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)

We evaluated the mechanisms of histamine-mediated adenylate cyclase stimulation in 18 human hearts obtained from cardiac transplant recipients or prospective donors. Mg2+ and guanyl nucleotide were required for histamine stimulation. In the presence of 10-5 M GTP, histamine produced a maximal stimulation of 1.54 +/- 0.06 times basal activity in left ventricle (39% of the isoproterenol maximum), which rose to 1.75 +/- 0.14 times basal activity (68% of the isoproterenol maximum) in the presence of a 10-5M concentration of the synthetic guanyl nucleotide 5'-guanylyl imidodiphosphate. Histamine stimulation of adenylate cyclase was antagonized by cimetidine (KB = 1.58 X 10-6 M) but not by H1-blocking doses of mepyramine or pyrrobutamine. The selective H2 agonist dimaprit stimulated adenylate cyclase to approximately the same extent as histamine, whereas a selective H1 agonist produced only minimal stimulation that was H2-mediated. The selective H2 agonist impromidine was a partial agonist and produced approximately 20-40% of maximal histamine stimulation at lower concentrations (10-7 and 10-6 M) and inhibition of histamine stimulation at higher concentrations (10-5 and 10-4 M). Histamine stimulated adenylate cyclase activity over the same dose range as that which produced a positive inotropic response in isolated papillary muscles. Under one set of assay conditions, contractile response and adenylate cyclase does-response curves were essentially super-imposable. We conclude that human myocardial adenylate cyclase is coupled to the H2 receptor and linked to the contractile response, whereas the H1 receptor does not mediate a biochemical or mechanical effect.
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PMID:Histamine-mediated adenylate cyclase stimulation in human myocardium. 612 79

Studies were conducted to explore the effects of vasoactive intestinal peptide (VIP), histamine, somatostatin-14 and -28 (S-14 and S-28), and prostaglandin E2 (PGE2) on cAMP production in gastric glands isolated from the guinea pig. VIP (EC50 = 5 X 10(-10) M) and PGE2 (EC50 = 10(-8) M) induced cAMP accumulation in glands isolated by means of EDTA from the fundus or antrum. The structurally related peptides PHI (peptide with N-terminal histidine and C-terminal isoleucine amide) and secretin also increased cAMP production in the system, but with 200 to 2000 times lower potencies than VIP. Combinations of VIP with PHI or secretin do not produce additive stimulation, indicating that PHI or secretin interact with the receptor-cAMP system highly sensitive to VIP. Histamine was about 10 times more potent in fundus (EC50 = 10(-5) M) than in antrum (EC50 = 9 X 10(-5) M) and did not produce any stimulation in enterocytes isolated from the upper part of the duodenum. Complete inhibitions caused by the H2 receptor antagonist cimetidine (Ki = 0.15-0.16 X 10(-6) M) (Ki is the inhibition constant) or by the H1 receptor antagonist diphenhydramine (DPH) (Ki = 13-17 X 10(-6) M) indicate that H interacts with typical H2 receptors mediating adenylate cyclase activation in fundic (Ka = 10(-5) M) (Ka is the association constant) or antral membranes (Ka = 3 X 10(-5) M). In fundus, S-14 inhibited partially (about 60%) cAMP production evoked by H or by its H1 or H2 agonists. The kinetics and the inhibitory potencies (2 X 10(-8) M) or efficacies of S-14 and -28 were identical. No effect of S-14 was found on basal or on cAMP production induced by VIP or PGE2 in either fundic or antral glands or by H in antral glands. The results support the hypothesis of a regulatory role for VIP and/or secretin in mucous and/or peptic secretions via a cAMP-dependent mechanism in gastric mucosa in mammals. Second, we propose that S-14 as well as S-28 may inhibit gastric acid secretion by a direct and selective control of H-induced cAMP production in parietal cells, through a common recognition site (receptor?) distinct from the H2 receptor. Third, not only parietal cells, but also nonparietal cells of the antrum possess an H2 receptor-cAMP system. This finding could be related to the in vivo regulation by cimetidine of endocrine (somatostatin) and exocrine (pepsin) secretions by the stomach.
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PMID:Regulation by vasoactive intestinal peptide, histamine, somatostatin-14 and -28 of cyclic adenosine monophosphate levels in gastric glands isolated from the guinea pig fundus or antrum. 613 13

Activation of adenylate cyclase (AC) by PGE2, histamine and gastrointestinal hormones was studied in parietal cell-free gastric biopsy specimens from the corpus of patients with proven high gastrin achlorhydria. PGE2, somatostatin, VIP, pentagastrin and secretin activated AC in a concentration-dependent manner both in normal and in atrophic mucosa. Histamine activated AC only in normal gastric mucosa, being entirely ineffective in mucosa devoid of parietal cells. The results indicate that histamine-sensitive AC disappears in patients with achlorhydria, probably due to their loss of parietal cells. Enzyme activity in response to somatostatin, VIP, pentagastrin, secretin and PGE2 remains unchanged in these patients indicating AC localization in nonparietal cells, e.g. chief or mucous cells.
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PMID:Adenylate cyclase in gastric mucosal biopsies from patients with achlorhydria. Stimulation by PGE2, histamine and gastrointestinal hormones. 613 85

Estradiol is demonstrated to induce histidine decarboxylase, and histamine is shown to activate adenylate cyclase in rat uterus. Histamine and cyclic 3',5'-AMP mimic the effects of estradiol in that they enhance RNA synthesis, induce glycolytic enzymes and uterus imbibition. The data suggest that estradiol enhances by induction of histidine decarboxylase the formation of histamine, the latter activates adenylate cyclase providing accumulation of cyclic 3',5'-AMP, which, probably, induces glycolytic enzymes through phosphorylation of chromatin proteins, and mediates other estradiol effects. The chain of successively acting enzymes and mediators constitutes, obviously, a cascade amplifying estradiol action. Since histamine is known to act as an intercellular mediator, attempts were made to find out the distribution of estradiol histamine and cyclic 3',5'-AMP among uterus cells. Autoradiography has shown that [3H]-estradiol is bound by the nuclei of myometrium cells, [3H]-histamine was found above the cytoplasm of these cells, E13H]-cyclic 3',5'-AMP is selectively bound by the cells of capillary endothelium of the uterus. The estradiol mediators seem to spread effect of hormone on cells of different types which form together a kind of multicellular functional system.
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PMID:Multistage functional system amplifying and spreading the effect of estradiol in rat uterus. 624 14

Using pig skin slices, we investigated the effects of hydrocortisone on the adenylate cyclase system of the skin. In short-term experiments, hydrocortisone, when added singly or in combination with other stimulators of adenylate cyclase in the skin (adrenaline or histamine), had no effect on cyclic AMP accumulation. However, when skin slices were incubated with hydrocortisone for more than 6 h, the response to adrenaline differed, with a greater accumulation of cyclic AMP in the hydrocortisone-treated skin. This effect was seen at a concentration of more than I micrometer hydrocortisone and was most marked 48 h later, while responses to adrenaline in control skin gradually decreased and remained low. Histamine, which is another stimulator of adenylate cyclase of the skin, did not cause a greater cyclic AMP accumulation in response to this hydrocortisone treatment. There was no significant difference in either low Km or high Km cyclic AMP phosphodiesterase activities as a result of this hydrocortisone treatment. Hydrocortisone seems to act by protecting the adrenaline-adenylate cyclase system of the skin.
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PMID:Effects of hydrocortisone on the adrenaline-adenylate cyclase system of the skin. 625 37

1 RMI 12330A, a lactam-imine, at concentrations of 10(-4) M and higher, inhibited basal as well as isoprenaline and NaF-stimulated adenylate cyclase activity of guinea-pig heart homogenates. However, RMI 12330A was a more potent inhibitor of histamine-stimulated adenylate cyclase (IC50 of 1.5 X 10(-5) M). 2 In the isolated work-performing heart of the guinea-pig, RMI 12330A (IC50 of 1.1 X 10(-6) M) depressed all cardiac functions: pressures developed, dP/dt, contractile force, dF/dt, work performance and stroke work. Left atrial pressure rose and the positive inotropic response to increasing heart rate (staircase) became negative. Histamine, isoprenaline and ouabain no longer caused positive inotropic effects. 3 Increasing the perfusate calcium concentration from 2.5 mM to 4.5 and 6.5 mM completely restored cardiac function after its depression by RMI 12330A. 4 RMI 12330A uncoupled mitochondrial oxidative phosphorylation; the classical uncoupler, dinitrophenol, had the same effects on cardiac dynamics as RMI 12330A. 5 RMI in high doses inhibited hydrolytic activity of Na+, K+-ATPase of crude and purified heart preparations (IC50 of 1.7 X 10(-4) M) and inhibited ouabain binding to the same enzymes (IC50 of 1.5 X 10(-4) M). 6 A lactam-imine analogue of RMI 12330A that had no effect on adenylate cyclase, was also without effect on any of the systems examined.
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PMID:Effects of RMI 12330A, a new inhibitor of adenylate cyclase on myocardial function and subcellular activity. 625 99

A great deal of knowledge has been gained concerning the activation of adenylate and guanylate cyclase in epidermal cells. Adenylate cyclase is activated by 4 different independent receptors-responding respectively to catecholamine (beta), to prostaglandins (E), to histamine (H2), and to adenosine and it phosphorylated derivatives. Upon activation, each of these receptors becomes unresponsive to further stimulation by its specific stimulator. Guanylate cyclase, on the other hand, is activated by histamine (H1) and epidermal growth factor (EGF). Unlike EGF, the histamine activation is extremely rapid (less than 5 minutes). Epidermal cells are permeable (leak) to cyclic GMP but not cyclic AMP. When the skin is traumatized or injured in any way (even by intradermal injection) there is a sudden catastrophic change in the intracellular levels of the cyclic nucleotides (and of ATP). Cyclic AMP rapidly rises to perhaps 5-10 times its normal resting level while cyclic GMP falls to 10-20% of its level in vivo. The rise in cyclic AMP is due to activation of adenylate cyclase while the fall in cyclic GMP is due in major part to activation of cyclic GMP phosphodiesterase (and perhaps the fall in ATP is due to activation of ATPase). The changes in ATP and cyclic AMP can be reversed by incubating the tissue in a buffered salt solution containing glucose, but this does not normalize the cyclic GMP content. The fall in cyclic GMP can be prevented by a phosphodiesterase inhibitor (IBMX ). This series of events has been called the "ischemia effect." However, it implies that a lack of oxygen is at fault, and that has not been shown to be the case. Its underlying cause and possible physiologic significance are not known. Do these changes in cyclic nucleotides have effects on epidermal proliferation? And does EGF? Agents which increase cyclic AMP do inhibit the epidermal outgrowth and mitotic activity of explant cultures of pig skin. Cyclic GMP does increase outgrowth at a particular concentration. Histamine, which elevates both cyclic nucleotides, has a biphasic action depending on its concentration. These findings imply that these nucleotides do act as one of the controls of epidermal proliferation. The action of cyclic GMP is not accompanied by detectably increased phosphorylation of epidermal proteins. On the other hand, EGF action which also enhances epidermal outgrowth is characterized by an increased protein phosphorylation that precedes any increase in cellular cyclic GMP. We conclude that the action of EGF is independent of the cyclic nucleotide system.
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PMID:Cyclic GMP system in the epidermis. 626 50

Histamine has been shown to activate cyclic AMP synthesis in brain slices and homogenates of certain species, although less is known about species differences in brain homogenates. Dutch Belted and New Zealand White rabbit brain homogenates contained a histamine-responsive adenylate cyclase similar to that of the guinea pig. In contrast, adenylate cyclase of gerbil and hamster brain exhibited little or no stimulation by histamine. Male rat hypothalamic homogenates contained adenylate cyclase, but also exhibited minimal stimulation by histamine, in disagreement with some recent reports. Detailed studies of the conditions of assay failed to resolve this discrepancy.
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PMID:Histamine-activated adenylate cyclase in brain homogenates of several species. 626 7

In view of the complexity of the regulation of gastric acid secretion, isolated parietal cells offer the appealing prospect of studying the receptors and mechanisms activating this cell after it has been removed from the confusing milieu of the intact mucosa. Histamine and cholinergic agents stimulate the function of canine parietal cells by interacting with typical H2 and muscarinic receptors. Gastrin produces only a small stimulation, interacting with a third, presumably specific, receptor. Combinations of histamine and carbachol and of histamine and gastrin produce potentiating interactions. When isolated parietal cells are treated with these combinations of agents, cimetidine and atropine display and apparent lack of specificity, reminiscent of that found in vivo, and probably resulting from interference with the histamine and cholinergic components of these potentiating interactions. The action of histamine, but not of carbachol or gastrin, is linked to stimulation of cyclic AMP production by parietal cells. Two potential inhibitors of acid secretion, secretin and prostaglandin E2, also stimulate cyclic AMP production, but these later effects appeared to occur largely in nonparietal cells. PGE2 however specifically inhibits histamine-stimulated parietal cell function, apparently by blocking activation of adenylate cyclase. Cholinergic action on the other hand is closely linked to enhanced influx of extracellular calcium.
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PMID:Effects of chemical transmitters on function of isolated canine parietal cells. 626 80

Asthma results from variable and often sudden changes in airway smooth muscle tone. Allergy is not an essential component of the asthmatic response; however, mediator release plays an important role in the human asthmatic response. Histamine may act directly to cause bronchoconstriction by stimulating the H1-receptor on airway smooth muscle or indirectly by stimulation of afferent vagal fibers in airways. Histamine may also act locally on airways to augment cholinergic and, possibly, alpha-adrenergic constrictor effects, or to antagonize beta-adrenergic relaxation of airway smooth muscle. Cholinergic neural output promotes bronchoconstriction in non-atopic asthma, but parasympathetic reflexes are not a major component of human bronchial responses to inhaled allergen. The physiologic significance of the sympathetic nervous system in relaxing airway smooth muscle is incompletely defined. Recent studies suggest that direct sympathetic innervation of airways is relatively unimportant and that purinergic fibers may be the predominant inhibitory neurons in human airways. Investigations focusing on intracellular calcium metabolism in airway smooth muscle have implicated the adenyl cyclase-cyclic adenosine monophosphate system in the regulation of bronchomotor tone. Cyclic nucleotides may modulate but do not mediate respiratory muscle contraction, and their precise role in regulating bronchomotor tone remains uncertain.
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PMID:Pathogenesis of asthma. Neurophysiology and pharmacology of bronchospasm. 627 7


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