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)

Concanavalin A (Con A) was shown to have inhibitory effect on platelet adenylate cyclase as well as 5-hydroxytryptamine (5HT) uptake. These effects of Con A were antagonized by alpha-methyl-D-mannoside, a specific inhibitor of Con A binding to glycoprotein. The effect of Con A on adenylate cyclase was partial inhibition, and Con A had no effect on prostaglandin E1 stimulated activity, indicating the adenylate cyclase which is thought to be involved in 5HT uptake might be a minor component. The same result as Con A was demonstrated in the inhibitory effect of N-ethylmaleimide (NEM) on this activity. Impermeable sulfhydryl blocking reagents and iodoacetamide had no effect on 5HT uptake. It might be necessary for the sulfhydryl blocking reagent to pass through the cell membrane in order to exert its inhibitory effect on 5HT uptake. Furthermore, the inhibitory effect of Con A on 5HT uptake was antagonized by sulfhydryl reducing reagents and adenosine. It is postulated that a NEM sensitive, sub-membrane contractile protein system might mediate the effect of Con A, and Con A might inhibit platelet 5HT uptake by affecting the adenylate cyclase system through some possible transmembrane regulatory mechanism.
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PMID:Effect of concanavalin A on 3H-5-hydroxytryptamine uptake in rabbit blood platelets: interaction with adenylate cyclase activity. 687 26

A previous study in intact animals assessed cardiovascular alterations in surgically thyroidectomized rats. Hemodynamic challenge via isoproterenol infusion identified abnormal left ventricular relaxation. Challenge by aortic occlusion revealed a latent deficiency in left ventricular contractility which was not apparent during beta-agonist challenge. The present study utilized left ventricular cardiac tissue obtained from the identical control and thyroidectomized animals from which intact heart hemodynamic information had been obtained. Biochemical systems were selected for evaluation based on demonstrated hemodynamic alterations, i.e., beta-adrenergic receptor number/function and contractile protein enzyme properties. The number of beta-receptors on hypothyroid cardiac membranes was significantly decreased, but receptor agonist affinity was not influenced. Basal adenylate cyclase activity in cardiac membranes from control and thyroidectomized rats was nearly identical; however, isoproterenol activation was diminished in hypothyroid cardiac membrane, particularly at the higher levels of beta-agonist stimulation. Adenylate cyclase enzyme activation by forskolin was not influenced by thyroidectomy; however, activation by sodium fluoride was reduced approximately 30% when compared with preparations from control rats. Cardiac myofibrillar enzyme activity for adenosinetriphosphatase (ATPase) was significantly lower in thyroidectomized rats. Despite reduced ATPase activity, myofibrillar calcium sensitivity was unaltered. Myofibrillar creatine kinase enzyme activity was not influenced by thyroidectomy; therefore, compartmentalized ATP regeneration potential via creatine kinase was enhanced relative to substrate utilization via ATPase. Thus hemodynamically significant cardiac influences of hypothyroidism are mediated, at least in part, via 1) reduced beta-receptor number, 2) diminished catecholamine-induced activation of adenylate cyclase, and 3) reduced myofibrillar ATPase activity.
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PMID:Beta-adrenergic receptors, adenylate cyclase activation, and myofibril enzyme activity in hypothyroid rats. 802 15

Chronic tachycardia-induced dilated cardiomyopathy causes increased plasma catecholamines and alterations in beta-adrenergic responsiveness in vivo. However, whether isolated myocyte contractile response to beta-stimulation is directly affected by the development of cardiomyopathy and how these changes are related to alterations in the beta-adrenergic receptor system remain unclear. Accordingly, isolated myocyte function and beta-adrenergic responsiveness were examined in two groups of 12 pigs each: sham controls, and with supraventricular tachycardia induced cardiomyopathy (SVT; pace: 240 beats/min, 3 weeks). Isolated LV myocyte percent and velocity of shortening were examined at baseline, with isoproterenol (2-100 nM), and forskolin (0.1-4 microM). Baseline percent and velocity of shortening were significantly reduced with SVT compared to controls (1.6 +/- 0.1 vs 5.4 +/- 0.2%, 56 +/- 3 vs 25 +/- 1 micron/s, respectively, P < 0.05). The maximal increase in the percent and velocity of shortening with isoproterenol was significantly blunted in the SVT myocytes compared with controls (3.2 +/- 0.4 vs 9.7 +/- 1.0%, 48.0 +/- 5.3 vs 122.6 +/- 15.5 micron/s, respectively, P < 0.05). Similarly, maximal increase in the percent and velocity of shortening with forskolin were reduced with SVT compared to controls (3.3 +/- 0.4 vs 10.5 +/- 0.6%, 50.7 +/- 6.4 vs 120.1 +/- 9.7 micron/s, respectively, P < 0.05). In order to determine the cellular basis for these changes in beta-adrenergic response, myocyte structure, sarcolemmal beta-receptor density and affinity, and adenylate cyclase activity were examined. There was a 25% reduction in beta-receptor number with SVT (P < 0.05) but no change in affinity. Basal adenylate cyclase activity was lower with SVT compared to control (46 +/- 3 vs 77 +/- 10 pmol cyclic AMP/mg/min, P < 0.05), and exhibited a blunted response with both isoproterenol (1 mM; 106 +/- 19 vs 203 +/- 26 pmol cyclic AMP/mg/min, P < 0.05) and forskolin (100 microns: 209 +/- 35 vs 378 +/- 58 pmol cyclic AMP/mg/min, P < 0.05). Finally, myofibrillar content within SVT myocytes was significantly reduced from controls (43 +/- 7 vs 63 +/- 4%, P < 0.05). In summary, the cellular basis for the depressed myocyte contractile response to beta-stimulation with tachycardia induced SVT are probably due to several factors which include: decreased expression of beta-receptors, alterations in beta-receptor transduction, reduced adenylate cyclase activity, and decreased myocyte contractile protein content.
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PMID:The cellular basis for the blunted response to beta-adrenergic stimulation in supraventricular tachycardia-induced cardiomyopathy. 826 55

LND-623 is a new aminosteroid analog of ouabain, with a greater separation between efficacy and toxicity than ouabain. To determine its mechanism of action, we studied its biochemical and physiological effects on human red blood cell sodium transports on different cellular structures regarded as sites of contractile control, and we compared its relative efficacy to ouabain in rat heart preparations and membrane-bound Na, K-ATPase isoenzymes. The response to ouabain was evaluated in Langendorff-perfused hearts and on purified membrane-bound Na, K-ATPase. LND-623 is 6.8-fold more efficient than ouabain in inhibiting the human Na+ pump (IC50 = 0.098 +/- 0.001 microM vs. 0.67 +/- 0.02 microM); (P < 0.0001). LND-623 had no effect on the following cellular functions: Na-Ca exchange, Na-K cotransport, Ca-ATPase, slow calcium channels, adenylate cyclase system, phosphodiesterase, and calcium sensitivity of the contractile protein system. The dose-response curve for the positive inotropic and inhibitory effects on rat cardiac isoenzymes produced by LND-623 were clearly biphasic. The amplitude of the maximum inotropic effect, without any toxic effect, was up to three-fold higher with LND-623 than with the same maximum dose of ouabain used. The strong positive inotropic effect of LND-623 in rats could be related to a specific inhibition of the two rat cardiac isoforms of the Na, K-ATPase.
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PMID:Mechanism underlying the strong positive inotropic effects of LND-623: specific inhibition of Na, K-ATPase isoforms and exclusion of cellular sites of contractile control. 1041 Aug 28

Myofibroblasts, the hallmark of fibrotic disease, contribute to the pathology of fibrosis by secreting large amounts of extracellular matrix and contributing to alveolar contraction. Myofibroblasts are characterized by the expression of alpha-smooth muscle actin (alpha-SMA), a contractile protein normally associated with smooth muscle cells. Transforming growth factor-beta1 (TGF-beta1) is a well characterized profibrotic cytokine that induces myofibroblast transformation both in vitro and in vivo. We report here that the lipid mediator prostaglandin E2 (PGE2) inhibits TGF-beta1-induced expression of alpha-SMA in primary fetal and adult lung fibroblasts. This inhibition of alpha-SMA expression is associated with a reduction in the expression of collagen I. Inhibitory actions of PGE2 are mediated via E prostanoid receptor 2 (EP2) signaling, but not by EP3 signaling, and increases in cyclic adenosine monophosphate production. The inhibitory effects of PGE2 on TGF-beta1-induced alpha-SMA expression are mimicked by an EP2 selective agonist, butaprost, and by forskolin-induced direct activation of adenyl cyclase. An EP2 antagonist blocks the inhibitory effects of PGE2, and an EP3 agonist does not inhibit TGF-beta1-mediated increases in alpha-SMA expression. Our results demonstrate that PGE2 inhibits transition of fibroblasts to myofibroblasts by an EP2 receptor-activated pathway. Augmenting this pathway may serve as a potent antifibrotic therapeutic strategy.
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PMID:Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. 1273 87


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