons also occur in
submucosa ganglia plexi (7) and are characterized as having
Dogiel type I or type II morphologies. GABAergic fibers project
within paravascular nerve bundles and, in some instances,
within perivascular innervation of the submucosa, as well as to
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the muscularis mucosae and the mucosa. Within the mucosa,
GABAergic nerve fibers ramify within the fine nerve plexus
underlying the base of the crypts, which serves as the interface
for the innervation of the mucosa.
Within the submucosa and mucosa, GABAergic cells were
seen to colocalize either somatostatin or NOS, but not both
(Fig. 2). No enkephalin-containing neural elements and only
low levels of methionine enkephalin itself occur in the submu-
cosa compared with the muscularis externa. Myenteric GABA
neurons colocalizing enkephalin may represent inhibitory
innervation of the muscularis, which modulates cholinergic-
mediated contractions (3). Conversely, somatostatin neurons
are found within the myenteric and submucosal plexi; however,
no somatostatin-immunoreactive fibers occur in the muscularis,
where most if not all axo-axonic interaction occurs. Indeed,
somatostatin has no direct myogenic actions; rather, fibers of
somatostatin-containing myenteric neurons project caudally
within the ganglionated meshworks of the myenteric plexus,
and release of somatostatin either depolarizes or hyperpolarizes
distinct populations of myenteric neurons.
Endocrine. In addition to the neural localization, GABA is
synthesized, stored, and secreted by mucosal endocrine-like
cells (see Fig. 1C) throughout the rat antrum and intestine (2,
9). The mucosa, therefore, may well be under the influence of
GABA released from local neurons (13) as well as GABA
“The highest L-glutamate decarboxylase activity
in the gut wall is found in the myenteric plexus.”
secreted from endocrine cells. In the rodent gastric antrum,
GABAergic endocrine-like cells resolve into subpopulations
of cells colocalizing either gastrin (G cells) or somatostatin
(D cells). In the rodent intestine, GABAergic endocrine-like
cells display a morphology similar to D-type endocrine cells
(9). GABA released from these cells into the local circulation
or interstitial space may act as a classic gastrointestinal hor-
mone or a local paracrine or autocrine factor. Together, this
evidence strongly supports the notion that, in addition to the
role of GABA within specific reflex motor responses of the gut
related to its myenteric neural localization, GABA originating
from submucosal nerves as well as mucosal cells is physio-
logically important in the control of mucosal activity. Direct
myenteric GABAergic neural control of mucosal function may
also occur (6); however, it is more likely that GABA effects on
mucosal function are related to submucosal GABAergic neu-
rons and/or GABAergic endocrine mucosal cells (13).
Sites of enteric GABA action
GABA exerts both stimulatory and inhibitory influence
over enteric neuronal activity, depending on the GABA
receptor subtypes activated: stimulation is via GABAA recep-
tors and inhibition is via GABAB receptors. In addition,
GABAA receptors are in pathways that target both excitatory
and inhibitory motor neurons, and in this way GABA can
News Physiol. Sci. • Volume 15 • December 2000 285
FIGURE 1. Examples of γ-aminobutyric acid (GABA) cells and nerve fibers in the intestine. A: intensely labeled myenteric nerve cells and nerve fibers in the cir-
cular muscle layer (cm) of a tissue section taken from a resected segment of human sigmoid colon and treated for GABA-transaminase histochemistry. B: laminar
preparation (whole mount) of the rat ileum (muscularis externa dissected away and positioned mucosa down) treated for [3H]GABA high-affinity autoradiography.
Densely labeled fibers within the fine fiber network at the circular muscle-submucosa interface are evident against the counterstained blood vessels of the under-
lying submucosa. C: endocrine cells of the rat proximal duodenum immunolabeled for GABA-transaminase. D and E: GABA-transaminase-positive neurons in the
submucosal plexus Meissner’s and Henle’s ganglia of the rat colon submucosa.

both positively and negatively influence smooth muscle
behavior and secretion. These GABA receptor-related actions
appear to be significant, since gut motility can be blocked or
reduced by GABAA or GABAB receptor blockade (3).
Enteric GABAA display a pharmacology analogous to cen-
tral GABAA receptors (3). Recently, enteric GABAA receptors
have been localized to a subpopulation of myenteric and
submucosal neurons in the rat intestine (10), consistent with
the well-established neurogenic action(s) of GABA on multi-
ple nerve cell types, including enteric motor nerves. In vitro
studies show that applied GABA or GABAA receptor agonists
stimulate enteric cholinergic excitatory and nonadrenergic,
noncholinergic inhibitory motor neurons (3). In support of
this notion, electrophysiological studies indicate that, unlike
the brain, in which GABAA mediates hyperpolarization of neu-
rons, enteric GABA mediates depolarization of AH/type II
286 News Physiol. Sci. • Volume 15 • December 2000
and S/type I myenteric neurons (1). The GABAA receptor-
mediated depolarization of AH/type II cells’ chloride-dependent,
bicuculline-sensitive process resembles the depolarizing
action of GABA on dorsal root ganglion cells (3) and presents
the researcher with a powerful tool for the study of enteric
nerve-nerve interaction.
GABAA receptors
GABAA receptors are heterooligomers composed of the α-,
β-, γ-, δ-, and ε-subunit families. The distribution of GABAA
receptor subunit mRNAs in adult rat ENS is heterogenous (17),
reflecting a varied physiological/pharmacological profile of
GABA-mediated transmission in both regions. The expression
of β2- and/or β3-subunits in the rat intestine (10) has been
identified with the use of a specific monoclonal antibody. We

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FIGURE 2. GABA innervation of the intestine. A: laminar preparation (whole mount) of the myenteric plexus dissected from the rat distal colon and treated for
[3H]GABA high-affinity autoradiography. Densely labeled fibers are profuse in the ganglia and interconnecting fiber trunks. B: laminar preparation of the myen-
teric plexus dissected from the rat proximal colon treated for GABAA receptor immunohistochemistry using a β2/ β3-receptor subunit monoclonal antibody.
A large number of myenteric neurons shows intense immunolabeling. C: immunolabeled laminar preparation depicted in B was subsequently treated for NADPH-
diaphorase histochemistry to identify nitric oxide (NO)-synthesizing cells. A large proportion of the NO synthesizing cells colocalize GABAA receptors.

also confirmed the presence of GABAA receptor subunit (α, β,
γ) mRNAs by in situ hybridization in myenteric and submu-
cosal neurons. We have preliminary data (unpublished) to
show that these mRNAs are translated into protein; polyclonal
antibodies raised against subunit-specific synthetic peptides
show marked immunocytochemical staining in subpopula-
tions of rat enteric neurons in primary culture.
Central GABAA receptors are potentiated by benzodi-
azepine (BZ) treatment. In the gut, barbiturates and BZ also
potentiate GABAA-induced responses, indicative of a “cen-
tral-type” enteric GABAA receptor (3). The expression of α-,
β-, and γ-subunit mRNA is the minimum requirement for
functional GABAA receptors with a complete range of BZ
pharmacology, and their presence in the gut wall indicates
that these GABAA receptors are heterogeneous with respect
to their subunit composition. Since GABA in the ENS is
excitatory and not inhibitory, the subunit expression and
hence function of enteric GABAA receptors and their sub-
unit composites may be fundamentally different from classic
central GABAA receptors. The data presented above predict
that in the gut, BZ type I (α1) and II (α3 and α5) binding
sites are present.
GABAB receptors
Enteric GABAB receptors are prejunctional, operating
through calcium channels coupled to G proteins. They are
sensitive to β-p-chlorophenyl GABA (baclofen), and their
pharmacological profile in enteric circuitry indicates an
involvement in prejunctional inhibition of cholinergic motor
neurons (3). Hence, activation of the myenteric GABAB
receptor system, like enteric enkephalin neurons, decreases
acetylcholine release from myenteric cholinergic motor neu-
rons, thereby modulating the intensity of enteric smooth mus-
cle contraction generated. In cultured myenteric neurons,
GABA also depresses nicotinic transmission (1) and decreases
the size of fast excitatory postsynaptic potentials without
changing postsynaptic response to neurotransmitters. This
action is indicative of some presynaptic/prejunctional effects
similar to those of enkephalin in the ENS.
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FIGURE 3. Representation of the myenteric and submucosal GABA neurons on the basis of their colocalization of neuropeptide or NO synthase activity. Each
grouping of neurons represents separate nonoverlapping subpopulations. ENK, enkephalin; SOM, somatostatin.
The GABAB receptor modulation of cholinergic neurons may
also be important in the regulation of acid secretion. Guo et al.
(5) demonstrated that infusion of GABA caused a significant
depression in bombesin-evoked somatostatin release from rat
antral mucosa. Hence, under physiological conditions, GABA
may both stimulate (via GABAA receptors) and inhibit (via
GABAB receptors) cholinergic innervation of the endocrine
G cells and D cells that control acid secretion. The relative
contribution of each GABA receptor input in the control of
acid secretion is further supported by our findings that duode-
nal ulceration is increased by systemic GABAA stimulation and
ameliorated by a GABAB agonist, baclofen (see below).
A third functional subclass of GABA receptor, GABAC, has
recently been described. These are relatively simple ligand-
gated chloride channels that are neither inhibited by the
classic GABAA receptor antagonist bicuculline nor activated
by the GABAB receptor agonist baclofen. Nothing is known
about GABAC receptors in the gut. It is likely that enteric
GABAC receptors will eventually be found, given that two of
the components of the CNS GABA system mediate signaling
in the gut wall.
GABA in enteric neural circuits
GABA release from enteric GABAergic nerve processes
can be elicited by electric stimulation or by substance P (19),
cholecystokinin, or neurotensin (16, 18). In the rat intestine,
a neural circuit consisting of GABA-, somatostatin-, and
enkephalin-containing interneurons is proposed to be impor-
tant for the regulation of descending relaxation. In this cir-
cuit, distension activated somatostatin neurons in the gut
wall and inhibited enkephalin neurons. This leads to disinhi-
bition of interneurons containing GABAA receptors and
subsequent activation of VIP- and/or nitric oxide (NO)-con-
taining motor neurons.
GABAergic interneurons may well represent the site of
integration for maintaining normal balance between the
excitatory and inhibitory neural influences. In addition to
stimulating cholinergic motor neurons, GABA, through
GABAA receptors, also stimulates the inhibitory motor neu-
288 News Physiol. Sci. • Volume 15 • December 2000
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rons that release ATP, VIP, and NO. Consistent with the
functional evidence for the influence of GABA on motor
neurons is the recent immunohistochemical data (10) that
showed that almost half of myenteric nerve cell perikarya,
including 35% of the NO-synthesizing neurons, contain
GABAA receptors (Fig. 3). NOS is colocalized in a subpop-
ulation of GABAergic neurons in the human colon and rat
intestine, suggesting that NO may also be a transmitter of
enteric interneurons.
The identification of GABAB receptor-mediated neural
circuits has been hampered by the lack of specific GABAB
receptor probes. The only study to date on GABAB receptor
localization in the gut (15) reveals a distribution of
immunolabeling remarkably coincident with the pattern of
high-affinity uptake of [3H]GABA by neural and nonneural
cells. Nakajima and coworkers (15) also report that GABAB
receptor immunoreactivity colocalized with 5-HT immuno-
reactivity in mucosal cells of the stomach and intestine.
These GABAB receptors modulate release of 5-HT from
endocrine cells. Moreover, Nakajima and colleagues (15)
also showed GABAB immunoreactivity on neuronal cell
somata. However, all of the functional studies to date show
only a prejunctional action of baclofen. If the labeling of
cell somata is specific, then these must be either nonfunc-
tional receptors or receptors that current pharmacologi-
cal/physiological techniques cannot assess. The cloning
of the GABAB receptor (20) will facilitate labeling of cells
containing GABAB receptors and will afford considerable
progress toward answering these questions. A highly schematic
diagram summarizing the extent of GABA innervation of the
gut wall is presented in Fig. 4.
GABA and gut behavior
Motility and secretion. Disruption of the enteric GABAer-
gic system may have widespread consequences on motility
and secretion. GABA and its GABAA receptor analogs affect
the release of acetylcholine, gastrin, and somatostatin from
rat gastric mucosa (5). GABA receptors also modulate 5-HT
release from enterochromaffin cells, histamine release from
FIGURE 4. A schematic depiction of the extent of GABA innervation in the mammalian gut wall. Neurochemically distinct subpopulations of myenteric and sub-
mucosal GABA neurons target either motor or secretomotor neurons and/or nonneuronal cells involved in paracrine control of the submucosa and mucosa. GABA
is also found in mucosal endocrine cells throughout the gut, and GABA released from these cells or neurons can influence submucosal/mucosal function. ACh,
acetylcholine motor neurons; NANC, inhibitory motor neurons; 5-HT, 5-hydroxytryptamine; HA, histamine; EC, enterochromaffin cell; PG, prostaglandins.

mast cells, gastric mucous secretion (12), prostaglandins
released from interstitial cells (4), and mucosal electrolyte
transport (6, 13). Mast cell-derived mediators such as hista-
mine transduce antigenic signals into alterations in elec-
trolyte transport, and GABA inhibits the allergic response.
Mucosal function. The influence of GABA on epithelial
transport processes has been demonstrated in the guinea pig
(13) and rat (6) small intestine. In the guinea pig, neural
GABAA receptors and hence GABAergic neurons form an
important link in the local submucosal circuits regulating
epithelial secretion; the rapid-onset first phase of electrolyte
transport in response to applied GABA or its analog 3-amino-
propanesulfonic acid is dependent on a GABAA receptor-
activated pathway to submucosal cholinergic secretomotor
neurons. The second phase of the response to GABA involves
a GABAA receptor-mediated submucosal neural pathway
that stimulates histamine-releasing cells. In the rat, GABA
also mediates mucosal electrolyte transport via GABAA
receptors; however, this involves myenteric cholinergic neu-
rons (6). This difference is not surprising, since myenteric vs.
submucosal control of mucosal water and electrolyte secre-
tion is well known.
The occurrence of GABAergic fibers at the base of the
intestinal crypts as well as GABAergic endocrine cells in the
epithelium raises the prospect that, in addition to effects on
mucosal function, enteric GABA may also influence epithe-
lial cell mitosis and migration. Interestingly, decreased
mucosal cell turnover has been shown to be involved in
stress-induced gastric ulceration, and this may be a mecha-
nism by which GABA exerts its protective effects in these gut
disease models. This warrants further investigation. A model
for this can be seen in the liver, in which GABA applied sys-
temically inhibits rat hepatic regenerative activity, whereas
GABAA receptor antagonism stimulates regeneration (14).
Blood flow. In addition to control of motility and secre-
tion, we have preliminary evidence for GABA modulation of
mucosal blood flow. GABA or Lioresal (baclofen) produces
a dose-dependent reduction in local mucosal blood flow
that was not prevented by the GABAA antagonist bicu-
culline. The effect appeared to be region specific, evident
primarily in the rat proximal duodenum with little or no
effect in the more distal regions of the duodenum. This effect
of GABA is consistent with that observed in the CNS, in
which GABA has been shown to inhibit cerebrovascular
adrenergic neurotransmission by GABAB receptors. The
extent of enteric GABAergic control of local mucosal blood
flow needs to be investigated.
Ulceration. Experimental duodenal ulceration in rats is
sensitive to systemic treatment with GABA analogs and
antagonists. Systemically applied GABA aggravates duode-
nal ulcers by stimulation of the GABAA receptor, whereas
treatment with the GABAB receptor agonist baclofen causes
a reduction in both the incidence and intensity of ulcers
(8). Baclofen was found to be more effective than the hist-
amine H2 blocker cimetidine, and, when given together,
the antiulcer actions of these agents were found to be
additive. Thus GABAB receptors present an alternative
pharmacological site for targeting of antiulcer drug thera-
pies. The mechanism of GABA involvement in duodenal
ulcers is unknown. However, since barbiturates and BZs
can directly potentiate GABAA receptor-mediated actions
in the gut, they could potentiate the aggravating actions of
GABA on duodenal ulcers.
Neurogenic interactions between GABA and 5-HT and
between GABA and somatostatin have been demonstrated.
Thus a GABA-, somatostatin-, and 5-HT-sensitive release of
acidic gastric secretions into the duodenum and/or alteration
in local blood flow following delayed gastric emptying may
be a key element in peptic ulcer disease. This likely repre-
sents only some of the interactions of GABA within neural
circuits underlying enteric reflex control of the gut wall that
may have importance for gut pathophysiology.
News Physiol. Sci. • Volume 15 • December 2000 289

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Summary
We are beginning to understand in some detail the types of
neural innervation and interaction occurring in the mam-
malian gastrointestinal tract. In this review, the reader is
alerted to the presence of a widespread and powerful GABA
signaling system in the gut. GABA is involved in the neural
and endocrine/paracrine regulation of diverse functions
within the gut. GABA can either stimulate (via GABAA recep-
tors) or inhibit (via GABAB receptors) intrinsic cholinergic
motor neurons that are responsible for the ascending excita-
tion limb of the peristaltic reflex. Thus disruption of enteric
GABA transmission could potentially contribute to the
cholinergic hypercontraction of the gut. Intrinsic enteric
GABAergic neurons also target (via GABAA receptors)
inhibitory gut motor neurons. Enteric GABAA receptor antag-
onism also stops spontaneous intestinal motility, and this
occurs because interference with GABAA transmission damps
the circuitry generating intestinal motor activity. This is con-
sistent with the view that, in the ENS, GABA is a transmitter
of interneurons within separate excitatory and inhibitory
pathways regulating gut motor and secretomotor function.
The division of GABAergic interneurons into distinct subpop-
ulations of neuropeptide or NOS-containing cells may reflect
the pharmacology of these transmitters with respect to the
pattern of transmitter release during reflex control of gut
motor and secretomotor function.
The extent of the enteric GABAergic system, together with
the disruption in gut behaviors following the perturbation of
either the GABAA or the GABAB receptor, suggests that the
GABAergic system presents potential new target sites for the
development of gastrointestinal drugs. For example, BZs
taken orally depress gastrointestinal motility. Diazepam is
commonly used for sedation before many gastroenterology
procedures as an adjunct to general anesthesia. Therefore,
understanding BZ actions in the gut will aid further develop-
ment of BZ sedatives. The fact that there is a heterogeneous
expression (within the enteric nerve layers) of GABAA recep-
tor subunits that define BZ sites will allow us to characterize
the physiology and pharmacology of enteric neural BZ sites
and their behavior. This will be further aided by the study of
synaptic mechanisms related to ganglionic GABA transmis-
sion and GABA actions within the enteric neuropil.
For the physiologist, an appreciation of this large yet
unheralded enteric nerve-nerve signaling system, which tar-
gets cholinergic, peptidergic, purinergic, and NO enteric
neurons, affords new opportunities for understanding ENS
function in health and disease. Furthermore, the biochemical
and pharmacological similarities between the CNS and ENS
makes the gut a model system in which to study GABA.
Indeed, considering its ease of accessibility, monolayer plex-
iform anatomic organization and sensitivity to pharmacolog-
ical, electrophysiological, and molecular analysis, it presents
an ideal model system to study GABA, its enzymes, and
receptor-related signaling.
290 News Physiol. Sci. • Volume 15 • December 2000
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