UNIPROT:P01350 - FACTA Search

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Query: UNIPROT:P01350 (gastrin)
9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of gastrin and histamine on rat gastric H+/K(+)-ATPase, the enzyme responsible for H+ secretion, gene expression in vivo. Gastrin 17 (G 17) or histamine dihydrochloride (histamine) was continuously infused through the femoral vein of anesthetized rats. Gastric H+/K(+)-ATPase mRNA levels were measured using northern blot analysis. Infusion of G 17 and histamine increased the H+/K(+)-ATPase mRNA level significantly compared with basal control level or vehicle control level (P < 0.01). However, pretreatment with famotidine, a potent histamine-2 (H2)-receptor antagonist, inhibited the increase of rat gastric H+/K(+)-ATPase mRNA following G 17 and histamine infusion. These findings indicate that both histamine and G 17 increase expression of H+/K(+)-ATPase mRNA by activating H2 receptor on the parietal cell.
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PMID:Famotidine, a histamine-2-receptor antagonist, inhibits the increase in rat gastric H+/K(+)-ATPase mRNA induced by intravenous infusion of gastrin 17 and histamine. 755 65

Biologically active amidated gastrin is synthesized by carboxyl-terminal alpha-amidation of a glycine-extended progastrin post-translational processing intermediate (G-Gly). Although plasma levels of G-Gly are equivalent to those of gastrin, G-Gly has essentially no acute effect on gastric acid secretion. However, we have observed that inhibition of gastrin amidation leads to increased plasma concentrations of G-Gly and enhanced gastric acid secretion. We hypothesized, therefore, that G-Gly might have a chronic effect to increase H+,K(+)-ATPase expression in gastric parietal cells. In the present studies, we observed that a 2-day preincubation with G-Gly significantly enhanced histamine-stimulated [14C]aminopyrine uptake by isolated canine gastric parietal cells but acutely administered G-Gly had no effect. On Northern blot analysis, both G-Gly and gastrin dose-dependently increased H+,K(+)-ATPase alpha-subunit gene expression with maximal induction (225 +/- 35 and 170 +/- 29% of basal, mean +/- S.E.) achieved at concentrations of 10(-9) M G-Gly and 10(-8) M gastrin, respectively. Using an H+,K(+)-ATPase alpha-subunit gene-luciferase chimeric reporter construct transfected into primary cultured parietal cells, we observed that both G-Gly and gastrin increased luciferase activity in a manner similar to that obtained by Northern blot analysis. L365,260, a specific gastrin/CCKB receptor antagonist, completely reversed the stimulation of luciferase activity induced by gastrin but had no effect on G-Gly-stimulated activity. Gastrin increased [Ca2+]i, although G-Gly did not, however, genistein (a tyrosine kinase inhibitor) significantly reduced induction of luciferase activity by both G-Gly and gastrin. Specific binding of 125I-Leu15-G2-17-Gly to gastric parietal cells was dose-dependently displaced by G2-17-Gly but not by gastrin nor L365,260. Gastrin peptides truncated at the carboxyl- (G1-13) and amino terminus (G5-17-Gly) both induced H+,K(+)-ATPase alpha-subunit gene expression and inhibited 125I-Leu15-G2-17-Gly binding, but were less potent than G2-17-Gly. These data indicate that G-Gly may have a functional role in potentiating gastric acid secretagogue action via enhanced expression of the gene responsible for H+ generation through action at a novel receptor that can be distinguished from the gastrin/CCKB receptor. Thus, both the substrate and product of the terminal progastrin processing reaction appear to have complementary functions in regulation of gastric acid secretion.
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PMID:Glycine-extended progastrin processing intermediates induce H+,K(+)-ATPase alpha-subunit gene expression through a novel receptor. 774 46

Chicken gastrin has a C-terminal sequence resembling mammalian cholecystokinin, but its biological properties resemble mammalian gastrin. The mechanisms controlling chicken gastrin release are poorly understood. We have investigated the factors which influence chicken gastrin secretion in vivo. Plasma gastrin concentration was decreased within 12 h of fasting, but tissue gastrin concentrations were not significantly changed even after 24 h of food deprivation. In birds fasted for 24 h and treated with the H+/K(+)-ATPase inhibitor, omeprazole, plasma gastrin concentration was greatly enhanced indicating the importance of acid inhibition of the gastrin cell. It is well established that amino acids (particularly aromatics like Phe and Trp) and peptides stimulate gastrin release in mammals. In chicken, however, Met, His and Arg were the strongest stimulant amongst the essential amino acids investigated. Of these three amino acids, Met rapidly stimulated gastrin release. The GRP antagonist M216140 did not suppress the Met-induced gastrin release, suggesting that Met did not stimulate GRP release. Aromatic amino acids did not strongly influence gastrin release. Medium chain triacylglycerol, which is rapidly hydrolyzed to fatty acids in the lumen, strongly stimulated gastrin secretion but long chain triacylglycerol had no effect. The data suggest that amino acids (Met, Arg and His) and fatty acids, but not triacylglycerol, are gastrin releasing factors in birds while acid inhibits secretion: there are therefore both similarities and differences between birds and mammals in the control of gastrin release.
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PMID:The regulation of gastrin secretion in the chicken. 776 24

To evaluate whether the general trophic effect of gastrin on the oxyntic mucosa is an indirect effect mediated by histamine H2 receptors, sustained 24 hour hypergastrinaemia was induced in Sprague-Dawley rats by treatment with the long acting and potent histamine H2 antagonist loxtidine for five months. The trophic effect was assessed by weight, enumeration of total mucosal cells, parietal cells, and enterochromaffin like cells in smears stained for the actual cells after enzymatic dispersion of the mucosa, and by biochemical analysis of oxyntic mucosal homogenates. The weight of the whole stomach and the oxyntic mucosa increased by 12.7% (p = 0.016) and 27.5% (p = 0.006), respectively. Total oxyntic mucosal protein content increased by 28.7% (p = 0.058). Total numbers of mucosal cells and parietal cells increased by 11.9% (NS) and 24.1% (NS), respectively. The amount of the parietal cell specific enzyme H+,K(+)-ATPase was unchanged. On the other hand, the number of enterochromaffin like cells and related parameters, histidine decarboxylase activity and histamine content of the oxyntic mucosa, showed a pronounced and significant increase. It is concluded that the general trophic effect of gastrin on the oxyntic mucosa is not mediated by the histamine H2 receptor. The tropic effect of gastrin on the parietal cell seems, in contrast with that on the enterochromaffin like cell, not to be specific but only reflecting the general trophic effect on the oxyntic mucosa.
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PMID:Evaluation of the trophic effect of longterm treatment with the histamine H2 receptor antagonist loxtidine on rat oxyntic mucosa by differential counting of dispersed cells. 782 70

The secretion of gastric acid is regulated both centrally and peripherally. The finding that H2-receptor antagonists are able to reduce or abolish acid secretion due to vagal, gastrinergic, and histaminergic stimulation shows that histamine plays a pivotal role in stimulation of the parietal cell. In the rat, the fundic histamine is released from the ECL cell, in response to gastrin, acetylcholine, or epinephrine, and histamine release is inhibited by somatostatin or by the H3-receptor ligand, R-alpha-methyl histamine. The parietal cell has a muscarinic, M3, receptor responsible for [Ca]i regulation. Blockade of muscarinic receptors by atropine can be as effective as H2-receptor blockade in controlling acid secretion. However, general effects on muscarinic receptors elsewhere produce significant side effects. The different receptor pathways converge to stimulate the gastric H+,K(+)-ATPase, the pump responsible for acid secretion by the stomach. This enzyme is an alpha,beta heterodimer, present in cytoplasmic membrane vesicles of the resting cell and in the canaliculus of the stimulated cell. It has been shown that acid secretion by the pump depends on provision of K+Cl- efflux pathway becoming associated with the pump. As secretion occurs only in the canaliculus, this K+Cl- pathway is activated only when the pump inserts into the canalicular membrane. Transport by the enzyme involves reciprocal conformational changes in the cytoplasmic and extracytoplasmic domain. These result in changes in sidedness and affinity for H3O+ and K+, enabling active H+ for K+ exchange. The acid pump inhibitors of the substituted benzimidazole class, such as omeprazole, are concentrated in the canaliculus of the secreting parietal cell and are activated there to form sulfenamides. The omeprazole sulfenamide, for example, reacts covalently with two cysteines in the extracytoplasmic loops between the fifth and sixth transmembrane and the seventh and eighth transmembrane segments of the alpha subunit of the H+,K(+)-ATPase, forming disulfide derivatives. This inhibits ATP hydrolysis and H+ transport, resulting in effective, long-lasting regulation of acid secretion. Therefore, this class of acid pump inhibitor is significantly more effective and faster acting than the H2 receptor antagonists. K+ competitive antagonists bind to the M1 and M2 transmembrane segments of the alpha subunit of the acid pump and also abolish ATPase activity. These drugs should also be able to reduce acid secretion more effectively than receptor antagonists and provide shorter acting but complete inhibition of acid secretion.
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PMID:Pharmacological aspects of acid secretion. 785 83

Transforming growth factor alpha (TGF alpha) evokes diverse responses in transgenic mouse tissues in which it is over-expressed, including the gastric mucosa, which experiences aberrant growth and a coincident repression of hydrochloric acid production. Here we show that ectopically expressed TGF alpha induces an age-dependent cellular reorganization of the transgenic stomach, in which the surface mucous cell population in the gastric pit is greatly expanded at the expense of cells in the glandular base. Immunohistochemical analysis of BrdU incorporation into DNA demonstrated that although mature surface mucous cells were not proliferating, DNA synthesis was enhanced by approximately 67% in the glandular base and isthmus, where progenitor cells reside. RNA blot and in situ hybridization were employed to determine temporal and spatial expression patterns of specific markers representing a variety of exocrine and endocrine gastric cell types. Mature parietal and chief cells were specifically depleted from the glandular mucosa, as judged by a 6- to 7-fold decrease in the expression of genes encoding H+,K(+)-ATPase, which is required for acid secretion, and pepsinogen C, respectively. The reduction of these markers coincided in time with the activation of TGF alpha transgene expression in the neonatal stomach. The rate of cell death in the glandular region was not overtly different. Significantly, the loss of parietal and chief cells occurred without a concomitant loss of their respective cellular precursors. In contrast to exocrine cells, D and G endocrine cells were much less severely affected, based on analysis of somatostatin and gastrin expression. Analysis of these dynamic changes indicates that TGF alpha can induce selective alterations in terminal differentiation and proliferation in the gastric mucosa, and suggests that TGF alpha plays an important physiological role in the normal regulation of epithelial cell renewal.
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PMID:Transforming growth factor alpha disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice. 786 96

Historically, the interplay between basic research and clinical observation has been essential in the development of new therapies for peptic ulcer disease. That histamine is an important regulator of acid secretion emerged from basic research, followed by the clinical development and use of the H2-receptor antagonists. Basic research contributed again by defining the importance of H+/K(+)-ATPase in acid secretion, resulting in a new class of useful antisecretory agents. Basic studies also gave us prostaglandins (PG) as mucosal protective agents. As 'replacement' therapy, clinicians have found that PG are protective against non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer (GU). Physiologic studies established that somatostatin is a potent inhibitor of acid secretion, providing the stimulus for clinical studies in Zollinger-Ellison (ZE) Syndrome with a synthetic analog (octreotide). Work on isoforms of the parietal cell gastrin receptor has shown differences in the cytoplasmic domain for G protein coupling. This will aid in understanding how receptor changes and coupling to second messengers relate to the aetiopathogenesis of abnormal gastric secretion. Immune cells express mRNA for histamine, muscarinic and gastrin receptors, supporting the relevance of mucosal immunology in gastroenterology, especially in light of Helicobacter pylori-associated gastritis and ulcers. Lab research has revealed a potential role for basic fibroblast growth factor (bFGF), and another endogenous peptide BPC-15, in ulcer healing. The former substance may be responsible for the antiulcer efficacy of sucralfate. Intensive basic work on how H. pylori organisms attach to gastric cells and initiate inflammatory reactions in the mucosa will have unquestionable impact on improved therapy for peptic ulcer disease.
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PMID:Clinical relevance of basic research in peptic ulcer disease. 788 Oct 29

Although gastric enterochromaffin-like (ECL) carcinoid tumors are known to develop in patients with long-standing hypergastrinemia, the expression of the gastrin receptor gene in ECL cells has not yet been demonstrated. Therefore, this study was designed to examine gastrin receptor gene expression in ECL cells. Mastomys gastric mucosal cells isolated by enzyme dispersion were separated into 10 fractions (F1-10) by centrifugal elutriation. Each fraction was examined histologically to determine whether they contained ECL and/or parietal cells and Northern blot analysis was used to confirm the presence of histidine decarboxylase and H+, K(+)-ATPase gene expression. ECL cells were found only in fractions 1 and 2, whereas parietal cells were detected in fractions 6-10. Gastrin receptor gene expression was demonstrated in both parietal cell-rich and ECL cell-rich fractions. In addition, the gastrin receptor cDNA sequences obtained from the two of the fractions (F1 and 8) were identical. These results suggest that gastrin receptor genes are expressed in ECL cells as well as in parietal cells and that these receptors are identical.
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PMID:Gastrin receptor genes are expressed in gastric parietal and enterochromaffin-like cells of Mastomys natalensis. 792 34

1. A 78 kDa protein (p78) has been partially purified from washed membranes isolated from the corpus of porcine gastric mucosa. The purification was monitored by covalent cross-linking of iodinated [Nle15]-gastrin. 2. A single N-terminal sequence extending for 33 amino acids was obtained from the p78 preparation. Partial sequences totalling 192 amino acids were also obtained from 14 tryptic and 3 Staphylococcal V8 peptides. 3. 10 peptides plus the N-terminal sequence were derived from a previously unsequenced protein which was distantly related to the product of the E. coli fadB gene (Baldwin G. S. (1993) Comp. Biochem. Physiol. 104B, 55-61). The remaining 7 peptides were derived from the beta-subunit of the gastric H+/K(+)-ATPase. 4. The gastrin-binding activity remained in association with p78, and could be separated from the beta-subunit of the gastric H+/K(+)-ATPase, during chromatography on tomato lectin-Sepharose. 5. We conclude that p78 binds gastrin, and is a novel member of the enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase family of enzymes.
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PMID:Isolation and partial amino acid sequence of a 78 kDa porcine gastrin-binding protein. 801 37

Gastric acid secretion is precisely regulated by neural (acetylcholine), hormonal (gastrin), and paracrine (histamine; somatostatin) mechanisms. The stimulatory effect of acetylcholine and gastrin is mediated via increase in cytosolic calcium, whereas that of histamine is mediated via activation of adenylate cyclase and generation of cAMP. Potentiation between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways and/or the ability of gastrin and acetylcholine to release histamine from mucosal ECL cells. The prime inhibitor of acid secretion is somatostatin. Its inhibitory paracrine effect is mediated predominantly by receptors coupled via guanine nucleotide binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+,K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion and the identification of specific receptor subtypes has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g. muscarinic M1-receptor antagonists and histamine H2-receptor antagonists) as well as non-competitive inhibitors of H+,K(+)-ATPase (e.g. omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine and roxatidine acetate) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac and endocrine effects, as well as interfering with the absorption, metabolism and elimination of various drugs. The dominance of the histamine H2-receptor antagonists is now being challenged by omeprazole. Omeprazole reaches the parietal cell via the bloodstream, diffuses through the cytoplasm and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. Here, it covalently binds to H+,K(+)-ATPase, the hydrogen pump of the parietal cell, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main potential drawback to its use is its extreme potency which sometimes leads to virtual anacidity, gastrin cell hyperplasia, hypergastrinaemia and, in rats, to the development of carcinoid tumours. The cholinergic receptor on the parietal cell has recently been identified as an M3 subtype and that on postganglionic intramural neurones of the submucosal plexus as an M1 subtype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacology of gastric acid inhibition. 809 11

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