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 biochemical signaling pathways involved in nitric oxide (NO)-mediated cholinergic inhibition of L-type Ca2+ current (ICa[L]) were investigated in isolated primary pacemaker cells from the rabbit sinoatrial node (SAN) using the nystatin-perforated whole-cell voltage clamp technique. Carbamylcholine (CCh; 1 microM), a stable analogue of acetylcholine, significantly inhibited ICa(L) after it had been augmented by isoproterenol (ISO; 1 microM). CCh also activated an outward K+ current, IK(ACh). Both of these effects of CCh were blocked completely by atropine. Preincubation of the SAN cells with L-nitro-arginine methyl ester (L-NAME; 0.2-1 mM), which inhibits NO synthase (NOS), abolished the CCh-induced attenuation of ICa(L) but had no effect on IK(ACh). Coincubation of cells with both L-NAME and the endogenous substrate of NOS, L-arginine (1 nM), restored the CCh-induced attenuation of ICa(L), indicating that L-NAME did not directly interfere with the muscarinic action of CCh on ICa(L). In the presence of ISO the CCh-induced inhibition of ICa(L) could be mimicked by the NO donor 3-morpholino-sydnonimine (SIN-1; 0.1 mM). SIN-1 had no effect on its own or after a maximal effect of CCh had developed, indicating that it does not inhibit ICa(L) directly. SIN-1 failed to activate IK(ACh), demonstrating that it did not activate muscarinic receptors. Both CCh and NO are known to activate guanylyl cyclase and elevate intracellular cGMP. External application of methylene blue (10 microM), which interferes with the ability of NO to activate guanylyl cyclase, blocked the CCh-induced attenuation of ICa(L). However, it also blocked the activation of IK(ACh), suggesting an additional effect on muscarinic receptors or G proteins. To address this, a separate series of experiments was performed using conventional whole-cell recordings with methylene blue in the pipette. Under these conditions, the CCh-induced attenuation of ICa(L) was blocked, but the activation of IK(ACh) was still observed. Methylene blue also blocked the SIN-1-induced decrease in ICa(L). 6-anilino-5,8-quinolinedione (LY83583; 30 microM), an agent known to decrease both basal and CCh-stimulated cGMP levels, prevented the inhibitory effects of both CCh and SIN-1 on ICa(L), but had no effect on the activation of IK(ACh) by CCh. In combination, these results show that CCh- and NO-induced inhibition of ICa(L) is mediated by cGMP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate. 749 38

Using a reverberatory epilepiform discharge of hippocampal-parahippocampal circuits termed "maximal dentate activation", this study investigated whether the local release of nitric oxide within these circuits functions as an antiepileptic agent. Two nitric oxide synthase inhibitors (L-nitro-arginine methyl ester and 7-nitro-indazole) and a guanylate cyclase inhibitor (methylene blue) were tested, and none had a significant effect on the time to onset or duration of maximal dentate activation. A membrane-permeable analogue of cyclic guanosine monophosphate (cGMP), 8-bromo-cGMP, caused an increase in the time to onset and a decrease in the duration of maximal dentate activation. The number of neurons expressing NADPH diaphorase activity (a marker for nitric oxide synthase) was also examined after repeated elicitation of maximal dentate activation. After 18 seizures there was a significant, but transient, decrease in the number of hilar/subgranular neurons that were NADPH diaphorase-positive. The decrease was only seen at 1 h after the last seizure. There was no induction of NADPH diaphorase activity. These results are not consistent with the hypothesis that, in hippocampal-parahippocampal circuits in vivo, nitric oxide is released in response to neuronal activity and then acts to terminate the neuronal activity.
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PMID:In the hippocampus in vivo, nitric oxide does not appear to function as an endogenous antiepileptic agent. 749 93

The role of nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) in cellular regulation of endothelin-1 (ET-1) secretion was investigated in cultured porcine aortic endothelial cells. NO synthase was inhibited with NG-nitro-L-arginine (L-NNA) and guanylyl cyclase with the novel selective inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (3 microM). Basal and phorbol ester (PMA)-stimulated ET-1 secretion were unaffected by ODQ, but stimulated secretion was increased by L-NNA. In the presence of the NO donors, spermine/NO, S-nitroso-glutathione (GSNO), and nitroprusside (NP) ET-1 secretion was reduced, but ODQ had no effect on this inhibition, although it effectively inhibited cyclic GMP production. NO release from donors, measured with a sensitive NO electrode, was greatest for spermine/NO, intermediate for GSNO, minimal for NP and paralleled inhibition of ET-1 secretion. The data suggest that in cultured endothelial cells, curtailment of ET-1 secretion is mediated by NO and independent of cyclic GMP.
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PMID:Novel guanylyl cyclase inhibitor, ODQ reveals role of nitric oxide, but not of cyclic GMP in endothelin-1 secretion. 749 55

There is growing evidence that nitric oxide serves as a neurotransmitter released from enteric inhibitory nerves in the gastrointestinal tract. The distribution of nitric oxide synthase suggests that nitric oxide may also be a neurotransmitter within enteric ganglia. Since many actions of nitric oxide are mediated by stimulation of soluble guanylate cyclase and a subsequent increase in 3',5'-cyclic guanosine monophosphate (cGMP) concentration, targets for nitric oxide in the canine proximal colon were investigated by immunohistochemical localization of cGMP. In the presence of phosphodiesterase inhibitors (M&B 22948, 100 microM and 3-isobutyl-1-methyl-xanthine, 1 mM), exogenous nitric oxide and electrical field stimulation caused an accumulation of cGMP-like immunoreactivity in several cell-types including colonic smooth muscle cells. cGMP-like immunoreactivity was also observed in a subpopulation of neurons in both myenteric and submucosal ganglia. Sequential labeling with the NADPH diaphorase technique showed that 94% of neurons that responded to exogenous nitric oxide with an increase in cGMP-like immunoreactivity were NADPH diaphorase negative. None of the myenteric neurons that responded to electrical field stimulation with an increase in cGMP-like immunoreactivity were NADPH diaphorase positive, and only one submucosal neuron with cGMP-like immunoreactivity was also NADPH diaphorase positive. The electrical field-stimulated increase in cGMP-like immunoreactivity was blocked by nitroarginine (100 microM). An increase in cGMP-like immunoreactivity also occurred in interstitial cells located at the submucosal surface of the circular muscle layer. These cells are interposed between nerve varicosities and smooth muscle cells and may partially mediate neuromuscular transmission. Sodium nitroprusside and nitric oxide also caused an accumulation of cGMP-like immunoreactivity in smooth muscle cells of intramural arterioles and venules. The results of this study further support the role of nitric oxide as a neurotransmitter in colonic muscles, and provide support for the hypothesis that interstitial cells are functionally innervated by enteric inhibitory neurons. The data also suggest that nitric oxide may serve as a neurotransmitter in enteric ganglia.
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PMID:Immunohistochemical localization of 3',5'-cyclic guanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. 750 18

Recent demonstration of cytokine-inducible production of nitric oxide (NO) in vascular smooth muscle cells (VSMC) from rat aorta has implicated VSMC-derived NO as a key mediator of hypotension in septic shock. Our studies to determine whether an inducible NO pathway exists in human VSMC have revealed a novel cytokine-inducible, NO-independent pathway of guanylate cyclase activation in VSMC from human saphenous vein (HSVSMC). Interleukin 1 (IL-1), tumor necrosis factor (TNF), interferon gamma (IFN-gamma) and Escherichia coli lipopolysaccharide (LPS) increased cGMP at 24 h, whereas IL-2 and IL-6 were ineffective. The effect of IL-1 on cyclic guanosine 3',5'-monophosphate (cGMP) was delayed, occurring after 6 h of exposure, and was maximal after 10 h. Methylene blue and LY83583 reversed the IL-1-induced increase in cGMP, suggesting that it was mediated by activation of soluble guanylate cyclase. However, IL-1-induced cGMP in HSVSMC was not inhibited by extracellular hemoglobin. Also, the effect of IL-1 on cGMP was not reversed by nitro- or methyl-substituted L-arginine analogs, aminoguanidine, or diphenyleneiodonium, all of which inhibit IL-1-induced NO synthase in rat aortic VSMC (RAVSMC). IL-1-induced cGMP in HSVSMC was also independent of tetrahydrobiopterin and extracellular L-arginine, as it was not affected by 2,4-diamino-6-hydroxyprytimidine, an inhibitor of tetrahydrobiopterin biosynthesis, and was similar in L-arginine-free and L-arginine-containing media. Analysis of NO synthase mRNA with the use of polymerase chain reaction indicates that levels of mRNA for inducible NO synthase are several orders of magnitude lower in IL-1-treated human HSVSMC than in IL-1-treated RAVSMC. IL-1-induced cGMP was also NO independent in human umbilical artery VSMC, and NO dependent in rat vena cava VSMC. Together these results indicate that IL-1 activates a novel NO-independent pathway of soluble guanylate cyclase activation in human VSMC.
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PMID:Interleukin 1 activates soluble guanylate cyclase in human vascular smooth muscle cells through a novel nitric oxide-independent pathway. 750 3

In patch-clamped Purkinje cells, bath application of the nitric oxide synthase inhibitor NG-methyl-L-arginine consistently prevents the induction of long-term depression (LTD) of parallel fibre-mediated excitatory postsynaptic potentials (EPSPs) induced by their pairing with calcium spikes. On the other hand, bath application of nitric oxide donors and of 8-bromoguanosine 3':5' cyclic monophosphate is able to reproduce an LTD-like phenomenon. LTD of parallel fibre-mediated EPSPs also occurs when nitric oxide donors or guanosine 3':5' cyclic monophosphate are directly dialysed into Purkinje cells, and this effect partially occludes LTD induced by pairing protocols. These results show that nitric oxide does play a role in LTD induction, and demonstrate for the first time that its site of action is probably the soluble guanylate cyclase of Purkinje cells.
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PMID:Long-term depression requires nitric oxide and guanosine 3':5' cyclic monophosphate production in rat cerebellar Purkinje cells. 750 17

The stimulation of excitatory amino acid receptors in the cerebellar cortex results in the Ca2+/calmodulin-dependent activation of nitric oxide synthase. This leads to an increase in tissue levels of cGMP following the interaction of nitric oxide with soluble guanylyl cyclase. The cerebellar cortex has the highest levels of nitric oxide synthase and cGMP in the brain; however, the levels of guanylyl cyclase and cGMP-phosphodiesterase are remarkably low. Thus, the mechanisms regulating cGMP levels in cerebellar cells are unclear. One report has noted that cGMP can be released from cerebellar slices. We have therefore used intracerebellar microdialysis in awake, freely moving rats to test the hypothesis that activation of nitric oxide synthase in the cerebellar cortex results in the release of cGMP. Climbing fibers, which release excitatory amino acids in the cerebellum, were activated with systemic harmaline. This resulted in an immediate increase in extracellular cGMP, which was blocked by TTX or the removal of extracellular Ca2+, and attenuated by prior lesion of the climbing fibers. Blockade of N-type calcium channels with omega-conotoxin also antagonized the harmaline-induced increase. In contrast, blockade of L-type calcium channels, or inhibition of anion transport with probenecid or bromosulfophthalein, potentiated the increase in cGMP seen in response to harmaline. Inhibitors of nitric oxide synthase or guanylyl cyclase prevented the harmaline-induced increase in extracellular cGMP, while phosphodiesterase inhibitors potentiated the increase. Local application of the NMDA antagonist 2-amino-5-phosphonopentanoic acid or the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione attenuated the effect of harmaline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide-dependent efflux of cGMP in rat cerebellar cortex: an in vivo microdialysis study. 750 65

The neuropeptide eclosion hormone triggers ecdysis behavior in lepidopteran insects. We have previously shown that the eclosion hormone stimulates the formation of two intracellular second messengers, cGMP and inositol(1,4,5)trisphosphate in the abdominal ganglia of Bombyx mori. In order to elucidate the intracellular signaling pathway involving these second messengers, we studied the eclosion hormone-mediated signal transduction using saponin-treated abdominal ganglia. We obtained the following results; i) eclosion hormone activated nitric oxide synthase, ii) the eclosion hormone-induced cGMP increase was inhibited by various enzyme inhibitors such as NG-nitro-arginine; a nitric oxide synthase inhibitor, EGTA; a calcium chelating reagent, W-5; a calmodulin inhibitor and compound 48/80; a phospholipase C inhibitor and iii) the inositol(1,4,5)-trisphosphate stimulated the formation of cGMP, in the Bombyx abdominal ganglia. Based on these findings we tentatively propose a hypothetical pathway: The signal initially triggered by eclosion hormone and eclosion hormone receptor complex induces activation of phospholipase C which produces inositol(1,4,5)trisphosphate. Inositol(1,4,5)trisphosphate increases intracellular Ca2+, followed by subsequent activation of nitric oxide synthase through the formation of Ca(2+)-calmodulin complex. The reaction product, nitric oxide acts on soluble guanylate cyclase to stimulate cGMP formation which induces the ecdysis behavior in Bombyx pharate adults.
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PMID:Eclosion hormone-mediated signal transduction in the silkworm abdominal ganglia: involvement of a cascade from inositol(1,4,5)trisphosphate to cyclic GMP. 750 67

Nitric oxide is a novel signalling molecule in the brain and a potent activator of the cyclic GMP-synthesising enzyme, soluble guanylate cyclase. To determine if stimulation of cyclic GMP formation is a widespread mechanism of nitric oxide signal transduction, we have compared the distribution of the nitric oxide-generating enzyme (nitric oxide synthase) with that of nitric oxide-stimulated cyclic GMP accumulation, throughout the rat brain. The former was done using NADPH diaphorase histochemistry and the latter by cyclic GMP immunohistochemistry following perfusion of the nitric oxide donor, nitroprusside, in vivo. At a gross level, there was generally a good match when the two were compared in adjacent sections. Although the relative staining intensity varied from area to area, in no grey matter region did we observe cyclic GMP accumulation in the absence of nitric oxide synthase staining. In detail, the locations were complementary rather than identical. In some areas, nitric oxide synthase was found in postsynaptic structures and cyclic GMP accumulation in presynaptic elements and fibres; in others, the locations were reversed. Glial cells and their processes also accumulated cyclic GMP in the cerebellum. The results suggest that soluble guanylate cyclase is a major nitric oxide "receptor" throughout the brain. They also support the hypothesis that nitric oxide generated therein primarily functions as a mediator of cell-cell signaling rather than as a conventional second messenger acting within the cells in which it is produced. The types of communication subserved by nitric oxide appear to be extraordinarily diverse.
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PMID:The nitric oxide-cyclic GMP signalling pathway in rat brain. 750 51

Recent immunocytochemical studies of cerebellar nitric oxide synthase (NOS) and cGMP have aided dramatically in defining possible cellular sources of cGMP generation in the signal transduction cascade evoked by excitatory amino acids in the cerebellum. Using a mouse mutant deficient in cerebellar Purkinje cells ("nervous" mouse) and chemical lesions of cerebellar neurons with methylazoxymethanol (MAM), we have examined in vivo generation of cGMP to determine the roles of different cerebellar neuronal populations. In the case of "nervous" mice, our data indicate that cerebellar Purkinje cells are not required for NMDA-dependent increases in cGMP in the cerebellum. In marked contrast, MAM lesions which reduce granule but not Golgi cells in the granule cell layer and reduce basket and stellate cells in the molecular layer, dramatically reduced the ability of NMDA to increase cerebellar cGMP. These data support immunocytochemical data of cerebellar NOS pools and indicate the importance of granule, basket and possibly stellate cells in the generation of nitric oxide, which in turn activates guanylate cyclase, in a diversity of cells, to increase cerebellar cGMP levels.
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PMID:Involvement of granule, basket and stellate neurons but not Purkinje or Golgi cells in cerebellar cGMP increases in vivo. 750 34


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