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

The linkage of the N-methyl-D-aspartate (NMDA) subtype of L-glutamate receptor to the nitric oxide (NO)/3, 5'-cyclic guanosine monophosphate (cGMP) intracellular signalling system was investigated in murine neocortical cultures by examining the effects of NMDA antagonists, NO synthase inhibitors, and drugs targeting second messenger systems on NMDA-stimulated synthesis of cGMP. NMDA-stimulated synthesis of cGMP was time- and concentration-dependent, and inhibited by competitive (LY 274614, 100 mu M) and non-competitive NMDA antagonists (MK-801 30 mu M, 7-chlorokynurenate 100 mu M, and ifenprodil 100 mu M). NO synthase inhibitors (NG-nitro-L-arginine, KN-62, diphenyleneiodonium) and LY 83583, an inhibitor of guanylate cyclase, all inhibited NMDA-stimulated cGMP synthesis in a concentration-dependent manner, demonstrating its dependence on the two enzymes. Phorbol 12-myristyl 13-acetate (0.1 mu M), arachidonic acid (1 mu M), and thapsigargin (10 mu M) produced approximately 50% inhibition of NMDA-induced cGMP synthesis. These observations demonstrate that all domains of the NMDA receptor-complex and of NO synthase are active in neocortical neuronal cultures, and that the essential NO/cGMP signalling system has complex interactions with other second messengers.
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PMID:NMDA-mediated activation of the NO/cGMP pathway: characteristics and regulation in cultured neocortical neurones. 883 97

We investigated the effects of endothelins (ETs) on cGMP production in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. ET-3 increased cGMP formation in a concentration-dependent manner (EC50 = 98nM), which was 2.5 times higher than that of ET-1. The ET(B)receptor agonists sarafotoxin-S6c and IRL 1620 also increased cGMP production, mimicking the effects of the ETs. The ET(B) receptor antagonist BQ 788, but not the ET(A) receptor antagonist BQ610, dose-dependently blocked ET-3-stimulated cGMP formation (IC50=10nM). The phorbol ester, Phorbol 12, 13-dibutyrate (PDBu), which inhibits particulate guanylyl cyclase in smooth muscle, dose-dependently inhibited ET-3-stimulated cGMP accumulation (IC50=66nM). LY83583 and ODQ, inhibitors of soluble guanylyl cyclases, as well as inhibitors of the nitric oxide cascade and of intracellular Ca2+ elevation had no appreciable effect on ET-3-induced cGMP production. ET-3 markedly inhibited carbachol-induced intracellular Ca2+ mobilization. We conclude that ET-3 increases intracellular cGMP levels in SV-CISM-2 cells through activation of the ET(B) receptor subtype and subsequent stimulation of the membrane-bound guanylyl cyclase. Elevation of cGMP by ET and the subsequent inhibition of muscarinic stimulation of intracellular Ca2+ mobilization by the cyclic nucleotide could serve to modulate the contractile effects of Ca2+-mobilizing agonists in the iris sphincter smooth muscle.
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PMID:Activation of particulate guanylyl cyclase by endothelins in cultured SV-40 transformed cat iris sphincter smooth muscle cells. 1002 47

This study examines the influence of hypertension on neuronal nitric oxide (NO) release and its modulation by protein kinase C (PKC). For this purpose, mesenteric segments without endothelium were obtained from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), and neurogenic NO release induced by electrical field stimulation (EFS) was examined in these segments. EFS induced frequency-dependent contractions. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) and the sensorial neurotoxin capsaicin increased EFS-induced contractions in SHR segments, but did not affect these contractions in segments from WKY rats. In segments from SHRs, the increase in EFS-induced response by capsaicin was further increased by the combination of capsaicin and L-NAME. EFS-induced contractions in SHR arteries were unaltered by the protein synthesis inhibitor cycloheximide or by 2-amine-5,6-dihydro-6-methyl-4H-1,3-tiazine (AMT), an inhibitor of inducible NO synthase, and increased by the guanylate cyclase inhibitor Methylene Blue. In these arteries, capsaicin plus the PKC inhibitor calphostin C increased the contractions elicited by EFS; the addition of L-NAME did not affect this increase. Phorbol 12,13-dibutyrate (PDBu) did not modify the response to EFS in these arteries pretreated with capsaicin, although a combination of PDBu and L-NAME was effective. These results indicate that, in mesenteric arteries, EFS induces the release of NO from perivascular nitrergic nerves and of neuropeptides from sensory nerves, but only in hypertensive rats. The NO released is synthesized by constitutive neuronal NO synthase in a manner that is positively modulated by PKC, an enzyme that seems to be activated in hypertension.
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PMID:Role of protein kinase C in electrical-stimulation-induced neuronal nitric oxide release in mesenteric arteries from hypertensive rats. 1099 92