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

---

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

The mechanism of action of gastrin was investigated using cytochemical quantitation of hydroxyl ion production (HIP) in guinea pig gastric oxyntic mucosa. The reaction depends upon the trapping of OH ions produced during gastric stimulation and is blocked by the benzimidazole, Hassle 149/94, which inhibits the K+ + H+-ATPase and by acetazolamide, an inhibitor of carbonic anhydrase activity. It is thus a measure of hydroxyl ions produced during stimulation of the oxyntic cell and reflects upon hydrogen ion production. Gastrin (2.5 X 10(-16) -2.5 X 10(-12) M) caused a linear dose-dependent stimulation of HIP in the oxyntic cells. The response was biphasic, with an early peak at 90 s and a secondary rise at 240 s, which persisted for 10 min. Natural human gastrin (sulfated and nonsulfated) and the active COOH-terminal octapeptide fragment of gastrin stimulated HIP, whereas the biologically inert NH2-terminal (1-13) fragment of gastrin had no effect. The activation of oxyntic cell HIP by gastrin was neutralized by an antiserum directed towards the COOH-terminus of gastrin and not by nonimmune serum. Cimetidine (10(-5) M) blocked 25% and atropine (10(-5) M) had no effect on gastrin-stimulated HIP. EGTA (10(-3) M) and LaCl3 (10(-3) M) inhibited the action of gastrin by 67 and 52%, respectively. The calmodulin antagonists, trifluoperazine (10(-5) M), pimozide (10(-5) M), and the naphthalene sulfonamides, W-7 and W-13 (10(-5) M), inhibited gastrin-stimulated HIP by 45.6 38.5, 42.3, and 37.2%, respectively. Higher doses of W-7 and W-13 (10(-4) M) inhibited gastrin-stimulated HIP by 83 and 67%. The Ca2+ ionophore, A23187 (10(-4) M), stimulated HIP. Thus, it appears that gastrin stimulation of HIP is complex. 25% of its action is via a histamine-dependent pathway. 45% of its action is dependent upon extracellular Ca2+. Its action is also in part dependent upon a Ca2+/calmodulin mechanism.
...
PMID:Action of gastrin in guinea pig oxyntic cells. Studies using quantitative cytochemistry. 633 Jan 72

We have studied the physiologic factors regulating oxyntic cell activity using cytochemical quantification of carbonic anhydrase (CA) activity. Gastrin (10 (-16) to 10(-12)M), histamine (10(-17) to 10(-13) M), and carbamylcholine (10(-13) to 10(-8) M) caused a dose-dependent increase in CA in the oxyntic cells in guinea pig gastric fundus, maximal at 90 sec. The stimulation of CA by all three secretagogues was inhibited by the CA inhibitor, acetazolamide. The agonist activities were selectively blocked by respective antagonists. The benzimidazole derivative compound Hassle 149/94 (10(-3)M) abolished the actions of all agonists. Thus, histamine, gastrin and carbamylcholine have independent actions on oxyntic cell CA. The inhibition of the activity of all three secretagogues by H149/94 suggests a close link between CA activity and the functioning of the proton pump H+ + K+-ATPase.
...
PMID:Cytochemical quantification of physiologic regulation of oxyntic cell carbonic anhydrase. 643 Jan 97

Isolated guinea pig parietal cells, the function of which is similar to that of human parietal cells, were used in this study. The accumulation of 14C-aminopyrine (14C-AP) was measured to study the inhibitory mechanism of leminoprazole in cells. Stimulation by 10 microM histamine, 0.1 mM carbachol, 1 microM gastrin or 1 mM db-cAMP brought about satisfactory incorporation of 14C-AP, and leminoprazole concentration-dependently inhibited acid secretion induced by these stimulants. At 10(-5) M, almost 100% inhibition was observed. The IC50 values of leminoprazole obtained from its inhibitory action on histamine, carbachol, gastrin and db-cAMP-stimulated acid secretion were 4.0 x 10(-7) M, 3.5 x 10(-7) M, 2.5 x 10(-7) M and 5.6 x 10(-7) M, respectively. Thus the extent of inhibition was the same for the responses to all the secretagogues. These results indicate that the site of action of leminoprazole is intracellular and distal from cAMP (intracellular second messenger), but not at the receptor sites. The results also strongly suggest that the inhibitory action of leminoprazole on H+,K(+)-ATPase may contribute to the inhibitory effect of this drug on gastric acid secretion.
...
PMID:Inhibitory effect of leminoprazole on acid secretion in parietal cells isolated from guinea pig gastric mucosa. 749 78

Peripheral regulation of gastric acid secretion is initiated by the release of gastrin from the G cell. Gastrin then stimulates the cholecystokinin-B receptor on the enterochromaffin-like cell beginning a calcium signaling cascade. An exocytotic release of histamine follows with concomitant activation of a C1- current. The released histamine begins the H2-receptor mediated sequence of events in the parietal cell, which results in activation of the gastric H+/K+ - ATPase. This enzyme is the final common pathway of acid secretion. The H+/K+ - ATPase is composed of two subunits: the larger alpha-subunit couples ion transport to hydrolysis of ATP, the smaller beta-subunit is required for appropriate assembly of the holoenzyme. Both the membrane and extracytoplasmic domain contain the ion transport pathway, and therefore, this region is the target for the antisecretory drugs of the post-H2 era. The 100 kDa alpha-subunit has probably 10 membrane spanning segments with, therefore, five extracytoplasmic loops. The 35 kDA beta-subunit has a single membrane spanning segment, and most of this protein is extracytoplasmic with the six or seven N glycosylation consensus sequences occupied. Omeprazole is an acid-accumulated, acid-activated, prodrug that binds covalently to two cysteine residues at positions 813 (or 822) and 892, accessible from the acidic face of the pump. Lansoprazole binds to cys321, 813 (or 822) and 892; pantoprazole binds to cys813 and 822. The common binding site for these drugs (cys813 or 822) is responsible for the inhibition of acid transport. Covalent inhibition of the acid pump improves control of acid secretion, but since the effective half life of the inhibition in man is about 48 hr, full inhibition of acid secretion, perhaps necessary for eradication of Helicobacter pylori in combination with a single antibiotic, will require prolongation of the effect of this class of drug.
...
PMID:Gastric acid secretion: activation and inhibition. 750 35

Both receptor antagonists and acid pump inhibitors are clinically useful suppressants of acid secretion. The latter class of drugs, the substituted benzimidazoles, inhibit acid secretion more effectively and, therefore, provide superior symptom relief and healing in all acid-related diseases. The H2-receptor antagonists competitively block the action of histamine on the H2-receptors of parietal cells. This histamine is released from enterochromaffin-like cells (ECL cells) due to gastrin, acetylcholine or epinephrine stimulation. In addition, parietal cells have M3-receptors which can function independently of H2-receptors. Hence, there is no single common pathway for parietal cell stimulation. Stimulation of acid secretion by parietal cells requires activation of the acid pump, the gastric H+,K(+)-ATPase. The target site for the benzimidazoles is the activated gastric H+,K(+)-ATPase, and, in particular, the cysteines of the pump that are exposed to the acid space of the secretory canaliculus of the parietal cells. Pantoprazole in its protonated form selectively reacts with cysteines present in both the fifth and sixth membrane segments of the ATPase, explaining its mechanism of inhibiting proton transport by this enzyme.
...
PMID:Continuing development of acid pump inhibitors: site of action of pantoprazole. 751 42

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.
...
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.
...
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.
...
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.
...
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.
...
PMID:Pharmacological aspects of acid secretion. 785 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---