Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptors for the main neural (acetylcholine), hormonal (gastrin) and paracrine (histamine) secretory stimulants and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of histamine is mediated via an increase in adenylate cyclase activity, whereas the effect of acetylcholine and gastrin are mediated via an increase in cytosolic levels of calcium. Strong synergism between histamine and either gastrin or acetylcholine may reflect postreceptor interaction between the distinct pathways. Acetylcholine and gastrin are also capable of releasing histamine from the gastric mucosa, probably from ECL cells. The inhibitory effects of somatostatin and prostaglandin E on acid secretion are mediated 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, ultimately responsible for acid secretion. The intramural neural and paracrine pathways involved in the regulation of gastrin secretion in the antrum and acid secretion in the fundus have also been identified. Of prime importance is the somatostatin cell, which exerts a paracrine restraint on gastrin secretion and acid secretion. Elimination of this restraint or disinhibition is one of the mechanisms by which the stimulatory influence of cholinergic neurons is exerted on gastrin and parietal cells. Gastrin secretion is regulated by a cholinergic neuron that causes inhibition of somatostatin secretion and thus stimulation of gastrin secretion (disinhibition) and a noncholinergic neuron that causes direct stimulation of gastrin secretion by releasing the neurotransmitter, bombesin (or gastrin-releasing peptide). Acid secretion is regulated by a cholinergic neuron that causes direct stimulation of the parietal cell and indirect stimulation by decreasing somatostatin secretion, thus eliminating its inhibitory effect on the parietal cell (disinhibition). In addition, a regulatory feedback mechanism exists whereby intraluminal acidification stimulates somatostatin secretion, which in turn attenuates acid secretion. Gastric acid secretion may also be regulated by one or more intestinal inhibitory hormones, the most likely candidates being secretin, intestinal somatostatin, and neurotensin. Enterogastrone activity probably reflects the combined effect of all these hormones. Precise information on receptors and signal transduction mechanisms as well as on intramural neural and paracrine regulatory pathways has led to the development of new drugs capable of inhibiting acid secretion. These include antagonists that interact with stimulatory receptors (histamine H2-receptor antagonists, muscarinic receptor antagonists, and gastrin receptor antagonists), agonists that interact with inhibitory receptors (somatostatin and prostaglandin E analogues), and irreversible inhibitors of the luminal enzyme, H+K(+)-ATPase.
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PMID:Control of acid secretion. 169 38

We have investigated the effects of melatonin (Mel) and N-acetylserotonin (NAc-5HT) on the mitotic activity of gastric and colonic mucosa in adult male rats under basal conditions and after an administration of omeprazole (OM) (H+,K(+)-ATPase inhibitor). The metaphase-arrest technique was applied in the study. Additionally, serum gastrin levels were measured by RIA method in the OM-treated group and in respective polyethyleneglycol (PEG)-administered controls. We have found that: 1) OM-treatment increased serum gastrin levels in rats; 2) OM enhanced the mitotic activity of the colonic mucosa cells, although, unexpectedly, it did not exert such an effect on the gastric mucosa cells; 3) Mel suppressed the OM-induced increase of the colonic epithelium cell proliferation, while NAc-5HT failed to reveal that action: 4) NAc-5HT decreased the proliferation of gastric mucosa epithelial cells. The value of the mean mitotic activity rate (MMAR) of gastric mucosa after Mel-treatment also decreased, but that change was not statistically significant. The obtained data are in compliance with previous results from our laboratory concerning the inhibitory effect of pineal indoleamines on the jejunal epithelium mitotic activity. The stimulatory effect of OM on the proliferation of colonic epithelium is probably mediated by OM-induced hypergastrinaemia. The possibility of Mel interaction with intestinal gastrin receptors (a structural similarity occurs between Mel and benzotript, a specific gastrin receptor antagonist), as well as of the opposite effects of Mel and gastrin on intracellular cAMP content in the gut, are considered in the discussion of results.
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PMID:Influence of pineal indoleamines on the mitotic activity of gastric and colonic mucosa epithelial cells in the rat: interaction with omeprazole. 205 33

Antibodies to a membrane-bound antigen, localized to the canalicular structures of the parietal cell, are found in most sera of patients with chronic atrophic gastritis and pernicious anemia. In the present study immunoglobulins containing parietal cell antibodies were found to inhibit the activity of H+,K+-adenosine triphosphatase (EC 3.6.1.36) in a tubulovesicular membrane preparation from porcine gastric mucosa. The degree of inhibition correlated to the titer of parietal cell antibodies as assessed by an enzyme-linked immunosorbent assay. The specificity of the enzymatic inhibition was confirmed by the lack of effect of parietal cell antibodies on membrane-bound esterase. A possible interaction of parietal cell antibodies with gastrin binding at the receptor level was investigated in a radioreceptor assay employing 125I-gastrin 1 and gastric mucosal cell suspension from the guinea pig. No blocking capacity was found with immunoglobulins from patients with pernicious anemia as compared with immunoglobulins from healthy controls. The results thus demonstrate a direct inhibitory effect of parietal cell antibodies on the acid producing H+,K+-adenosine triphosphatase of the parietal cell, but also a lack of interaction with the gastrin receptor, and indicate that in the development of hypo/achylia H+,K+-adenosine triphosphatase autoantibodies could have a major pathogenic role.
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PMID:Parietal cell antibodies in pernicious anemia inhibit H+, K+-adenosine triphosphatase, the proton pump of the stomach. 254 Oct 40

Parietal cell secretory function may be inhibited by three mechanisms. (1) Receptors for gastrin, histamine and acetylcholine are present on the canine parietal cell, and parietal cell function may be directly inhibited by specific antagonists for each of these receptors. (2) Receptor activation of parietal cell function is mediated by cyclic AMP-dependent (histamine) and calcium-dependent (cholinergic agents and gastrin) mechanisms. The antisecretory action of prostaglandins reflect interference with histamine activation of adenylate cyclase. The current generations of calcium channel blockers have only weak antisecretory actions in vivo and are unlikely to be useful in clinical practice. (3) A third mechanism of inhibition is blockade of H+/K(+)-ATPase by substituted benzimidazoles, such as omeprazole. Each of these three mechanism provides modalities of potential clinical usefulness for treating acid-peptic disease. Gastrin and acetylcholine receptors are present on other fundic cells, in addition to the parietal cell. These other cells include the somatostatin cell in the dog fundic mucosa and the histamine-containing enterochromaffin-like (ECL) cell present in the fundic mucosa of several species. The relative impact of these receptors on different cell types on the regulation of acid secretion remains uncertain, and is probably variable among different species. One gastrin receptor of considerable importance is the gastrin receptor that exerts a trophic effect on the ECL cell in the fundic mucosa. Sustained hypergastrinaemia in response to profound hypochlorhydria is associated with hyperplasia of this cell type; the elucidation of the conditions that promote this hyperplasia and the clinical consequences of this association are pressing challenges.
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PMID:Review: antisecretory drugs: cellular mechanisms of action. 297 19

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.
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PMID:Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa. 321 80

1. Isolated, lumen-perfused, whole stomach preparations from mouse and immature rat produced a stable basal acid output which, although not blocked by histamine H2-, acetylcholine M- or CCKB/gastrin receptor antagonists, was almostly completely blocked by the H+/K(+)-ATPase inhibitor, omeprazole, and the metabolic inhibitor, sodium thiocyanate (NaSCN). 2. Fully-defined concentration-effect curves could be obtained on both assays with the phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX) and with dibutyryl cyclic AMP. 3. On the rat stomach assay, histamine H2-receptor blockade had no effect on the IBMX curve. In contrast, the IBMX response in the mouse was abolished by histamine H2-receptor blockade. On both assays responses to dibutyryl cyclic AMP were resistant to H2-receptor blockade. 4. In the absence of suprathreshold endogenous histamine, it is argued that H+/K(+)-ATPase mediated basal acid secretion from the mouse stomach assay is regulated by something other than cyclic AMP.
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PMID:Comparative study of the control of basal acid output from rodent isolated stomachs. 769 65

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

Many peptide hormone and neurotransmitter receptors belonging to the seven membrane-spanning G protein-coupled receptor family have been shown to transmit ligand-dependent mitogenic signals in vitro. However, the physiological roles of the mitogenic activity through G protein-coupled receptors in vivo remain to be elucidated. Here we have generated G protein-coupled cholecystokinin (CCK)-B/gastrin receptor deficient-mice by gene targeting. The homozygous mice showed a remarkable atrophy of the gastric mucosa macroscopically, even in the presence of severe hypergastrinemia. The atrophy was due to a decrease in parietal cells and chromogranin A-positive enterochromaffin-like cells expressing the H+,K(+)-ATPase and histidine decarboxylase genes, respectively. Oral administration of a proton pump inhibitor, omeprazole, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophy of the homozygotes. These results clearly demonstrated that the G protein-coupled CCK-B/gastrin receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.
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PMID:G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo. 887 22

The aim of this study was to investigate whether gastrin regulates morphological changes and alpha-subunit gene expression in parietal cells through the gastrin/CCK-B receptor on enterochromaffin-like cells by histamine release. Treatment with 100 mg/kg of YM022, a potent and selective gastrin/CCK-B receptor antagonist, for one week in rats did not alter mRNA levels of histidine decarboxylase or H+, K+-ATPase. However, parietal cell morphology predominantly changed to the resting form, although the serum gastrin concentration was significantly increased. Additional treatment with YM022 and oral omeprazole, 100 mg/kg, for one week markedly suppressed the increases of mRNA levels of histidine decarboxylase and H+, K+-ATPase and completely blocked the morphological transformation of the parietal cells to a stimulated form induced by treatment with omeprazole alone. This indicates that the morphological transformation of parietal cells to an activated form with a subsequent increase in H+, K+-ATPase synthesis caused by hypergastrinemia is mediated by increased histidine decarboxylase gene expression in enterochromaffin-like cells via gastrin/CCK-B receptors.
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PMID:Role of gastrin/CCK-B receptor in the regulation of gastric acid secretion in rat. 933 Nov 53


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