Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

This multicenter, randomized, double-blind, 8-wk study compared the new H+/K(+)-ATPase inhibitor, lansoprazole, 30 mg daily, to ranitidine 150 mg bid for treatment of erosive reflux esophagitis resistant to histamine-2 receptor antagonists (H2RA). Patients were evaluated after 2, 4, 6, and 8 wk of treatment by symptom assessment and endoscopy. Healing rates for lansoprazole were 71%, 80%, 88%, and 89% at 2, 4, 6, and 8 wk, respectively, compared to 21%, 33%, 45%, and 38% for ranitidine (p < 0.001 at all points). Lansoprazole was significantly more effective than ranitidine for relief of heartburn and reduction of antacid tablet use. Increases in serum gastrin concentrations between the baseline and the 8-wk visit were greater in lansoprazole-treated than in ranitidine-treated patients. Lansoprazole was safe and well tolerated. In patients with erosive reflux esophagitis resistant to standard doses of H2RA, lansoprazole 30 mg/day is more effective than continuation of an H2RA (ranitidine 150 mg bid) for healing of esophagitis and improvement of symptoms.
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PMID:Treatment of reflux esophagitis resistant to H2-receptor antagonists with lansoprazole, a new H+/K(+)-ATPase inhibitor: a controlled, double-blind study. Lansoprazole Study Group. 810 95

H+, K(+)-ATPase inhibitors such as omeprazole are the antisecretory agents of choice for the management of gastric acid hypersecretory states, including the Zollinger-Ellison syndrome. However, long-term follow-up data on the overall efficacy and safety of these agents in large numbers of patients are lacking. In the current study we examined the long-term efficacy and safety of omeprazole in 116 patients with Zollinger-Ellison syndrome treated with oral omeprazole at a single centre for up to 114 months (mean +/- S.E.M. = 38 +/- 3 months). The initial omeprazole maintenance dose was established according to the acute upward dose titration method in 89/116 patients (77%). Gastric acid output was effectively controlled using 60 mg of omeprazole once daily in 41/89 patients (46%) and 22/89 patients (25%) required twice daily omeprazole therapy. The mean ranitidine equivalent dose for patients who required 60 mg omeprazole once daily (2.5 +/- 0.2 g/day) was significantly lower than the mean ranitidine equivalent dose for patients who required more than 60 mg omeprazole once daily (4.3 +/- 0.3 g/day). Long-term omeprazole maintenance therapy was discontinued in 36/116 patients (31%) but in no cases was discontinuation due either to drug-induced side-effects or uncontrolled gastric acid output. Fasting serum gastrin levels were significantly elevated above pre-treatment levels at only one time point during follow-up and were likely due to tumour growth rather than a drug effect. The final long-term omeprazole maintenance doses were lower than the initial doses but correlated closely with the pre-omeprazole basal acid output (r = 0.41, P < 0.001) and ranitidine equivalent dose requirements (r = 0.49, P < 0.001). We conclude that omeprazole effectively and safely controls gastric acid hypersecretion in all patients with Zollinger-Ellison syndrome for up to nine years without evidence by tachyphylaxis.
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PMID:Use of omeprazole in Zollinger-Ellison syndrome: a prospective nine-year study of efficacy and safety. 816 65

The H(+)-K(+)-adenosinetriphosphatase (ATPase) is expressed in the parietal cell and is responsible for acid secretion by the stomach. Histamine binds to an H2 receptor and activates adenylate cyclase and intracellular calcium concentration ([Ca2+]i) elevation, stimulating acid secretion. It has been shown that omeprazole administered to rats increases serum gastrin and transiently increases the level of mRNA for the alpha-subunit of the pump, but this increase is blocked by the presence of the H2-receptor antagonist, famotidine [A. Tari, G. Yamamoto, K. Sumii, M. Sumii, Y. Takehara, K. Haruma, G. Kajiyama, V. Wu, G. Sachs, and J. H. Walsh. Am. J. Physiol. 265 (Gastrointest. Liver Physiol. 28): G752-G758, 1993]. These observations suggest that the release of histamine induced by gastrin is essential for the increase of the expression of mRNA induced by omeprazole. Infusion of histamine at 15 mumol.kg-1.h-1 i.v. for 1 h increased the alpha-subunit mRNA level by 144 +/- 2.4% and induced a stimulated morphological appearance of the parietal cell. These changes were inhibited completely by the competitive H2-receptor antagonist famotidine, which elevated gastric pH and serum gastrin. Famotidine also reduced the level of H(+)-K(+)-ATPase mRNA compared with control animals. No change in the expression of beta-actin mRNA was observed in any group of animals. These data provide direct evidence for histamine stimulation of H(+)-K(+)-ATPase alpha-subunit gene expression by activation of the H2 receptor.
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PMID:Effect of histamine on rat gastric H(+)-K(+)-ATPase alpha-subunit expression. 816 83

The gastric proton pump H+/K(+)-ATPase in the parietal cell is central to acid secretion into the stomach. We performed the following experiment to examine the pattern of expression of the alpha- and beta-subunits of the H+/K(+)-ATPase at the transcriptional level during 7 days' application of the proton pump inhibitor omeprazole, in relation to the expression of gastrin and histamine, two stimuli of gastric acid secretion. Serum gastrin concentrations and mRNA levels of antral gastrin, fundic histidine decarboxylase (HDC) and H+/K(+)-ATPase alpha- and beta-subunits were determined after 8 h, 1, 3 and 7 days. Omeprazole treatment rapidly caused an increase in the serum gastrin concentration and the antral gastrin mRNA level after 3 days. HDC mRNA expression showed a steady increase with a 5-fold induction after 1 week. However, mRNA levels of the alpha- and beta-subunits of the H+/K(+)-ATPase were unchanged during the course of omeprazole treatment. These results suggest that omeprazole inhibition of the gastric proton pump does not result in feedback activation of H+/K(+)-ATPase gene expression despite adaptive changes of the endocrine stomach.
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PMID:Expression of the gastric H+/K(+)-ATPase and histidine decarboxylase during omeprazole treatment. 818 77

Lansoprazole, a new proton pump inhibitor, selectively inhibits the H+/K(+)-ATPase. Its inhibitory effect on basal and gastrin stimulated gastric acid secretion is equal to omeprazole and stronger than that of H2-receptor antagonists. Healing rates concerning gastric and duodenal ulcers and refluxesophagitis are significantly higher compared to H2-receptor antagonists and at least comparable to omeprazole. Regarding pilot studies in H. pylori eradication therapy, lansoprazole in combination with various antibiotics is expected to show good eradication rates. Considering its excellent safety and interaction profile lansoprazole is effective and safe in treating acid related disorders.
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PMID:[Lansoprazole--profile of a new proton pump inhibitor]. 819 67


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