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)

The effect of guanosine on insulin secretion, adenylyl and guanylyl cyclase activities of isolated rat islets of Langerhans was investigated. Guanosine (1-100 micron) inhibited glucose, tolbutamide, theophylline and prostaglandin E2-stimulated insulin secretion although it failed to affect glucagon stimulated secretion. Prostaglandin E2-stimulated adenylyl cyclase activity of islets was inhibited by guanosine although guanosine had no effect on basal, fluoride, glucagon or GTP-stimulated activity. Guanosine markedly decreased basal guanylyl cyclase activity of islets. These results suggest that guanosine may affect insulin release by inhibiting adenylyl and guanylyl cyclase activities in the beta-cell thereby decreasing the intracellular concentrations of cyclic nucleotides. This effect may be important in modulating the secretory response of the islets to a variety of hormonal agents.
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PMID:Effects of guanosine on insulin secretion and adenylyl and guanylyl cyclase activities of isolated rat islets of Langerhans. 1 8

1. The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline-precontracted endothelium-intact and endothelium-denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5'-triphosphate (ATP) and adenosine. 2. GTP (10 microM-1 mM) dose-dependently relaxed endothelium-intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed endothelium-denuded artery rings. The acetylcholine- and GTP-induced relaxations of endothelium-intact rings were attenuated by NG-nitro L-arginine methyl ester (L-NAME, 330 microM) which attenuation was reversed with L-arginine (1 mM). 3. Guanosine (10 microM-1 mM) relaxed both endothelium-intact and -denuded artery rings in a dose-dependent manner. The relaxations were more pronounced in endothelium-intact preparations and were only slightly attenuated by L-NAME (330 microM). 4. ATP (1 microM-1 mM) and adenosine (10 microM-1 mM) dose-dependently relaxed endothelium-intact and -denuded artery rings. The responses were more pronounced in endothelium-intact vascular preparations. 5. GTP (100 microM) and guanosine (100 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) accumulation in both endothelium-intact and -denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were not affected. 6. ATP (100 microM) increased cyclic GMP concentration of endothelium-intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 microM) and adenosine (100 microM) in endothelium-intact and -denuded vascular preparations.7. These results provide evidence that exogenous GTP and guanosine relax precontracted endothelium-intact and -denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of endothelium-intact rings can mainly be explained by the release of endothelium-derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of endothelium-dependent and -independent effects. The endothelium-independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.
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PMID:Endothelium-dependent and -independent effects of exogenous ATP, adenosine, GTP and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery. 131 22

The effects of exogenous guanosine 5'-triphosphate (GTP), guanosine, adenosine 5'-triphosphate (ATP) and adenosine on platelet aggregation, serotonin secretion and cyclic nucleotide accumulation were studied using thrombin-stimulated washed human platelets. GTP (10 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion. The inhibition of aggregation was accompanied by an increase in platelet cyclic GMP. GTP did not affect cyclic AMP concentration. Adenosine (1 microM-1 mM) dose-dependently inhibited thrombin-induced aggregation and serotonin secretion, and increased cyclic AMP. ATP at high concentrations (100 microM-1 mM) inhibited aggregation and serotonin secretion, and 1 mM ATP increased cyclic AMP. Guanosine was relatively ineffective in preventing aggregation and serotonin secretion and did not affect cyclic GMP. The rank order of inhibition of thrombin-induced aggregation of washed human platelets was adenosine > GTP > ATP > guanosine. In conclusion, exogenous GTP inhibits thrombin-induced aggregation and serotonin secretion of washed human platelets by increasing cyclic GMP. The results raise the possibility of a cell membrane site of action for GTP in platelets which mediates the activation of soluble guanylate cyclase suggesting that GTP may have a local antithrombotic effect also in vivo.
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PMID:Exogenous GTP increases cyclic GMP and inhibits thrombin-induced aggregation of washed human platelets: comparison with ATP, adenosine and guanosine. 133 96

The stereochemical course of the reaction catalyzed by guanylate cyclase from bovine retinal rod outer segments was investigated using phosphorothioate analogs of GTP as chiral probes. (Sp)-Guanosine 5'-O-(1-thiotriphosphate) (Sp-GTP alpha S) is a substrate, whereas (Rp)-GTP alpha S is a competitive inhibitor (K1 = 0.1 mM), but not a substrate. (Sp)-GTP alpha S is converted into (Rp)-guanosine 3':5'-monophosphorothioate, showing that the reaction proceeds with inversion of configuration at the alpha-phosphorus atom. Km and Vmax for (Sp)-GTP alpha S (at low [Ca2+], 20 nM) are 3.7 mM and 1.1 nmol/min/mg of rhodopsin, respectively, compared with 1.1 mM and 23.1 nmol/min/mg of rhodopsin for GTP. Vmax for the cyclization of (Sp)-GTP alpha S, as for GTP, increases 10-20-fold when the calcium level is lowered. This activity change is centered at approximately 90 nM and has a Hill coefficient of 4.8. The configuration of the metal-substrate complex was determined by measuring the effectiveness of the Sp and Rp isomers of GTP alpha S and guanosine 5'-O-(2-thiotriphosphate) (GTP beta S) in the presence of Mg2+ or Mn2+. (Sp)-GTP alpha S is a substrate with either Mg2+ or Mn2+, whereas (Rp)-GTP beta S is a substrate with only Mn2+. These findings suggest that the substrate is a metal-beta, gamma-bidentate complex with delta screwsense. We also found that the cyclization reaction catalyzed by the membrane-bound guanylate cyclase from sea urchin sperm proceeds with inversion of configuration at the alpha-phosphorus atom. The stereochemical course of the reactions catalyzed by all prokaryotic and eukaryotic adenylate cyclases and guanylate cyclases studied thus far is the same.
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PMID:Stereochemical course of the reaction catalyzed by guanylate cyclase from bovine retinal rod outer segments. 197 55

Atrial natriuretic factor (ANF) specifically stimulated the endogenous phosphorylation of a protein band in an isolated membrane fraction of human placenta. The apparent molecular weight of the substrate protein as determined by SDS-polyacrylamide gel electrophoresis is 160-170,000. In the same membrane fraction, ANF also stimulated guanylate cyclase activity in a dose-dependent manner. Guanosine 3':5'-cyclic monophosphate (cyclic GMP), added to the membrane fraction in lieu of ANF, also stimulated the phosphorylation of several protein bands, one of which have the same apparent molecular weight as the one stimulated by ANF. In contrast, adenosine 3':5'-cyclic monophosphate (cyclic AMP) at a similar concentration and hormones such as angiotensin II, insulin and vasopressin had no effect on the phosphorylation state of this protein band. The finding that ANF alters the phosphorylation state of a certain membrane protein and that this effect is mimicked by cyclic-GMP suggests that at least some of the biological action of ANF may be mediated by the phosphorylation of membrane protein involving a cyclic GMP-dependent protein kinase.
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PMID:Atrial natriuretic factor induced phosphorylation of human placental membrane protein: an effect mimicked by guanosine 3':5'-cyclic monophosphate. 287 3

In our studies with purified soluble guanylate cyclase from rat lung, we have tested a number of guanosine 5'-triphosphate (GTP) analogues as substrates and inhibitors, 5'-Guanylylimidodiphosphate (GMP-P(NH)P), guanylyl (beta, gamma-methylene) diphosphate (GMP-P(CH2)P), and guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) were found to be substrates for guanylate cyclase. GTP gamma S supported cyclic GMP formation at 20 or 75% of the rate seen with Mn2+-GTP and Mg2+-GTP, respectively. GMP-P(NH)P and GMP P(CH2)P supported cyclic GMP formation at 10-20% of the GTP rate with either cation cofactor. These analogues were found to have multiple Km values; one Km value was similar to GTP (150 microM with Mg2+, 20-70 microM with Mn2+), but an additional high affinity catalytic site (3 microM) was also observed. Guanosine tetraphosphate (Ki = 10 microM), adenosine triphosphate (Ki = 9 microM) and the 2'3'-dialdehyde derivative of GTP (dial GTP) (Ki = 1 microM) were not good substrates for the enzyme; however, they were potent competitive inhibitors. These GTP analogues will be useful tools for the study of GTP binding sites on guanylate cyclase and they may also help elucidate the effects of free radicals and other agents on guanylate cyclase regulation.
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PMID:Effect of GTP analogues on purified soluble guanylate cyclase. 612 Jan 66

Guanosine 3'-phosphate and 2'-deoxyguanosine 3'-phosphate are potent inhibitors of guanylate cyclase of various tissues of the silkworm, Bombyx mori. The inhibitory activity is specific for guanine 3'-nucleotides. Thus, 2'-GMP and 5'-GMP are one order or more less potent than 3'-GMP, and the other 3'-nucleotides except 3'-IMP, i.e. 3'-AMP, 2'-deoxy-3'-AMP, 3'-CMP, and 3'-TMP, have no inhibitory activity. Guanosine and 2'-deoxyguanosine are only weakly active. The 3'-nucleotide inhibition is dependent on the concentration of Mn2+. The concentrations of 2'-deoxy-3'-GMP and 3'-GMP required for 50% inhibition are 0.12 and 0.15 mM, respectively, with 5 mM Mn2+.
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PMID:Inhibition of guanylate cyclase by guanosine 3'-phosphate and 2'-deoxyguanosine 3'-phosphate in silkworm fat body. 612 83

The stereochemical course of the reaction catalyzed by the soluble form of bovine lung guanylate cyclase has been investigated using [alpha-18O]guanosine 5'-triphosphate (Rp diastereomer) and guanosine 5'-O-(1-thiotriphosphate) (Sp diastereomer) as substrates. The product from the 3-thiomorpholino-1',1'-dioxide sydnonimine-stimulated enzymatic cyclization of [alpha-18O] guanosine 5'-triphosphate was esterified with diazomethane. 31P NMR analysis of the triesters indicated that all of the 18O label was present in the axial position. Guanosine 5'-O-(1-thiotriphosphate) (Sp diastereomer) was cyclized under stimulated and basal enzyme activities and, in both cases, the Rp diastereomer of guanosine 3',5'-cyclic phosphorothioate was formed. This was determined by direct comparison with material synthesized chemically from guanosine 5'-phosphorothioate. The results from these experiments show that the reaction catalyzed by guanylate cyclase proceeds with inversion of configuration at phosphorus and this indicates that the reaction proceeds by way of a single direct displacement reaction.
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PMID:The stereochemical course of the reaction catalyzed by soluble bovine lung guanylate cyclase. 613 67

Guanosine triphosphatase (GTPase) activity was studied histo- and cytochemically in the rod outer segments of the rat retina by means of a newly developed method. Differences in the distribution pattern of the enzyme activity exist within the outer segment: the activity is more intense at the tip of the rod outer segments near the pigment epithelium than in their proximal portion. Ultracytochemically, the new procedure reveals the reaction product of GTPase activity partly (i) on the extradisk membrane side and (ii) on the disk membranes. This result is in contrast to the cytochemical localization of guanylate cyclase (GCLase), an enzyme also localized at the tip of the rod outer segments: GCLase activity is restricted to the intradisk membrane area of the rod outer segments. The functional role of GTPase activity in the outer segments of rods is discussed.
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PMID:Histo- and cytochemical demonstration of guanosine triphosphatase activity in the outer segments of rods in the rat retina by means of a newly developed method. 613 70

Guanosine 5'-cyclic monophosphate (cGMP) is an important modulator of fluid balance in many epithelia. We examined its metabolism in primary cultures of human airway epithelia. Sodium nitroprusside increased cGMP levels 30-fold, suggesting that the respiratory epithelium expresses a soluble guanylate cyclase; however, endogenous nitric oxide production was not detected. cGMP levels could also be increased by C-type natriuretic peptide (CNP), but not by atrial natriuretic peptide, brain natriuretic peptide, or Escherichia coli heat-stable enterotoxin, indicating expression of a CNP-specific membrane-bound guanylate cyclase. The one-half effective concentration for CNP was 40 nM and the maximal velocity was 56.7 pmol cGMP.mg protein-1.h-1. After CNP stimulation, approximately 60% of the total synthesized cGMP was preferentially exported from the polarized epithelial cells across the basolateral membrane by a probenecid-sensitive process. Isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) export revealed a similar export pattern and probenecid sensitivity, although a lower efficiency of export (27% of total cAMP was exported). Consistent with previous reports, export of neither cyclic nucleotide was saturable at the concentrations tested. We conclude that the respiratory epithelium expresses a soluble guanylate cyclase, a CNP-specific receptor, and a novel vectorial cyclic nucleotide export mechanism.
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PMID:Synthesis and vectorial export of cGMP in airway epithelium: expression of soluble and CNP-specific guanylate cyclases. 750 95


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