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 mature rat testis contains both a soluble guanylate cyclase and a soluble adenylate cyclase. Both these soluble enzymes prefer manganous ion for activity. It is known that guanylate cyclase can, when activated by a variety of agents, catalyze the formation of cyclic AMP. The following experiments were performed to determine whether the testicular soluble adenylate and guanylate cyclase activities were carried on the same molecule. Analysis of supernatants from homogenized rat testis by gel filtration and sucrose density gradient centrifugation showed that the two activities were clearly separable. The molecular weight of guanylate cyclase is 143 000, while that of adenylate cyclase is 58 000. Treatment of the column fractions with 0.1 mM sodium nitroprusside allowed guanylate cyclase activity to be expressed with Mg(2+) as well as with Mn(2+). Sodium nitroprusside did not affect the metal ion or substrate specificity of adenylate cyclase. These experiments show that adenylate and guanylate cyclase activities are physically separable.
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PMID:Separation of soluble adenylate and guanylate cyclases from the mature rat testis. 3 43

Nitric oxide (NO), formed by conversion of arginine to citrulline and NO by NO synthase, mediates relaxation of vascular smooth muscle. NO synthase has been demonstrated by immunocytochemical methods in neurons in various parts of the central nervous system including the hypothalamus. The latter finding suggested to us that NO might play a role in controlling the release of hypothalamic peptides. We have previously shown that norepinephrine mediates the release of luteinizing hormone-releasing hormone (LHRH) from LHRH terminals in the median eminence into the hypophyseal portal veins, which transport LHRH to the anterior pituitary gland to trigger release of luteinizing hormone from gonadotrophs. LHRH release from these terminals requires increased release of prostaglandin E2 (PGE2). PGE2 activates adenylate cyclase to produce cAMP, and then cAMP induces the exocytosis of LHRH secretory granules. In view of the evidence above and because of the developing evidence for the importance of NO in the central nervous system, it occurred to us that NO might be involved in this process. Consequently, we evaluated the role of NO in the release of PGE2 from medial basal hypothalamic fragments. As previously reported, norepinephrine (10 microM) increased PGE2 release from the hypothalamic fragments. The inhibitor of NO synthase NG-monomethyl-L-arginine (NMMA, 300 microM) blocked the stimulation of PGE2 release induced by norepinephrine but had no effect on the basal release of PGE2. Sodium nitroprusside (100 microM), which liberates NO, also elevated PGE2 release from the hypothalamic fragments. This elevation was not affected by NMMA, presumably because NMMA blocks enzymatic generation of NO but does not alter NO liberated by nitroprusside. When the NO liberated by nitroprusside was inactivated by hemoglobin (2 micrograms/ml), the effect of nitroprusside on PGE2 release was completely inhibited. Neither NMMA nor hemoglobin altered the basal release of PGE2, which indicates that NO is not responsible for basal PGE2 release. Addition of L-arginine (10 microM to 1 mM), the substrate for NO synthase, had no effect on basal PGE2 production. These results indicate that NO synthase is not activated in unstimulated hypothalamic fragments in vitro. The results suggest that norepinephrine activates NO synthase leading to the production of NO, which subsequently activates cyclooxygenase and results in the production of PGE2. PGE2 then activates adenylate cyclase leading to generation of increased cAMP, which induces exocytosis of secretory granules of LHRH and other neuropeptides released by PGE2. The indication that NO is essential to norepinephrine-induced release of PGE2 from hypothalamic fragments provides insight into the mechanism of LHRH release and the results open the possibility that the importance of NO to neuronal functions may be widespread in the nervous system.
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PMID:Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus. 128 Aug 29

The purine metabolites inosine and adenosine selectively increase the catecholamine, but not the acetylcholine production in cultured chick superior cervical ganglion neurons via an as yet unknown intracellular pathway. In order to elucidate some of the molecular events involved in this differential regulation of neurotransmitter production by purines, the SCG neurons were cultured in the presence of cyclic nucleotide analogs and activators of adenylate and guanylate cyclase. Neither 8-bromo-cyclic AMP (8-Br-cAMP), 8-bromo-cyclic GMP (8-Br-cGMP), or forskolin, an activator of adenylate cyclase, could mimic the effect of inosine, i.e. differentially increase catecholamine production. Sodium nitroprusside, an activator of guanylate cyclase, however, has a strong potentiating action on the effect of inosine. The noradrenergic properties of chick sympathetic neurons may thus be differentially modulated by a cGMP-dependent pathway.
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PMID:Catecholaminergic traits of chick sympathetic neurons may be differentially regulated by a cGMP-dependent pathway. 167 90

Isometric contractions of rabbit isolated aortic spirals were induced by noradrenaline (1 microM), potassium chloride (51 mM) or phorbol-12,13-dibutyrate (1 microM). A cumulative concentration-response curve for adenosine, N-ethylcarboxamidoadenosine (NECA), verapamil, sodium nitroprusside, isoprenaline or forskolin was then constructed. Sodium nitroprusside displayed selectivity towards noradrenaline- compared with potassium-contracted tissues. In contrast, verapamil selectively relaxed the potassium-contracted tissues. Adenosine preferentially relaxed the noradrenaline-contracted aorta. Adenosine, in the presence of the transport inhibitor dipyridamole (10 microM), and NECA were without effect upon potassium-contracted tissues. This absolute selectivity for noradrenaline-contracted aortas indicates that adenosine A2-receptor agonists do not interfere with calcium influx through voltage-operated channels but inhibit calcium influx via receptor-operated channels or its intracellular release. The inhibition by dipyridamole of a small relaxation by adenosine in potassium-contracted tissues indicates that this was due to stimulation of an additional intracellular site. The selectivity profile of adenosine and NECA was similar to that of forskolin and isoprenaline indicating that their relaxations were due to a common activation of adenylate cyclase and cAMP accumulation. Only sodium nitroprusside- and forskolin-relaxed aortas contracted with phorbol dibutyrate. Adenosine and NECA also failed to cause relaxation of noradrenaline-contracted aortas preincubated with the phorbol ester indicating that it may desensitize A2-receptors.
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PMID:Comparison of adenosine receptor agonists with other vasodilators on noradrenaline-, potassium- and phorbol ester-contracted rabbit aorta. 176 74

To determine if the presence of an activator of guanylate cyclase alters the depressor response to a selective inhibitor of low Km cyclic GMP (cGMP) phosphodiesterase (PDE), zaprinast (3-30 mg/kg) was given i.v. to conscious, spontaneously hypertensive rats during a steady state of i.v. infusion of sodium nitroprusside (15 micrograms/kg per min). Sodium nitroprusside significantly increased the magnitude of the depressor response to zaprinast. In contrast, fenoldopam (20 micrograms/kg per min), an activator of adenylate cyclase, did not affect the depressor response to zaprinast. Zaprinast (10 mg/kg) significantly decreased mean arterial pressure (MAP) in rats given an infusion of sodium nitroprusside, an activator of soluble guanylate cyclase, at doses of 15 and 25 micrograms/kg per min but not at a dose of 5 micrograms/kg per min. However, in rats given atrial natriuretic peptide (ANP; 0.5, 1 and 2 micrograms/kg per min), an activator of particulate guanylate cyclase, zaprinast (10 mg/kg) did not affect MAP. In contrast to the potentiation of the depressor response to zaprinast, sodium nitroprusside (15 micrograms/kg per min) significantly attenuated the reductions in MAP produced by CI-930, a selective inhibitor of low Km cAMP PDE. It is concluded that sodium nitroprusside, but not ANP or fenoldopam, potentiates the depressor response to zaprinast. Furthermore, the potentiation of the depressor response to zaprinast is dependent upon the dose of sodium nitroprusside and is selective for zaprinast; the depressor response to CI-930 is attenuated by sodium nitroprusside.
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PMID:Sodium nitroprusside potentiates the depressor response to the phosphodiesterase inhibitor zaprinast in rats. 197

We developed a method for cAMP and cGMP immunocytology based upon fixation by microwave irradiation. Fixation by microwave irradiation prevented three problems found with other fixation methods: nucleotide loss from cells, nucleotide diffusion within cells, and chemical modification of immunologic epitopes. Six agonists (four that stimulate adenylate cyclase and two that stimulate guanylate cyclase) produced cAMP or cGMP accumulation patterns that were agonist-specific, dose-dependent, detectable at physiologic concentrations of hormone, and time-dependent within 15 sec to 30 min. cAMP accumulation after 1 mM forskolin was greatest in the nucleus. Isoproterenol, prostaglandin E2, or calcitonin caused initial accumulation of cAMP along the plasma membrane, but later accumulation was greater in the cytoplasm. With calcitonin the later accumulation of cAMP was selectively perinuclear and along the nuclear membrane. Sodium nitroprusside stimulated cGMP accumulation diffusely throughout the cytoplasm. Atrial natriuretic peptide initiated cGMP accumulation near the plasma membrane, and cGMP accumulation moved from there into the cytoplasm. In conclusion, microwave irradiation preserved cell structure and allowed visualization of expected as well as unsuspected changes in intracellular accumulation patterns of cAMP and cGMP.
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PMID:Immunocytology on microwave-fixed cells reveals rapid and agonist-specific changes in subcellular accumulation patterns for cAMP or cGMP. 215 73

In order to obtain more insight into the possible role of cyclic AMP or cyclic GMP in modulating the initial cellular processes following activation of lymphocytes, we measured the effects of the T-cell mitogen concanavalin A and other substances including hormones on the cyclic nucleotide levels in human peripheral blood lymphocytes. The enzyme activities of the corresponding nucleotide cyclases, adenylate cyclase and guanylate cyclase were measured in both isolated plasma membranes or the cytosol of resting or concanavalin A stimulated rabbit thymocytes. Concanavalin A in a mitogenic concentration of about 5-10 micrograms/ml caused small, but consistent increases in cAMP but no changes in cGMP levels during the first hour of activation. Concomitantly, the specific activity of plasma membrane-bound adenylate cyclase was always increased at least 1.5-fold 30 min after stimulation of rabbit thymocytes with concanavalin A, but no effect could be detected on the specific activities of plasma membrane-bound or soluble guanylate cyclase. At high, supraoptimal concentrations of concanavalin A (more than 20 micrograms/ml) cAMP levels dramatically increased in human lymphocytes within minutes, but cGMP levels again were unaffected. Forskolin and beta-adrenergic hormones elevated cAMP in human lymphocytes, whereas cGMP levels were increased by the addition of sodium nitroprusside or alpha-adrenergic hormones. Sodium nitroprusside, in concentrations which elevated cGMP in human lymphocytes, had no influence on the incorporation of [3H]uridine into RNA of resting or concanavalin A stimulated human lymphocytes. Addition of forskolin resulted in an increase of cAMP levels and a dose-dependent decrease of [3H]uridine incorporation into RNA of concanavalin A-stimulated lymphocytes with no effect on resting lymphocytes. The data suggest that cGMP does not play a role in the initial phase of mitogenic activation of lymphocytes, whereas cAMP may be involved in the blast transformation process as an inhibitory signal.
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PMID:Are cyclic nucleotides involved in the initiation of mitogenic activation of human lymphocytes? 241 Dec 97

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by a variety of agents. Previous workers have found that cyclic AMP-dependent protein kinase and calcium-stimulated protein kinases activate tyrosine hydroxylase. We wanted to determine whether cyclic GMP might also be involved in the regulation of tyrosine hydroxylase activity. We found that treatment of rat PC12 cells with sodium nitroprusside (an activator of guanylate cyclase), 8-bromocyclic GMP, forskolin (an activator of adenylate cyclase), and 8-bromocyclic AMP all produced an increase in tyrosine hydroxylase activity measured in vitro or an increased conversion of [14C]tyrosine to labeled catecholamine in situ. Sodium nitroprusside also increased the relative synthesis of cyclic GMP in these cells. In the presence of MgATP, both cyclic GMP and cyclic AMP increased tyrosine hydroxylase activity in PC12 cell extracts. The heat-stable cyclic AMP-dependent protein kinase inhibitor failed to attenuate the activation produced in the presence of cyclic GMP. It eliminated the activation produced in the presence of cyclic AMP. Sodium nitroprusside also increased tyrosine hydroxylase activity in vitro in rat corpus striatal synaptosomes and bovine adrenal chromaffin cells. In all cases, the cyclic AMP-dependent activation of tyrosine hydroxylase was greater than that of the cyclic GMP-dependent second messenger system. These results indicate that both cyclic GMP and cyclic AMP and their cognate protein kinases activate tyrosine hydroxylase activity in PC12 cells.
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PMID:Activation of tyrosine hydroxylase in PC12 cells by the cyclic GMP and cyclic AMP second messenger systems. 287 73

Low concentrations of ACTH, 7 x 10(-12) M, caused a marked stimulation of the 100,000 x g particulate guanylate cyclase without any detectable change in the adenylate cyclase activity. The lowest concentration of the hormone that elicited adenylate cyclase stimulation was 7 x 10(-10) M, a concentration 100--fold higher than that required to stimulate the guanylate cyclase. Although calcium was found to be obligatory in the hormonally--dependent guanylate cyclase activity, calcium alone could not duplicate the ACTH effect. Sodium nitroprusside and ascorbic acid inhibited the particulate guanylate cyclase activity. While ACTH was unable to stimulate the soluble guanylate cyclase, sodium nitroprusside markedly stimulated this enzyme. From these data, we conclude that the adrenal guanylate cyclase exists in two forms, particulate and soluble. The particulate form is specifically responsive to ACTH, and calcium is one of the essential coupling factors of this hormonally--responsive guanylate cyclase.
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PMID:Adrenocorticotropic hormone-responsive guanylate cyclase in the particulate fraction of rat adrenal glands. 611 49

Sodium nitroprusside effected a rapid, dose-dependent increase in intracellular cGMP accumulation in freshly dispersed bovine parathyroid cells. The effect was half-maximal between 10(-4) and 3 X 10(-4)M, maximal at 3 X 10(-3)M nitroprusside and could be amplified (approximately 50%) by the addition of methylisobutylxanthine (4 X 10(-4)M). The dose-response characteristics were similar to those previously described for the inhibition of cAMP accumulation and PTH release by this agent. Neither dibutyryl cGMP (10(-3)M) nor 8'-bromo-cGMP (10(-3)M) mimicked the inhibitory effect of nitroprusside on cAMP accumulation or PTH release. Dose-dependent stimulation of guanylate cyclase was found in a particulate preparation of parathyroid cells; activity was maximal at 10(-4)M nitroprusside while higher concentrations appeared to inhibit the enzyme. Nitroprusside significantly reduced both (-)isoproterenol and guanine nucleotide-stimulated adenylate cyclase activity in the particulate preparation with maximum inhibition between 10(-3)-10(-2)M. cGMP concentrations as high as 10(-4)M did not affect agonist-stimulated cAMP synthesis. Thus, although the kinetic and dose-response characteristics of the nitroprusside effect on cGMP suggest a linkage to its previously described effects on cAMP and PTH secretion, no direct evidence was found to indicate a causal relationship between the two. Rather it would appear that the effects on the adenylate and guanylate cyclase enzymes occur in parallel, possibly the result of some common primary perturbation of cellular physiology.
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PMID:Sodium nitroprusside inhibition of parathyroid hormone release is not mediated through cyclic GMP. 611 8


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