News Physiol Sci 15: 284-290, 2000;
1548-9213/00 $5.00
News in Physiological Sciences, Vol. 15, No. 6, 284-290,
December 2000
© 2000 Int. Union Physiol. Sci./Am. Physiol. Soc.
GABA in the Mammalian Enteric Nervous System
Anthony Krantis
A. Krantis is a Professor in the Department of Cellular and Molecular Medicine, Digestive Diseases Research Group, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
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Abstract
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-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.
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Introduction
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Since 1980, a considerable body of literature has accumulated on the occurrence, distribution, and actions of -aminobutyric acid (GABA) in the mammalian gastrointestinal 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 (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 neurons appear to be exclusively interneurons that release GABA as an excitatory neurotransmitter, in contrast to its inhibitory 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 distal 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, vasoactive 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 pharmacological 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 mammalian 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.
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GABA in the gut
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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 activity in the gut wall is found in the myenteric plexus. Autoradiographic 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 varicose and often form a rich arbor around ganglion cells. In the rat, GABAergic neurons account for >5–8% of the total number 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
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FIGURE 1. Examples of -aminobutyric acid (GABA) cells and nerve fibers in the intestine. A: intensely labeled myenteric nerve cells and nerve fibers in the circular 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 underlying 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.
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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) neurons with NADPH diaphorase-related nitric oxide synthase (NOS) activity, which account for ~20% of the GABA population (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 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.
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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 myenteric plexus dissected from the rat proximal colon treated for GABAA receptor immunohistochemistry using a ß2/ ß3-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.
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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 submucosa 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 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 hormone 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 physiologically 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 neurons and/or GABAergic endocrine mucosal cells (13).
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Sites of enteric GABA action
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GABA exerts both stimulatory and inhibitory influence over enteric neuronal activity, depending on the GABA receptor subtypes activated: stimulation is via GABAA receptors 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 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 central 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 multiple 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 neurons, enteric GABA mediates depolarization of AH/type II 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.
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GABAA receptors
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GABAA receptors are heterooligomers composed of the 
-, ß-, -, 
-, and 
-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 ß2- and/or ß3-subunits in the rat intestine (10) has been identified with the use of a specific monoclonal antibody. We also confirmed the presence of GABAA receptor subunit (, ß, ) mRNAs by in situ hybridization in myenteric and submucosal 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 subpopulations of rat enteric neurons in primary culture.
Central GABAA receptors are potentiated by benzodiazepine (BZ) treatment. In the gut, barbiturates and BZ also potentiate GABAA-induced responses, indicative of a "central-type" enteric GABAA receptor (3). The expression of -, ß-, and -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 subunit composites may be fundamentally different from classic central GABAA receptors. The data presented above predict that in the gut, BZ type I (1) and II (3 and 5) binding sites are present.
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GABAB receptors
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Enteric GABAB receptors are prejunctional, operating through calcium channels coupled to G proteins. They are sensitive to ß-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 neurons, thereby modulating the intensity of enteric smooth muscle 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.
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 duodenal 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.
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GABA in enteric neural circuits
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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 important for the regulation of descending relaxation. In this circuit, distension activated somatostatin neurons in the gut wall and inhibited enkephalin neurons. This leads to disinhibition of interneurons containing GABAA receptors and subsequent activation of VIP- and/or nitric oxide (NO)-containing 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 neurons 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 subpopulation of GABAergic neurons in the human colon and rat intestine, suggesting that NO may also be a transmitter of enteric interneurons.
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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.
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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 immunoreactivity 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 nonfunctional receptors or receptors that current pharmacological/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.
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FIGURE 4. A schematic depiction of the extent of GABA innervation in the mammalian gut wall. Neurochemically distinct subpopulations of myenteric and submucosal 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.
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GABA and gut behavior
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Motility and secretion.
Disruption of the enteric GABAergic 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 mast cells, gastric mucous secretion (12), prostaglandins released from interstitial cells (4), and mucosal electrolyte transport (6, 13). Mast cell-derived mediators such as histamine transduce antigenic signals into alterations in electrolyte 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-aminopropanesulfonic 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 neurons (6). This difference is not surprising, since myenteric vs. submucosal control of mucosal water and electrolyte secretion 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 epithelial 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 mechanism 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 systemically inhibits rat hepatic regenerative activity, whereas GABAA receptor antagonism stimulates regeneration (14).
Blood flow.
In addition to control of motility and secretion, 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 bicuculline. 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 duodenal 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 histamine 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 therapies. 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 represents 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.
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Summary
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We are beginning to understand in some detail the types of neural innervation and interaction occurring in the mammalian 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 receptors) or inhibit (via GABAB receptors) intrinsic cholinergic motor neurons that are responsible for the ascending excitation 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 antagonism also stops spontaneous intestinal motility, and this occurs because interference with GABAA transmission damps the circuitry generating intestinal motor activity. This is consistent 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 subpopulations 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 development of BZ sedatives. The fact that there is a heterogeneous expression (within the enteric nerve layers) of GABAA receptor 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 transmission and GABA actions within the enteric neuropil.
For the physiologist, an appreciation of this large yet unheralded enteric nerve-nerve signaling system, which targets 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 plexiform anatomic organization and sensitivity to pharmacological, electrophysiological, and molecular analysis, it presents an ideal model system to study GABA, its enzymes, and receptor-related signaling.
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References
|
|---|
-
Cherubini E and North RA. -Aminobutyric acid actions on neurones of guinea-pig myenteric plexus. Br J Pharmacol 82: 93–100, 1984.[Web of Science][Medline]
-
Davenger S, Hjelle OP, Babaie E, Larsson LI, Hougaard D, Storm-Mathisen J, and Ottersen OP. Colocalization of gamma-aminobutyrate and gastrin in the rat antrum: an immunocytochemical and in situ hybridization study. Gastroenterology 107: 137–148, 1994.[Medline]
-
Erdo SL and Bowery NG. GABAergic Mechanisms in the Mammalian Periphery. New York: Raven, 1986.
-
Girdhar A, Dhumal VR, Gulati OD, Bhavsar VH, and Hemavathi G. Effect of gamma-aminobutyric acid on the rabbit isolated intestine. J Pharm Pharmacol 33: 614–615, 1981.[Medline]
-
Guo YS, Thompson JC, and Singh P. Effect of -aminobutyric acid on bombesin-evoked release of somatostatin and gastrin from isolated rat stomach. Regul Pept 24: 179–186, 1989.[Medline]
-
Hardcastle J, Hardcastle PT, and Mathias WJ. The influence of the -aminobutyric acid (GABA) antagonist bicuculline on transport processes in rat small intestine. J Pharm Pharmacol 43: 128–130, 1991.[Medline]
-
Jessen KR, Mirsky R, Dennison ME, and Burnstock G. GABA may be a neurotransmitter in the vertebrate peripheral nervous system. Nature 281: 71–74, 1979.[Medline]
-
Krantis A and McKay A. Cystemine interacts with enteric GABAergic mechanisms: effects on experimental duodenal ulceration. In: Hans Selye Symposia on Neuroendocrinology and Stress, edited by Szabo S. Berlin: Springer Verlag, 1990.
-
Krantis A, Nichols K, de Blas A, and Staines W. Demonstration of benzodiazepine receptors in submucosal neurons of the gastrointestinal tract. Neurosci Lett 176: 32–36, 1994.[Medline]
-
Krantis A, Shabnavard L, Nichols K, de Blas AL, and Staines W. Localization of GABAA receptor immunoreactivity in NO synthase positive myenteric neurones. J Auton Nerv Syst 53: 157–165, 1995.[Web of Science][Medline]
-
Krantis A and Webb T. Autoradiographic localization of [3H]gamma-aminobutyric acid in neural elements of the rat antrum and intestine. J Auton Nerv Syst 29: 41–49, 1989.[Web of Science][Medline]
-
Luzzi S, Franchi-Micheli S, Ciuffi M, Rosi E, and Zilletti L. Effect of various GABA-receptor agonists and antagonists on anaphylactic histamine release in the guinea-pig ileum. Agents Actions 20: 181–184, 1987.[Medline]
-
MacNaughton WK, Pineau BC, and Krantis A. -Aminobutyric acid stimulates electrolyte transport in the guinea-pig ileum in vitro. Gastroenterology 110: 498–507, 1996.[Web of Science][Medline]
-
Minuk GY and Gauthier T. The effect of gamma aminobutyric acid (GABA) on hepatic regenerative activity following partial hepatectomy in rats. Gastroenterology 104: 217–221, 1993.[Web of Science][Medline]
-
Nakajima K, Tooyama I, Kuriyama K, and Kimura H. Immunohistochemical demonstration of GABAB receptors in the rat gastrointestinal tract. Neurochem Res 21: 211–215, 1996.[Medline]
-
Nakamoto M, Tanaka C, and Taniyama K. Release of -aminobutyric acid and acetylcholine by neurotensin in guinea-pig ileum. Br J Pharmacol 90: 545–551, 1987.[Web of Science][Medline]
-
Poulter MO, Singhal R, Brown LA, and Krantis A. GABAA receptor subunit messenger RNA expression in the enteric nervous system of the rat: implications for functional diversity of enteric GABAA receptors. Neuroscience 93: 1159–1165, 1999.[Medline]
-
Sano I, Taniyama K, and Tanaka C. Cholecystokinin, but not gastrin, induces -aminobutyric acid release from myenteric neurons of the guinea pig ileum. J Pharmacol Exp Ther 248: 378–383, 1989.[Abstract/Free Full Text]
-
Tanaka C and Taniyama K. Substance P provoked gamma-aminobutyric acid release from the myenteric plexus of the guinea-pig small intestine. J Physiol (Lond) 362: 319–329, 1985.[Abstract/Free Full Text]
-
White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, and Marshall FH. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396: 679–682, 1998.[Medline]
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Top
Introduction
GABA in the gut
