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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of forskolin and several H2-agonists was investigated on the activity of adenylate cyclase in homogenates of guinea-pig lung parenchyma. Histamine, 0.1 microM to 1 mM, dimaprit, 1 microM to 10 mM, 4-methyl histamine, 0.1 microM to 10 mM, impromidine, 10 nM to 10 microM and forskolin, 1 nM to 100 microM, all produced a dose-dependent stimulation of adenylate cyclase activity above the basal level. The histamine H1-receptor antagonist mepyramine, 10 microM, and beta-adrenoceptor antagonist propranolol, 10 microM, had no effect on the stimulation by histamine of adenylate cyclase. The dose-response curve for stimulation by histamine of adenylate cyclase was shifted to the right in a dose-dependent manner by increasing concentrations of several H2-antagonists. Schild plots constructed for each H2-antagonist produced straight lines with slopes not significantly different from unity. The equilibrium dissociation constants obtained for the H2-antagonists in this study were similar to those previously reported for inhibition of dimaprit-induced relaxation of the pre-contracted lung strip, inhibition of [3H]-tiotidine binding to homogenates of guinea-pig lung parenchyma and inhibition of histamine-stimulated adenylate cyclase in guinea-pig gastric mucosa.
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PMID:A study of the H2-receptor for histamine stimulating adenylate cyclase in homogenates of guinea-pig lung parenchyma. 286 13

Cellular mechanisms underlying the actions of antisecretory agents were studied with dispersed canine fundic cells; aminopyrine accumulation monitored parietal cell (PC) function. Canine PC have pharmacologically typical histamine (H) H2 and muscarinic (M) receptors. PC also have gastrin (G) receptors, which were selectively blocked by gastrin/CCK antagonists. Potentiating interactions occurred between secretagogues, one of the components of the interdependency between regulatory pathways. Prostaglandins (PG) E2 inhibited H-stimulated PC function. Treatment of PC with pertussis toxin (PT), which inactivates the inhibitory GTP-binding protein of adenylate cyclase (Gi), markedly reduced PG inhibition, indicating PG action via Gi. PC function can also be directly inhibited by H+/K+-ATPase inhibitors, such as omeprazole. When canine mucosal cells were studied, stimulatory G and inhibitory M receptors were present on fundic somatostatin (S) cells. Histamine was localized to canine fundic mast cells, which lacked G or M receptors, a conclusion that may not pertain to fundic histamine cells in other species. Nonparietal cell receptors may be important modulators of the regulation of acid secretion.
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PMID:Mechanisms of action of antisecretory drugs. Studies on isolated canine fundic mucosal cells. 288 44

Gastric acid secretion is controlled by neurocrine, endocrine, and paracrine pathways. At the organ level, the neurocrine and endocrine systems provide long-range regulation; and near the target cell the paracrine system appears to predominate. The integration of the regulatory commands from these various pathways is complex and, as a result, some pathways have not yet been clearly defined. Present evidence suggests that acetylcholine from mucosal nerve endings acts by 2 possible pathways. It interacts with muscarinic receptors on the oxyntic cell stimulating acid production. It is also capable of releasing histamine from the paracrine cell in the gastric glands, and histamine then acts on the oxyntic cells. The endocrine effect on acid secretion mediated by gastrin is less clear. Gastrin binds to oxyntic cell plasma membranes but has little or no direct stimulatory effect on the acid-secreting cell. It is assumed that its stimulatory action on acid secretion in vivo is mediated primarily by increasing histamine levels near the oxyntic cells. Histamine, released from paracrine cells near the oxyntic cells, is probably controlled by acetylcholine and gastrin, but other mechanisms are being explored. Histamine binds to the H2-receptors on the oxyntic cell plasma membrane, activating adenylate cyclase, which catalyzes the production of the intracellular messenger cyclic AMP. Cyclic AMP in turn activates a specific protein kinase, which phosphorylates a yet unknown substrate for the propagation of the stimulatory signal. The action of acetylcholine on the oxyntic cell receptors does not stimulate the production of cyclic AMP; instead, it acts on Ca++ channels, increasing the Ca++ entrance into the cell, which initiates the intracellular events.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of gastric acid secretion at the cellular level. 288 22

We have previously reported histamine desensitization of human blood mononuclear leukocytes resulting in reduced cAMP responses to beta-adrenergic agonists, histamine and prostaglandin E1. This heterologous desensitization occurred at low, micromolar histamine concentrations and was accompanied by elevation of cAMP-phosphodiesterase (PDE) activity in these cells. We have now investigated the activity of PDE in the lymphocyte and monocyte fractions of mononuclear leukocytes to determine the site of histamine effect. PDE activity per cell was higher in monocytes (0.075 +/- 0.070 units) than lymphocytes (0.026 +/- 0.08) units). Monocytes responded to 10(-6) M histamine stimulation with a much greater increase in PDE activity (0.354 +/- 0.1 units) than did lymphocytes (0.047 +/- 0.015 units). Histamine receptor studies, using thiazolylethylamine and chlorpheniramine as H1-agonist and antagonist respectively and dimaprit and cimetidine as H2-agonists and antagonists respectively, indicated that the histamine stimulation of PDE activity is mediated predominantly through H1 histamine receptor in the monocytes and the H1 receptor in the lymphocytes. Previously histamine had been thought to increase cyclic AMP by acting on H2 receptors to activate adenylate cyclase. Our studies show that stimulation of H1 or H2 receptors by low histamine concentration can cause the opposite effect i.e. increased catabolism and a net reduction in cAMP levels. The localization of this effect predominantly to monocytes indicates a potentially important mechanism for histamine action on immune regulation.
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PMID:Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes. 289 Dec 64

Histamine stimulated the enzymatic synthesis of phosphatidylcholine from phosphatidylethanolamine in crude synaptic membranes of rat brain containing the methyl donor S-adenosyl-L-methionine (SAM). In the presence of, but not in the absence of SAM, histamine increased cyclic AMP accumulation at the concentrations that stimulate phospholipid methylation. S-Adenosyl-L-homocysteine, an inhibitor of phospholipid methyltransferases, inhibited histamine-stimulated phospholipid methylation and histamine-induced cyclic AMP accumulation in the presence of SAM in a concentration-dependent manner. Histamine-induced [3H]methyl incorporation into phospholipids exhibited a marked regional heterogeneity in rat brain in the order of cortex greater than medulla oblongata greater than hippocampus greater than striatum greater than midbrain greater than hypothalamus. The regional distribution of histamine-induced cyclic AMP accumulation exactly paralleled histamine-stimulated [3H]methyl incorporation in rat brain. Histamine-induced cyclic AMP accumulation was inhibited by the addition of cimetidine or famotidine, but not by mepyramine or diphenhydramine. The accumulation of cyclic AMP in the presence of SAM was observed by the addition of impromidine or dimaprit, but not by 2-pyridylethylamine. These results indicate that phospholipid methylation is induced by histamine and may participate in H2-receptor-mediated stimulation of adenylate cyclase in rat brain.
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PMID:Histamine increases phospholipid methylation and H2-receptor-adenylate cyclase coupling in rat brain. 289 30

The tricyclic antidepressants trimipramine and doxepin, and the neuroleptic agents trifluoperazine and haloperidol were tested for their effect on histamine H2-receptor-mediated adenylate cyclase activity and H+ secretion in guinea-pig parietal cells. All compounds inhibited histamine-stimulated adenylate cyclase and H+ secretion in a concentration-dependent manner. The antisecretory potency was 1-2 orders of magnitude higher than that for adenylate cyclase inhibition. All drugs caused a rightward shift in the concentration-response curves of histamine-induced adenylate cyclase activation with Schild-plot lines having a slope significantly different from unity. Histamine-stimulated H+ secretion was inhibited by the drugs in a noncompetitive fashion. These results demonstrate that antidepressants and neuroleptics interfere noncompetitively with the parietal cell histamine H2-receptor and that this receptor blocking activity is not related to the antisecretory activity of the drugs.
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PMID:Interaction of antidepressants and neuroleptics with histamine stimulated parietal cell adenylate cyclase and H+ secretion. 289 27

There was no significant difference between the concentration-dependent inhibitory effects produced by roxatidine acetate, roxatidine and ranitidine on adenylate cyclase derived from isolated and enriched guinea-pig parietal cells. All the compounds shifted the concentration-response curve of histamine to the right and transformation of this data to Schild-plots produced straight lines with slopes greater than 1 but not significantly different from each other. The pA2 values characterising the potencies were roxatidine acetate 6.85 +/- 0.86, roxatidine 7.14 +/- 0.04, and ranitidine 6.92 +/- 0.01. Histamine-stimulated acid production from isolated guinea-pig parietal cells, measured by the 14C-aminopyrine accumulation technique, was similarly affected by the 3 compounds. Schild-plot slopes of roxatidine acetate and ranitidine were not significantly different from unity and pA2 values were similar to those of the adenylate cyclase inhibition, roxatidine acetate 7.15 +/- 0.09, roxatidine 7.03 +/- 0.02, and ranitidine 6.83 +/- 0.10. In conclusion, roxatidine acetate and its major metabolite roxatidine behave like competitive antagonists with potencies similar to ranitidine on H2-receptors on the guinea-pig parietal cell.
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PMID:Comparative pharmacology of histamine H2-receptor antagonists. 290 46

Histamine (1-100 microM) induced a concentration-dependent increase in intracellular cyclic AMP in monolayer cultures of human, canine and foetal-bovine articular chondrocytes. The dose-response curve for histamine in each culture was progressively displaced to the right with increasing concentrations of cimetidine, an H2-receptor antagonist. The histamine-induced cyclic AMP elevation in human articular chondrocytes was also significantly decreased by ranitidine, another H2 antagonist, but not by the H1 antagonists mepyramine and chlorpheniramine. These findings indicate that histamine activates chondrocyte adenylate cyclase through an H2 receptor. The cyclic AMP response of human chondrocytes to histamine was many times greater than that measured for synovial fibroblasts under similar conditions. Such findings suggest that mast-cell-chondrocyte interactions in vivo may contribute to changed chondrocyte metabolism in joint disease.
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PMID:Histamine H2 receptors on chondrocytes derived from human, canine and bovine articular cartilage. 298 67

The direct effect of glucagon on human parietal cell function in vitro was tested by measuring adenylate cyclase (AC) activity and H+ production in homogenates of human gastric mucosa obtained during surgery or at biopsy. Cells isolated from mucosa obtained during surgery showed an increase in AC with histamine and glucagon. In parietal cell enriched fractions (75%) glucagon and histamine stimulated AC much more effectively than in parietal cell depleted fractions (15% and 7%). In contrast, glucagon did not affect basal or histamine stimulated 14C amino pyrine uptake. In homogenates of mucosal biopsy specimens 2 X 10(-7) mol/l glucagon enhanced AC activity by 76% (corpus) and 20% (antrum). In the same homogenates 10(-4) mol/l histamine caused a stimulation by 161% (corpus) and 38% (antrum). In fundic biopsy specimens glucagon displayed a biphasic concentration response curve with an increase at 10(-10) mol/l (46% above basal AC activity) and a maximum at 2 X 10(-7) mol/l (97%). Histamine elicited the maximal response (192%) at 10(-3) mol/l. Increasing histamine and glucagon concentrations caused additive stimulation of AC. Ranitidine did not change AC in response to glucagon but abolished the effect of histamine. Data suggest that the glucagon action is mediated by separate (glucagon?) receptors. As H+ production was not affected by glucagon, the coexistence of two AC systems in the human parietal cell is postulated: One that is activated via histamine H2-receptors and which stimulated H+ production; another that is activated by glucagon and is directed towards other, possibly metabolic effects.
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PMID:Effect of glucagon on adenylate cyclase activity and acid production of isolated human parietal cells. 302 Mar 13

Allergen challenge of allergic patients with asthma caused various changes in the beta-receptor-adenylate cyclase system of lymphocyte membranes from these patients. These changes included uncoupling and down regulation of beta-adrenergic receptors and nonspecific refractoriness of adenylate cyclase, as demonstrated by reduced responses to isoproterenol (beta 2), histamine (H2), 5'-guanylylimidodiphosphate, and sodium fluoride. Since these changes could be due to desensitization by enhanced plasma levels of catecholamines and/or histamine during the allergic response, we explored the effects of these agonists on the beta-receptor-adenylate cyclase system in vitro with normal lymphocytes. In addition, we assessed the effect of the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), on this system, since phorbol esters have been demonstrated to modulate several receptor systems, presumably via activation of protein kinase C. That both the agonists and PMA may cause refractoriness of lymphocyte adenylate cyclase was demonstrated, but, however, by apparently different mechanisms. The agonists isoproterenol and histamine induced only a specific desensitization of the homologous responses, whereas PMA-induced refractoriness was nonspecific in nature. Radioligand-binding studies demonstrated that both uncoupling and down regulation contributed to the isoproterenol-induced beta-adrenergic hyporesponsiveness, whereas beta-adrenergic receptor uncoupling but not beta-adrenergic receptor down regulation was involved in PMA-induced desensitization. Histamine had no effect on the beta-adrenergic system at all. The data suggest that the agonist-induced changes in the adenylate cyclase system are specifically located at the receptors, whereas PMA-induced refractoriness can be explained by alterations distal to the receptors, presumably at the stimulatory guanine nucleotide regulatory protein. Thus, enhanced levels of catecholamines or histamine could be involved in the development of receptor-specific changes in the lymphocyte adenylate cyclase system of allergic patients with asthma. However, they are unlikely to cause the nonspecific changes distal to the receptors. The latter changes could be induced by physiologic activation of protein kinase C during the allergic response by a still unknown stimulus, possibly via the receptor-mediated turnover of phosphatidylinositol 4,5-diphosphate.
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PMID:Regulation of the beta-receptor-adenylate cyclase system in lymphocytes of allergic patients with asthma: possible role for protein kinase C in allergen-induced nonspecific refractoriness of adenylate cyclase. 304 Aug 37


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