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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of a variety of purine and pyrimidine nucleotides were tested for their capacity to inhibit mammalian soluble guanylate cyclase activity. Adenosine 5'-tetraphosphate (ATetP), ATP, ADP, AMP, guanosine 5'-tetraphosphate (GTetP) and GDP were found to inhibit soluble guanylate cyclase activity from rat lung and other mammalian tissues. The corresponding cytosine and thymine nucleotides showed little or no inhibitory activity, except for thymidine 5'-tetraphosphate, which inhibited glanylate cyclase activity but to a lesser extent than did the purine nucleoside tetraphosphates. ATetP and GTetP were found to be potent inhibitors of soluble guanylate cyclase activity from rat, guinea pig and mouse lung, rat heart and rat brain. Both purine nucleoside tetraphosphates were competitive inhibitors of the rat lung soluble enzyme. ATetP and GTetP had Ki values of 1 muM and 2.5 muM, respectively. The experimental data suggest that purine nucleoside tetraphosphates, and perhaps other purine nucleotides, may play a biologic role in modulating mammalian soluble guanylate cyclase activity.
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PMID:Inhibition of mammalian soluble guanylate cyclase activity by adenosine 5'-tetraphosphate, guanosine 5'-tetraphosphate and other nucleotides. 1 93

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

The second messenger systems involved in the final stages of the phototransduction cascade in Limulus photoreceptors remain unclear. Excised patches of transducing membrane contain cGMP-gated channels, suggesting the involvement of cGMP in the excitation process. To further explore this possibility, we tested the effects of inhibitors and agonists of guanylate cyclase. The active site cyclase inhibitors guanosine 5'-tetraphosphate and adenosine 5'-tetraphosphate produced a reversible reduction of the response to light without affecting resting membrane properties. The cyclase inhibitor Rp-GTPalphaS produced a similar reduction, but the effect was only slightly reversible. The reduction in the response produced by these inhibitors was robust, often producing over a 95% decrease in the amplitude of the light response. Previous work had shown that an end-product cyclase inhibitor, imidodiphosphate, also inhibited the response. The consistent results with four different guanylate cyclase inhibitors strongly support the involvement of this enzyme in the phototransduction cascade. To determine whether the guanylate cyclase involved is the NO-dependent soluble form, we applied inhibitors and activators of the nitric oxide synthase/guanylate cyclase pathway such as L-N5-(1-iminoethyl) ornithine, sodium nitroprusside, and carboxy-PTIO. None of these agents had any substantial effect on phototransduction. Taken together, these results support a role for a particulate guanylate cyclase in Limulus photoreceptor excitation.
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PMID:Inhibitors of guanylate cyclase inhibit phototransduction in limulus ventral photoreceptors. 1182 8

Extracellular diadenosine polyphosphates (Ap_nA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular Ap_nA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie Ap_nA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap₄A) effects in the rat heart has been investigated for the first time. Extracellular Ap₄A caused significant decreasing of the ventricular inotropy. Ap₄A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca²⁺ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap₄A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap₄A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective. In conclusion, our results allow suggesting that Ap₄A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap₄A-caused inhibition of the rat heart contractility.
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PMID:Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart. 2923 60

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