Membrane receptors in the gastrointestinal tract

This review focusses on the roles that membrane receptors and their transducers play in the physiology and pathology of the gastrointestinal tract. The multifactorial: factorial regulation of mucosal growth and function is discussed in relation to the heterogeneity of exocrine and endocrine populations that originate from progenitor cells in stomach and intestine.     

Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract

Luminal acidity is a physiological challenge in the foregut, and acidosis can occur throughout the gastrointestinal tract as a result of inflammation or ischemia. These conditions are surveyed by an elaborate network of acid-governed mechanisms to maintain homeostasis. Deviations from physiological values of extracellular pH are monitored by multiple acid sensors expressed by epithelial cells and sensory neurons. Acid-sensing ion channels are activated by moderate acidification, whereas transient receptor potential ion channels of the vanilloid subtype are gated by severe acidosis. Some ionotropic purinoceptor ion channels and two-pore domain background K(+) channels are also sensitive to alterations of extracellular pH.     

Immunohistochemical demonstration of GABAB receptors in the rat gastrointestinal tract

Immunohistochemical localization of GABA_B-receptors was demonstrated in the rat gastrointestinal tract using a monoclonal antibody (GB-1) raised against the purified GABA_B-receptor. Immunoreactive staining for GABA_B-receptors was found in some populations of endocrine, muscular and neuronal components in the stomach and gut wall. Positive mucosal epithelial, probably endocrine, cells were distributed throughout the stomach and intestine. Double immunostaining indicated that such positive cells for GABA_B-receptors often co-possessed serotonin in the small intestine but not in the gastric body. In the muscular layer of the digestive canal, positive staining was seen as dotty granules punctuated on the surface of muscle fibers. In the enteric nervous system, positive neuronal somata were found in both submucosal and myenteric ganglia throught the entire canal extending from the stomach to the rectum. This is the first report to visualize the cellular localization of GABA_B-receptors in the gastrointestinal system of the rat, and should provide a fundamental basis for future studies on gastrointestinal functions regulated by GABA_B-receptors. Special issue dedicated to Dr. Kinya Kuriyama.     

Distribution of prostaglandin E receptors in the rat gastrointestinal tract

: In order to study the role of prostaglandin in the regulation of the gastrointestinal functions, gene expression of prostaglandin receptors along the rat gastrointestinal tracts were investigated.

: Rats were used for the study. The combination of counterflow elutriation separation of mucosal cells and Northern blot analysis was used to detect the gene expression of prostaglandin receptors in gastrointestinal tracts.

: In small intestine and colon, prostaglandin E2 EP1 and EP3 receptor mRNAs were mainly localized in the deeper intestinal wall containing muscle layers. EP4 receptor gene expression, on the other hand, was detected in the intestinal mucosal layer.

In the stomach, EP1 mRNA was detected in gastric muscle layers, whereas EP3 and EN receptor gene expression was mainly present in the gastric mucosal layer containing epithelial cells. In gastric epithelial cells, parietal cells were found to have both EP3 and EP4 receptors. At lower concentrations, prostaglandin E2 inhibited gastric acid secretion by parietal cells probably through EP4 receptors. At higher concentrations, however, it stimulated it. On the other hand, mucous cells possessed only EP4 receptor mRNA.

: Thus, it is suggested that prostaglandin E2 modulates gastrointestinal functions through at least three different prostaglandin receptors (EP1, EP3, and EP4), each of which has a distinct distribution in the gastrointestinal tract.     

Distribution of neurokinin-2 receptors in the guinea-pig gastrointestinal tract

The distribution of neurokinin-2 (NK2) tachykinin receptors was investigated by immunohistochemistry in the guinea-pig oesophagus, stomach, small and large intestine. Receptor immunoreactivity occurred at the surfaces of smooth muscle cells throughout the digestive tract. Nerve fibre varicosities in enteric ganglia were also immunoreactive. In myenteric ganglia, these varicosities were most numerous in the ileum, frequent, but less dense, in the proximal colon and caecum, rare in the distal colon, extremely infrequent in the rectum and duodenum, and absent from the stomach and oesophagus. Reactive varicosities were rare in the submucous ganglia. Reactive nerve fibres in the mucosa were only found in the caecum and proximal colon. Strong NK2 receptor immunoreactivity was also found on the surfaces of enterocytes at the bases of mucosal glands in the proximal colon. Receptors were not detectable on the surfaces of nerve cells or on non-terminal axons. Reactivity did not occur on nerve fibres innervating the muscle. Denervation studies showed that the immunoreactive varicosities in the myenteric plexus of the ileum were the terminals of descending interneurons. Immunoreactivity for nitric oxide synthase was colocalised with NK2 receptor (NK-R) immunoreactivity in about 70% of the myenteric varicosities in the small intestine. Bombesin immunoreactivity occurred in about 30% of NK2-R immunoreactive varicosities in the small intestine. Received: 10 April 1996 / Accepted: 13 May 1996     

Gastrointestinal functions of proteinase-activated receptors

Proteinase-activated receptors (PARs) are a family of G-protein-coupled-seven-trans-membrane-domain receptors, consisting of four family members. PARs, especially PAR-1, a thrombin receptor, and PAR-2, a receptor for trypsin, tryptase and coagulation factors VIIa and Xa, are abundantly distributed throughout the gastrointestinal tract. PAR-2, but not other PARs, induces salivary and pancreatic exocrine secretion. Both PAR-2 and PAR-1 play protective roles in the gastric mucosa, modulating a variety of gastric functions. However, the mechanisms underlying the mucosal protection caused by PAR-2 and PAR-1 are entirely different. In the intestinal mucosa, PAR-2 appears to play a dual role, being pro- and anti-inflammatory. PAR-1, PAR-2 and also PAR-4 modulate the motility of the smooth muscle in the gastrointestinal tract including the esophageal muscularis mucosae, producing contraction and/or relaxation upon activation. Thus, PARs, especially PAR-1 and PAR-2, play extensive roles in modulating the gastrointestinal functions.     

Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing

Changes in the luminal contents of the gastrointestinal tract modulate gastrointestinal functions, including absorption of nutrients, food intake, and protection against harmful substances. The current notion is that mucosal enteroendocrine cells act as primary chemoreceptors by releasing signaling molecules in response to changes in the luminal environment, which in turn activate nerve terminals. The recent discovery that taste receptors and G protein subunits alpha-gustducin and alpha-transducin, involved in gustatory signal transduction, are expressed in the gastrointestinal mucosa supports the concept of a chemosensory machinery in the gastrointestinal tract. An understanding of luminal sensing processes responsible for the generation of the appropriate functional response to specific nutrients and nonnutrients is of clinical importance since aberrant or unsteady responses to changes in luminal contents might result in disease states ranging from intoxication to feeding disorders and inflammation. The purpose of this theme article is to discuss the functional implications of bitter taste signaling molecules in the gastrointestinal tract deduced by their localization in selected populations of epithelial cells and their relationship with neural pathways responsible for the generation of specific responses to luminal contents.     

Prostaglandins: effects on the gastrointestinal tract

Several prostaglandins have been shown to exert five major gastrointestinal actions. Inhibition of gastric acid secretion, orally and parenterally. Antiulcer activity (they prevent gastric and duodenal ulcers produced experimentally in animals, and they accelerate the rate of healing of duodenal ulcers in humans). Cytoprotection for the stomach, the small and the large intestine. Cytoprotection is defined as the property of many prostaglandins to protect the mucosa of the stomach and intestine from becoming inflamed and necrotic when this mucosa is exposed to noxious agents. Cytoprotection is separate from, and unrelated to, inhibition of gastric secretion. In humans, certain prostaglandins of the E type given at very low doses prevent gastric bleeding produced by aspirin and indomethacin. Stimulation of intestinal secretion, through increase of cyclic AMP formation. Stimulation of smooth muscle contraction. Certain prostaglandins are likely to be beneficial in the treatment of gastric ulcers, stress ulcers, duodenal ulcers, and perhaps gastritis and certain forms of inflammatory bowel disease.     

Somatostatin receptors in the gastrointestinal tract in health and disease.

The multiple actions of somatostatin are mediated by specific membrane-bound receptors present in all somatostatin target tissues, such as brain, pituitary, pancreas, and gastrointestinal tract. Three different types of tissues in the human gastrointestinal tract express somatostatin receptors: (1) the gastrointestinal mucosa, (2) the peripheral nervous system, and (3) the gut-associated lymphoid tissue, where the receptors are preferentially located in germinal centers. In all these cases, somatostatin binding is of high affinity and specific for bioactive somatostatin analogs. Somatostatin receptors are also expressed in pathological states, particularly in neuroendocrine tumors of the gastrointestinal tract. Ninety percent of the carcinoids and a majority of islet-cell carcinomas, including their metastases, usually have a high density of somatostatin receptors. Only 10 percent of the colorectal carcinomas and none of the exocrine pancreatic carcinomas, however, contain somatostatin receptors. The somatostatin receptors in tumors are identified with in vitro binding methods or with in vivo imaging techniques; the latter allow the precise localization of the tumors and their metastases in the patients. Since somatostatin receptors in gastroenteropancreatic tumors are functional, their identification can be used to assess the therapeutic efficacy of octreotide to inhibit excessive hormone release in the patients.     

Muscarinic receptors and gastrointestinal tract smooth muscle function

Over the last decade, several lines of evidence have shown that both muscarinic M2 and M3 receptors are postjunctionally expressed in many smooth muscles, including the gastrointestinal tract. Although in vitro data suggests that both receptors are functional in that they inhibit adenylate cyclase activity and activate non-selective cation channels, few studies support a role in vivo. Thus, data from procedures that ablate the signaling pathway of the muscarinic M2 receptor, including receptor antagonism, pertussis toxin pretreatment reveal little effect on gastrointestinal smooth muscle responsiveness to muscarinic agonists. Recently, information from knockout mice, lacking either M2 or M3 receptor, indicate reveal a role for both subtypes. However, the contribution of the M2 receptor appears greater in the ileum than in the urinary bladder. Therapeutically, non-selective, as well as selective M3 receptor antagonists are being clinically studied, although it remains to be shown which is the optimal approach to disorders of smooth muscle motility.     

Cellular distribution of prostanoid EP receptors mRNA in the rat gastrointestinal tract

The inhibition of PGE(2) synthesis resulting from sustained NSAIDs therapy has been linked to gastrointestinal irritations and ulceration. The multiple physiological effects of PGE(2) in the gut are mediated through the activation of four receptors termed EP(1-4). The aim of the study was to determine the precise distribution of the four prostaglandin E(2) receptors in the rat stomach, small intestine, and colon. We used non-radioactive in situ hybridization techniques on paraffin-embedded tissue. Mucous cells of the stomach and goblet cells of the small intestine and colon were found to express mRNA for all four EP subtypes. A positive hybridization signal for EP(1), EP(3), and EP(4) was detected in the parietal cells of the stomach whereas the chief cells expressed low levels of EP(1) and EP(3). The EP(1) and EP(3) receptor mRNA could also be detected in the muscularis mucosa, longitudinal muscle and enteric ganglias of the stomach and small intestine. However, close examination of the enteric ganglias indicated that most of the positive labeling was localized to the glial cells, although some neurons did express EP(3). In conclusion, we have detailed the distribution of prostanoid EP receptors in the gut at the cellular level, giving new insights to the role of prostaglandins in gastrointestinal functions.     

Look who's talking: nuclear receptors in the liver and gastrointestinal tract

The Nuclear Receptors in Liver and Digestive Diseases research workshop was held in Rockville, Maryland, on November 7 and 8, 2007, under the auspices of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Over 130 researchers from around the world gathered to assess the pathophysiology of nuclear receptors in the liver and gastrointestinal tract and to explore their potential use as therapeutic targets. This review covers some of the highlights of the meeting, including important areas of future investigation.     

Vasoactive intestinal peptide (VIP) receptors in the canine gastrointestinal tract

Vasoactive intestinal peptide (VIP) is a putative neurotransmitter in both the brain and peripheral tissues. To define possible target tissues of VIP we have used quantitative receptor autoradiography to localize and quantify the distribution of ¹²⁵I-VIP receptor binding sites in the canine gastrointestinal tract. While the distribution of VIP binding sites was different for each segment examined, specific VIP binding sites were localized to the mucosa, the muscularis mucosa, the smooth muscle of submucosal arterioles, lymph nodules, and the circular and longitudinal smooth muscle of the muscularis externa. These results identify putative target tissues of VIP action in the canine gastrointestinal tract. In correlation with physiological data, VIP sites appear to be involved in the regulation of a variety of gastrointestinal functions including epithelial ion transport, gastric secretion, hemodynamic regulation, immune response, esophageal, gastric and intestinal motility.     

Taste receptors in the gastrointestinal tract. I. Bitter taste receptors and alpha-gustducin in the mammalian gut

Molecular sensing by gastrointestinal (GI) cells plays a critical role in the control of multiple fundamental functions in digestion and also initiates hormonal and/or neural pathways leading to the regulation of caloric intake, pancreatic insulin secretion, and metabolism. Molecular sensing in the GI tract is also responsible for the detection of ingested harmful drugs and toxins, thereby initiating responses critical for survival. The initial recognition events and mechanism(s) involved remain incompletely understood. The notion to be discussed in this article is that there are important similarities between the chemosensory machinery elucidated in specialized neuroepithelial taste receptor cells of the lingual epithelium and the molecular transducers localized recently in enteroendocrine open GI cells that sense the chemical composition of the luminal contents of the gut.     

Immunolocalization of histamine H3 receptors on endocrine cells in the rat gastrointestinal tract

The histamine H3 receptor (H3R) has been identified in the gastrointestinal tract of the rat by immunohistochemistry, using the first validated anti-H3 receptor antibody. Immunoreactivity to H3R was exclusively localized to the endocrine cells scattered in the gastrointestinal mucosa, with positive cells being prominently abundant in the gastric fundus, while they were rarely found in the other regions. In the fundus, positive cells were distributed in the lower half of the mucosa and their number significantly decreased after a 24 h-fasting period. Double-labeling studies were undertaken to identify the H3R-immunoreactive cell types in the fundic and antral mucosa. The H3R-immunoreactive cells were positive for chromogranin A. In the fundus, approximately 90% of cells positive to H3R were also positive to the histamine-forming enzyme, histidine decarboxylase. None of the cells expressing H3R displayed immunoreactivity for gastrin, somatostatin or ghrelin. Location, the influence of food deprivation and colocalization with histidine decarboxylase indicate that H3R positive cells correspond to the enterochromaffin-like cells (ECL).     

Tachykinins and tachykinin receptors: effects in the genitourinary tract

Tachykinins (TKs) are a family of peptides involved in the central and peripheral regulation of urogenital functions through the stimulation of TK NK1, NK2 and NK3 receptors. At the urinary system level, TKs locally stimulate smooth muscle tone, ureteric peristalsis and bladder contractions, initiate neurogenic inflammation and trigger local and spinal reflexes aimed to maintain organ functions in emergency conditions. At the genital level, TKs are involved in smooth muscle contraction, in inflammation and in the modulation of steroid secretion by the testes and ovaries. TKs produce vasodilatation of maternal and fetal placental vascular beds and appear to be involved in reproductive function, stress-induced abortion, and pre-eclampsia. The current data suggest that the genitourinary tract is a primary site of action of the tachykininergic system.     

Ghrelin receptors in human gastrointestinal tract during prenatal and early postnatal development

The aim of our study was to investigate the appearance, density and distribution of ghrelin cells and GHS-R1a and GHS-R1b in the human stomach and duodenum during prenatal and early postnatal development. We examined chromogranin-A and ghrelin cells in duodenum, and GHS-R1a and GHS-R1b expression in stomach and duodenum by immunohistochemistry in embryos, fetuses, and infants. Chromogranin-A and ghrelin cells were identified in the duodenum at weeks 10 and 11 of gestation. Ghrelin cells were detected individually or clustered within the base of duodenal crypts and villi during the first trimester, while they were presented separately within the basal and apical parts of crypts and villi during the second and third trimesters. Ghrelin cells were the most numerous during the first (∼11%) and third (∼10%) trimesters of gestation development. GHS-R1a and GHS-R1b were detected at 11 and 16 weeks of gestation, showed the highest level of expression in Brunner's gland and in lower parts of duodenal crypts and villi during the second trimester in antrum, and during the third trimester in corpus and duodenum. Our findings demonstrated for the first time abundant duodenal expression of ghrelin cells and ghrelin receptors during human prenatal development indicating a role of ghrelin in the regulation of growth and differentiation of human gastrointestinal tract.     

Contractile effects of ghrelin-related peptides on the chicken gastrointestinal tract in vitro

Ghrelin is an endogenous ligand for growth hormone secretagogue receptor (GHS-R), and it stimulates growth hormone (GH) release, food intake and gastrointestinal motility in mammals. Ghrelin has also been identified in the chicken, but this peptide inhibits food intake in the chicken. We examined the effects of ghrelin and related peptides on contractility of the isolated chicken gastrointestinal tract in vitro. Among ghrelin-related peptides examined (1 microM of rat ghrelin, human ghrelin, chicken ghrelin and growth hormone releasing peptide-6 (GHRP-6)), only chicken ghrelin was effective on contraction of the chicken gastrointestinal tract. Des-acyl chicken ghrelin was ineffective, suggesting that octanoylation at Ser3 residue of chicken ghrelin was essential for inducing the contraction. Amplitude of chicken ghrelin-induced contraction was region-specific: highest in the crop and colon, moderate in the esophagus and proventriculus, and weak in the small intestine. The contractile response to chicken ghrelin in the crop was not affected by tetrodotoxin (TTX), but that in the proventriculus was decreased by TTX and atropine to the same extents. D-Lys3-GHRP-6 (a GHS-R antagonist) caused a transient contraction and inhibited the effect of chicken ghrelin without affecting the high-K+-induced contraction. Chicken ghrelin potentiated electrical field stimulation-induced cholinergic contraction without affecting the responsiveness to bath-applied carbachol in the proventriculus. The location of GHS-R differs in the crop (smooth muscle) and proventriculus (smooth muscle and enteric neurons). These results indicate that ghrelin has contractile activity on gastrointestinal tract in the chicken in vitro, and the effect was region-specific. The action would be mediated through the GHS-R, which is highly sensitive to chicken ghrelin.