Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial relaxing factor has been identified as nitric oxide, formed from L-arginine by the soluble enzyme nitric oxide synthase. Nitric oxide inhibits platelet aggregation and adhesion by stimulating a soluble guanylate cyclase and increasing the intracellular concentration of cyclic GMP. Nitrovasodilators, such as sodium nitroprusside, release the active moiety, nitric oxide. In the present study, we have investigated the effect of sodium nitroprusside and of a permeable cGMP derivative on the aggregation and ATP secretion of human platelets stimulated with the protein kinase C activators 1-oleoyl-2-acetylglycerol or 4 beta-phorbol-12- myristate-13-acetate. Human platelets were treated with lysine acetylsalicylate, washed and resuspended in Tyrode-buffered solution. ATP secretion was evaluated by luciferin-luciferase luminescence. Nitroprusside (4-40 microM) or 8-Br-cGMP (0.1-2.4 mM) inhibited both platelet aggregation and ATP secretion evoked by 1-oleoyl-2-acetylglycerol (40 microM) or 4 beta-phorbol-12-myristate-13- acetate (4 nM) in a dose-dependent manner, in the presence of the selective inhibitor of cGMP phosphodiesterase, M&B 22948 (5 microM). The inhibitory effect of nitroprusside was reversed by hemoglobin, known to bind and inactivate nitric oxide. To study the calcium-dependent pathway, we treated platelets with the ionophore ionomycin. The ensuing aggregation and ATP secretion were rapid and were dependent on agonist concentration. Nitroprusside (4-40 microM) inhibited the aggregation evoked by ionomycin (0.4 microM) as well as ATP release, in a dose-dependent manner. We conclude that cGMP is able to inhibit both the protein kinase C-dependent and the calcium-dependent pathways leading to platelet activation.
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PMID:Nitrovasodilators and cGMP inhibit human platelet activation. 166 Mar 21

The effect of aging on the ATP-induced relaxation of rat thoracic aorta was examined. Haemoglobin, methylene blue and NG-nitro L-arginine, and removal of the endothelium inhibited or reversed the relaxation induced by ATP. The relaxant response of the aorta to ATP was greatest in the preparations from 4-week-old rats. As the age of rats increased to 45 and 105 weeks, the concentration-response curve for ATP was shifted to the right with reduction of maximal relaxation. ATP elevated cyclic GMP levels. This action was endothelium-dependent and inhibited by methylene blue, haemoglobin and NG-nitro L-arginine. With an increase in age of the rats from 4 weeks to 45 weeks, ATP-stimulated cyclic GMP production was attenuated, and in the aorta from 105-week-old rats cyclic GMP level was no longer elevated by ATP. In contrast to the age-associated marked change in cyclic GMP levels, cyclic AMP production was not affected by aging. It is suggested that age-related changes in ATP-induced relaxation and cyclic GMP formation occur mainly at the level of the vascular smooth muscle. Alterations in soluble guanylate cyclase, at step(s) distal to the guanylate cyclase, or in cyclic GMP-phosphodiesterase might contribute.
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PMID:Possible association of decrease of ATP-induced vascular relaxation with reduction of cyclic GMP during aging. 166 32

This experiment was designed to determine whether chronic hypoxia affects endothelium-dependent relaxation and cGMP content of rat pulmonary artery (PA). Both Ach and ATP were found to induce endothelium-dependent relaxation of PA; and this relaxation was not prevented by indomethacin, but was completely abolished by methylene blue. Chronic hypoxia significantly depressed the endothelium-dependent relaxation: the relaxation responses of intra-PA (IPA) and extra-PA (EPA) to 10(-6) mol/L Ach in the hypoxic group were 61.3% and 59.2% of those in control, and the relaxation responses of IPA and EPA to 1.8 x 10(-5) mol/L ATP in the hypoxic group were 64.9% and 55.2% of those in the control, respectively. Chronic hypoxia significantly decreased the basic level and Ach-induced accumulation of cGMP in the PA. Our data suggest that chronic hypoxia might depress rat pulmonary artery endothelium-dependent relaxation through the inhibition of cytosolic soluble guanylate cyclase in vascular smooth muscle cells.
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PMID:Effect of chronic hypoxia on endothelium-dependent relaxation and cGMP content in rat pulmonary artery. 166 62

Atrial natriuretic peptide (ANP) binds to a transmembrane receptor having intrinsic guanylyl cyclase activity; this receptor has been designated GC-A. Binding of ANP to GC-A stimulates its catalytic activity, resulting in increased production of the second messenger, cyclic GMP. Here we show that GC-A can be expressed in insect cells using a recombinant baculovirus and that the expressed protein retained its abilities to bind ANP and to function as an ANP-activated guanylyl cyclase. In addition, GC-A produced in insect cells was absolutely dependent on the presence of adenine nucleotides for activation by ANP. Millimolar concentrations of ATP were required for optimal activation. The relative potencies of various nucleotides for activation was adenosine 5'-O-(thiotriphosphate) greater than ATP greater than ADP, adenosine 5'-(beta, gamma-imino)triphosphate greater than ADP beta S. AMP had no effect. These studies suggest that binding of an adenine nucleotide, most likely to the protein kinase-like domain of GC-A, is absolutely required for ANP activation. Regulation of guanylyl cyclase activation by adenine nucleotides represents a novel mechanism for the modulation of signal transduction, possibly analogous in some respects to the role of guanine nucleotides and G proteins in the regulation of adenylyl cyclase activity.
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PMID:Adenine nucleotides are required for activation of rat atrial natriuretic peptide receptor/guanylyl cyclase expressed in a baculovirus system. 167 58

Guanylate cyclase is regulated by adenine nucleotides in membranes of intestinal mucosal cells. Basal guanylate cyclase was activated about twofold by adenine nucleotides. Activation was specific for adenine, as compared with the pyrimidine nucleotides UTP and CTP. In addition, enzyme activation was obtained in the presence of saturating concentrations of GTP, the substrate for guanylate cyclase. The most potent adenine nucleotide was the nonhydrolyzable analog of ATP, adenosine 5'-O-(3-thiotriphosphate). Adenine nucleotide activation was specific for the particulate form of guanylate cyclase, as compared with the soluble form. Also, adenine nucleotides potentiated the activation of guanylate cyclase by the heat-stable enterotoxin produced by Escherichia coli. Indeed, enzyme activation by adenine nucleotides and toxin was greater than the sum of individual activations by these agents. Adenine nucleotides regulate guanylate cyclase by increasing the maximum velocity of the enzyme without altering its affinity for substrate or its cooperativity. In addition to stimulating guanylate cyclase, adenine nucleotides decreased the specific binding of the heat-stable enterotoxin to receptors in intestinal membranes. The coordinated regulation of the toxin-receptor interaction and guanylate cyclase activity by a process utilizing nonhydrolyzable analogs of a purine nucleotide is similar to the mechanisms involved in the hormone regulation of adenylate cyclase by guanine nucleotide-binding proteins. These data suggest that an adenine nucleotide-dependent protein may couple the toxin-receptor interaction to the regulation of particulate guanylate cyclase in intestinal membranes.
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PMID:Activation of particulate guanylate cyclase by Escherichia coli heat-stable enterotoxin is regulated by adenine nucleotides. 167 3

The 'second messenger' of certain atrial natriuretic factor (ANF) signals is cyclic GMP. One type of ANF receptor linked to the synthesis of cyclic GMP is a transmembrane protein which contains both the ANF-binding and guanylate cyclase activities. The consensus is that the maximal activity of this guanylate cyclase is observed in the presence of ATP. We now show that depending upon the cofactors Mg2+ or Mn2+, ATP stimulates or inhibits the ANF-dependent guanylate cyclase activity in the testicular plasma membranes: stimulation in the presence of Mg2+ and inhibition in the presence of Mn2+. With Mg2+ as cofactor neither ATP nor ANF stimulate the cyclase activity--it is only when the two are together that the enzyme is activated. Furthermore, this investigation for the first time demonstrates binding of ATP to the ANF receptor guanylate cyclase, suggesting that ATP-mediated responses could occur by direct ATP binding to the cyclase.
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PMID:Dual regulation of atrial natriuretic factor-dependent guanylate cyclase activity by ATP. 167 3

CaCl2 inhibited ATP-stimulated guanylate cyclase activity, but had little effect on basal and atrial natriuretic factor-stimulated guanylate cyclase activity in rat lung membranes. LaCl3 had similar effects as CaCl2 on basal and stimulated guanylate cyclase activity. LiCl and other monovalent salts inhibited ATP-stimulated guanylate cyclase activity more than basal enzyme activity. However, atrial natriuretic factor somehow stabilized the enzyme against the inhibitory effect of LiCl. These results suggest that ATP and atrial natriuretic factor activate the enzyme through different mechanisms. Since the effect of calcium on guanylate cyclase activity is different from that of monovalent salts and can be mimicked by lanthanum, it may be mediated by a specific calcium binding site or binding protein.
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PMID:Calcium reveals different mechanisms of guanylate cyclase activation by atrial natriuretic factor and ATP in rat lung membranes. 167 90

Light activation of cyclic GMP hydrolysis in rod outer segments is mediated by a G-protein which is active in the GTP-bound form. Substitution of GTP with a nonhydrolyzable GTP analogue is thought to leave the G-protein in a persistently activated state, thereby prolonging the hydrolysis of cyclic GMP. Restoration of cyclic GMP concentration in the cell also depends upon GTP since it is the substrate for guanylate cyclase, but little is known about the effects of GTP analogues on this enzyme. We report here the effects of the analogues of GTP and ATP as inhibitors and substrates of rod disk membrane guanylate cyclase. The rate of cyclic GMP synthesis from GTP in rod disk membranes was about 50 pmol min-1 (nmol of rhodopsin)-1. Analogues of GTP and adenine nucleotides competitively inhibited the cyclase activity. The order of inhibition, with magnesium as metal cofactor, was ATP greater than GMP-PNP greater than AMP-PNP approximately GTP-gamma-S; with manganese, AMP-PNP was more inhibitory than GTP-gamma-S. The inhibition constants, with magnesium as cofactor, were 0.65-2.0 mM for GTP-gamma-S, 0.4-0.8 mM for GMP-PNP, 1.5-2.3 mM for AMP-PNP, and 0.07-0.2 mM for ATP. The fraction of cyclase activity inhibited by analogues was similar at 1 and 0.03 microM calcium. Besides inhibition of cyclase, the analogues also served as its substrates. GTP-gamma-S substituted GTP with about 85% efficiency while GMP-PNP and ATP were about 5 and 7% as efficient, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions of nucleotide analogues with rod outer segment guanylate cyclase. 167 98

In endothelium-denuded rat aortic rings, the sustained contractile effects produced by endothelin-1 (ET-1; 3.2 nM) were concentration-dependently overcome by nicorandil, aprikalim (RP 52891), a specific K+ channel opener, and nitroglycerin, a stimulant of guanylate cyclase (EC50: 2.55 +/- 0.06, 0.37 +/- 0.05 and 0.3 +/- 0.008 microM respectively, n = 13-16/group). The decontractant activity of aprikalim was not affected by the guanylate cyclase inhibitor methylene blue (10 microM), whereas it was markedly antagonized by glibenclamide (1 microM) (pKB: 7.19 +/- 0.15), an antagonist of ATP-gated K+ channels in pancreatic beta cells. This sulfonylurea failed to modify nitroglycerin-induced effects, but slightly reduced (10-15%) those produced by high concentrations of nicorandil. By contrast, methylene blue significantly displaced (4-fold) the control concentration-vasorelaxant response curves obtained with nitroglycerin and nicorandil. Zaprinast (20 microM), an inhibitor of soluble low Km cyclic GMP phosphodiesterase, enhanced the effects of nitroglycerin and nicorandil but did not alter those of aprikalim. Nicorandil relaxed ET-1-contracted rings from micropig left circumflex coronary artery with an EC50 of 24 +/- 2.8 microM (n = 7); this effect was antagonized by methylene blue (10 microM) and glibenclamide (3 microM) (2- and 4-fold dextral shift of the control concentration-response curve, respectively). In rat Langendorff-perfused heart with base-line coronary flow reduced by the addition of ET-1 to the perfusion medium, nicorandil and aprikalim increased coronary flow, while nitroglycerin did not. The vasodilator effects of the two compounds were also inhibited by glibenclamide (pKB congruent to 7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nicorandil: differential contribution of K+ channel opening and guanylate cyclase stimulation to its vasorelaxant effects on various endothelin-1-contracted arterial preparations. Comparison to aprikalim (RP 52891) and nitroglycerin. 168 78

Recoverin, a new calcium binding protein from bovine rod photoreceptor cells, activates guanylyl cyclase below a free calcium concentration of 200 nM. We show here that recoverin is phosphorylated by an endogenous kinase and Mg-ATP at the same decreased calcium concentration. The calcium-dependent activation of guanylyl cyclase is enhanced in the presence of ATP. We suggest that phosphorylation of recoverin reinforces the stimulation of guanylyl cyclase at decreased calcium concentrations.
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PMID:Phosphorylation of recoverin, the calcium-sensitive activator of photoreceptor guanylyl cyclase. 168 52


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