Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SNARE proteins - rab3A - parietal cells - H+/K+-ATPase When stimulated by histamine, acetylcholine, or gastrin the luminal compartments of oxyntic parietal cells display conspicuous morphological changes. The luminal plasma membrane surface becomes greatly expanded, while the cytoplasmic tubulovesicles are decreased in parallel. Due to these membrane rearrangements the H+/K(+)-ATPase obtains access to the luminal surface, where proton secretion occurs. The stimulation-induced translocation of H+/K(+)-ATPase involves a fusion process. Exocytotic membrane fusion in neurons is achieved by the highly regulated interaction of mainly three proteins, the vesicle protein synaptobrevin and the plasma membrane proteins syntaxin and SNAP25 (synaptosomal-associated protein of 25 kDa), also referred to as SNARE proteins. Using immunofluorescence microscopy we analysed the subcellular distribution of neuronal synaptic proteins and rab3A in resting and stimulated parietal cells from pig and rat. In resting cells all synaptic proteins colocalized with the H+/ K(+)-ATPase trapped in the tubulovesicular compartment. After stimulation, translocated H+/K(+)-ATPase showed a typical canalicular distribution. Syntaxin, synaptobrevin, SNAP25 and rab3A underwent a similar redistribution in stimulated cells and consequently localized to the canalicular compartment. Using immunoprecipitation we found that the SNARE complex consisting of synaptobrevin, syntaxin and SNAP25, which is a prerequisite for membrane fusion in neurons, is also assembled in parietal cells. In addition the parietal cell-derived synaptobrevin could be proteolytically cleaved by tetanus toxin light chain. These data may provide evidence that SNARE proteins and rab3A are functionally involved in the stimulation-induced translocation of the H+/K(+)-ATPase.
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PMID:SNARE proteins and rab3A contribute to canalicular formation in parietal cells. 1060 54

AU-461 (1-(2-methyl-4-methoxyphenyl)-4-[(2-hydroxyethyl)amino]-6-beta,beta, beta-trifluoroethoxy-2,3-dihydropyrrolo[3,2-c]quinoline) was tested for its ability to act as an anti-ulcer agent. AU-461 inhibited gastric H(+)/K(+) ATPase activities with IC(50) values of 12.15 and 4.20 micromol/l for rabbit and pig enzymes, respectively. The inhibition was reversible, and competitive with respect to the activating cation K(+). When AU-461 was examined for the in vivo antisecretory activity, we found that AU-461 reduced the histamine-stimulated acid secretion as well as the basal secretion in rat stomach. Duration of the antisecretory effect was about 6 h upon oral administration. AU-461 prevented dose-dependently the ulcer formation produced by either ethanol or NaOH. This protective effect was not altered by indomethacin pretreatment. In addition, the elevated plasma gastrin by the oral administration of AU-461 was returned to control by 12 h. Taken together, these results suggest that AU-461 could be developed as a new therapeutic agent for peptic ulcer disease.
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PMID:Pharmacological properties of the gastric H(+)/K(+) ATPase inhibitor, AU-461. 1075 53

Nuclear mutants of Saccharomyces cerevisiae assigned to complementation group G34 are respiratory-deficient and lack cytochrome oxidase activity and the characteristic spectral peaks of cytochromes a and a(3). The corresponding gene was cloned by complementation, sequenced, and identified as reading frame YGR062C on chromosome VII. This gene was named COX18. The COX18 gene product is a polypeptide of 316 amino acids with a putative amino-terminal mitochondrial targeting sequence and predicted transmembrane domains. Respiratory chain carriers other than cytochromes a and a(3) and the ATPase complex are present at near wild-type levels in cox18 mutants, indicating that the mutations specifically affect cytochrome oxidase. The synthesis of Cox1p and Cox3p in mutant mitochondria is normal whereas Cox2p is barely detected among labeled mitochondrial polypeptides. Transcription of COX2 does not require COX18 function, and a chimeric COX3-COX2 mRNA did not suppress the respiratory defect in the null mutant, indicating that the mutation does not impair transcription or translation of the mRNA. Western analysis of cytochrome oxidase subunits shows that inactivation of the COX18 gene greatly reduces the steady state amounts of subunit 2 and results in variable decreases in other subunits of cytochrome oxidase. A gene fusion expressing a biotinylated form of Cox18p complements cox18 mutants. Biotinylated Cox18p is a mitochondrial integral membrane protein. These results indicate Cox18p to be a new member of a group of mitochondrial proteins that function at a late stage of the cytochrome oxidase assembly pathway.
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PMID:Cloning and characterization of COX18, a Saccharomyces cerevisiae PET gene required for the assembly of cytochrome oxidase. 1080 34

Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion.
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PMID:The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion. 1150 3

Gastrin-deficient mice have impaired basal and agonist-stimulated gastric acid secretion. To analyze whether an intrinsic parietal cell defect contributed to the reduced acid secretion, we analyzed parietal cell calcium responses and acid secretory function in vitro. Parietal cells were purified by light-scatter cell sorting and calcium responses to gastrin, histamine, and carbachol were measured in gastrin-deficient and wild-type mice cell preparations. Surprisingly, basal and histamine-induced calcium concentrations were higher in the mutant cell preparations. [(14)C]aminopyrine uptake analysis in acutely isolated gastric glands revealed that basal acid accumulation was enhanced in gastrin-deficient cell preparations as well as on treatment with carbachol or histamine. These results suggested that an intrinsic parietal cell defect was not responsible for the reduced acid secretion in gastrin-deficient mice. Flow cytometric analysis of dispersed, H(+)-K(+)-ATPase-immunostained gastric mucosal preparations revealed a marked increase in parietal cell number in gastrin-deficient mice, which may have accounted for the enhanced in vitro acid secretion detected in this study. Parietal cells were found to be significantly smaller in the mutant cell preparations, suggesting that gastrin stimulation modulates parietal cell morphology.
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PMID:Enhanced calcium signaling and acid secretion in parietal cells isolated from gastrin-deficient mice. 1238 85

Helicobacter pylori infection is a causal factor of gastric cancer (which is associated with low gastric acid secretion) or duodenal ulcer (high acid secretion). Parietal cells and ECL cells in the stomach are controlled by gastrin, which plays a crucial role in the regulation of acid secretion. The present study was undertaken to identify a possible role of gastrin in determining the different responses of the parietal cells and ECL cells to chronic H. pylori infection. Wild-type (C57BL/6J) gastrin(+/+) mice and gastrin(-/-) knockout mice, generated through targeted gene disruption and backcrossed eight times to C57BL/6J, were infected with H. pylori for 9 months. The acid output was measured 4 h after pylorus ligation (known to cause vagal excitation). The gastric mucosa was examined by immunocytochemistry with antisera to alpha-subunit of H+/K(+)-ATPase for the parietal cells, and to histamine and vesicle monoamine transporter-2 for the ECL cells, and by quantitative electron microscopy. In infected gastrin(+/+) mice, the acid output and the percentage of secreting parietal cells (freely fed state) were 20-30% of the values in uninfected controls, while the density and ultrastructure of parietal cells were normal. The infected mice had hypergastrinemia and displayed hypertrophy and hyperplasia of ECL cells. Although uninfected gastrin(-/-) mice had lower the acid output than uninfected gastrin(+/+) mice, there was a higher acid output (approximately 3 times) in infected gastrin(-/-) mice than their uninfected homologues. The numbers of parietal cells and ECL cells remained unchanged in infected gastrin(-/-) mice. In conclusion, chronic H. pylori infection results to impaired parietal-cell function (acid hyposecretion), hypergastrinemia and hyperplasia of ECL cells in wild-type mice but leads to vagally induced hypersecretion in gastrin-deficient mice.
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PMID:Chronic Helicobacter pylori infection results in gastric hypoacidity and hypergastrinemia in wild-type mice but vagally induced hypersecretion in gastrin-deficient mice. 1455 57

Proton pump inhibitors, which act at the terminal point of acid secretion--the H+, K+-ATPase--are currently the most effective pharmacological treatments available for reflux disease. Despite the efficacy of the proton pump inhibitors, there is still potential for clinical improvement in gastro-oesophageal reflux disease pharmacotherapy. Faster onset of complete acid inhibition and improved duration of efficacy are two potential areas for improvement A number of novel pharmaceutical agents are currently undergoing clinical evaluation for the treatment of gastro-oesophageal reflux disease. These include transient lower oesophageal sphincter relaxation-reducing agents, serotonergic agents/prokinetics, potassium-competitive acid blockers, mucosal protectants, histamine H3 agonists and anti-gastrin agents. One or more of these drug groups may represent the future medical therapy for gastro-oesophageal reflux disease, should they prove effective in the clinical setting. This review summarizes the state of the art with these agents.
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PMID:Review article: new pharmacological agents for the treatment of gastro-oesophageal reflux disease. 1514 93

A prominent pathological feature of murine autoimmune gastritis is a pronounced mucosal hypertrophy. Here, we examined factors that may be responsible for inducing this hypertrophy. Because gastrin is known to be both an inducer of gastric mucosal cell proliferation and is elevated in autoimmune gastritis, mice deficient in gastrin were thymectomised at day 3 and assessed for autoimmune gastritis. Gastrin-deficient mice showed all the characteristic features of murine autoimmune gastritis, including gastric unit hypertrophy due to hyperproliferation and accumulation of immature epithelial cells, decreases in the number of zymogenic and parietal cells, and autoantibodies to the gastric H+/K+-ATPase. Hence, gastrin is not required for either the establishment of chronic gastritis or development of the typical pathological features of this disease. We also examined mRNA levels of a number of gastric mucosal growth factors in RNA samples from mice with hypertrophic autoimmune gastritis. Members of the Reg family, RegIIIbeta and RegIIIgamma, were greatly elevated in mice with hypertrophic gastritis, whereas RegI and amphiregulin (an EGF receptor ligand) were more modestly and/or inconsistently induced. These data demonstrate that induction of gastric mitogenic factors, such as members of the Reg family, can be achieved in inflammatory situations by gastrin-independent pathways. Members of the Reg family, in particular RegIIIbeta and RegIIIgamma, are good candidates to be involved in inducing the mucosal hyperproliferation in autoimmune gastritis. These findings are likely to be of relevance to other gastric inflammatory conditions.
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PMID:Growth factors associated with gastric mucosal hypertrophy in autoimmune gastritis. 1520 19

Juvenile patients affected with autoimmune thyroid disorders showed a 14-21% prevalence of parietal cell antibodies (PCA) reacting against the H+/K+-ATPase of the gastric parietal cells. PCA are the principal immunological markers of atrophic body gastritis (ABG).ABG is characterized by loss of oxyntic glands, achlorhydria, and hypergastrinemia. The aim of this study was to determine whether PCA positivity could be associated with biochemical and histological manifestations of gastric autoimmunity in juvenile patients with autoimmune thyroid disease (AITD). We studied 129 children (96 females and 33 males) with chronic lymphocytic thyroiditis (n = 115) or Graves' disease (n = 14). Mean age at diagnosis of AITD was 9.7 +/- 3.3 yr, and mean age at sampling was 12.3 +/- 3.7 yr. We determined PCA and Helicobacter pylori antibodies, gastrin, and pepsinogen I plasma levels. Gastroscopy with multiple biopsies was carried out in a subgroup of patients with PCA positivity. We found that 30% of children had detectable PCA. Hypergastrinemia was found in 45% of the PCA-positive children (range, 40-675 pg/ml) vs. 12% of PCA-negative children (range, 35-65 pg/ml; P < 0.001). Eighteen patients with PCA positivity underwent gastroscopy; eight of these children had normogastrinemia, which showed no signs of ABG, and 10 children had hypergastrinemia, of whom five had mild to severe ABG. Our study shows that autoimmune gastritis is an early event in juvenile AITD with detectable PCA. Gastrin plasma level is a reliable marker of gastric atrophy.
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PMID:Early manifestations of gastric autoimmunity in patients with juvenile autoimmune thyroid diseases. 1547 89

Omeprazole, a proton pump inhibitor (PPI), is widely used in treatment of peptic ulcer, gastro esophageal reflux disease and eradication of Helicobacter pylori. PPIs inhibit final gastric acid secretion stage by blocking H+/K+-ATPase. But the mechanism except for gastric antisecretory effect has not understood clearly. So, we examined the effects of omeprazole on the levels of gastrointestinal peptides (somatostatin, motilin, gastrin, vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP)) in plasma from healthy subjects. After a single oral administration of omeprazole, the plasma omeprazole concentration was highest at 120 min. Omeprazole caused a significant increase of plasma somatostatin-immunoreactive substance (IS) levels at 60-240 min and plasma motilin-IS levels at 120-180 min, compared with a placebo group, respectively. The physiological release of plasma gastrin-IS was reduced by the administration of omeprazole at 60 min, but the medicine did not alter the levels of VIP-, CGRP- and SP-IS. These results suggested that the pharmacological effects of omeprazole on regulation of gastrointestinal function are closely related to changes of somatostatin-, motilin- and gastrin-IS levels in human plasma.
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PMID:Omeprazole raises somatostatin and motilin in human plasma. 1568 3


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