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)

Nitric oxide (NO) is a messenger molecule of vascular endothelial cells, macrophages, and neurons. Here, we demonstrate that the activity of NO synthase increases transiently but dramatically in chick embryonic myoblasts that are competent for fusion. This activity requires Ca2+, calmodulin, and NADPH. In addition, the increase in NO synthase activity coincides with an increase in cellular cGMP level. Furthermore, NO generated by treatment with sodium nitroprusside induces precocious myoblast fusion, while treatment with NG-monomethyl-L-arginine, a competitive inhibitor of NO synthase, or methylene blue, an inhibitor of guanylate cyclase, delays fusion. These results provide the first evidence for a strong association of NO with myoblast fusion.
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PMID:Nitric oxide as a messenger molecule for myoblast fusion. 751 68

1 The effect of the Ca(2+)-ATPase inhibitor, cyclopiazonic acid (CPA), was studied on rat thoracic aortic ring preparations. 2 At concentrations above 0.3 microM, CPA induced relaxation in the arteries precontracted with phenylephrine. Removal of the endothelium abolished CPA-induced relaxation. 3 The nitric oxide (NO) synthase inhibitor NG-nitro L-arginine (3-300 microM), the free radical scavenger haemoglobin (0.1-3 microM), the soluble guanylate cyclase inhibitor, LY83583 (0.1-10 microM), each inhibited the endothelium-dependent relaxation to CPA. The potassium channel blocker, glibenclamide (10 microM) and cyclo-oxygenase inhibitor, indomethacin (100 microM for 60 min and then washed out) did not alter the action of CPA. 4 The calmodulin inhibitors calmidazolium (3-10 microM) and W-7 (100 microM) also abolished CPA-induced relaxation. 5 CPA (10 microM) increased guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in arteries with an intact endothelium, without affecting adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 6 The inhibitors of NO synthesis and actions, the calmodulin inhibitor and removal of the endothelium abolished the CPA-stimulated increase in the levels of cyclic GMP. 7 In Ca(2+)-free solution, CPA failed to induce relaxation or to stimulate cyclic GMP production. Relaxation to nitroprusside was not affected under these conditions. 8 These results suggest that CPA can stimulate NO synthesis, possibly by inhibiting a Ca(2+)-ATPase, which replenishes Ca2+ in the intracellular storage sites in endothelial cells. Depletion of the Ca2+ store in the endothelium may then trigger influx of extracellular Ca2+, contributing to an increase in free Ca2+ in the endothelial cells, which activates NO synthase and NO formation.
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PMID:Relaxation of rat thoracic aorta induced by the Ca(2+)-ATPase inhibitor, cyclopiazonic acid, possibly through nitric oxide formation. 751 25

Available studies indicate that the adrenergic stimulation of pineal cyclic GMP production involves stimulation of guanylyl cyclase activity by nitric oxide (NO) derived from arginine. This line of investigation was extended in the present study. Using a highly sensitive microassay, it was found that pineal NO synthase activity is present at levels approximately 30% of those in the cerebellum, that approximately 95% of enzyme activity is cytoplasmic, that the enzyme is Ca2+/calmodulin-dependent and that enzyme activity is inhibited by the arginine analog NG-nitro-L-arginine methyl ester (L-NAME). Norepinephrine treatment of intact glands in culture increased [3H]citrulline formation from [3H]arginine. This treatment also increased the formation of an NO-like compound, indicating that NO synthase activity in the intact gland is elevated by adrenergic stimulation. Studies on the effects of inhibition of NO synthase activity indicated that treatments known to inhibit NO synthase activity and the adrenergic stimulation of cyclic GMP accumulation did not inhibit adrenergic stimulation of pineal cyclic AMP, N-acetyltransferase activity or melatonin production. These observations support the hypothesis that NE stimulation of pineal cyclic GMP accumulation involves stimulation of a Ca2+/calmodulin-sensitive form of NO synthase, resulting in enhanced accumulation of NO; and, that although NO appears to play a role in the adrenergic stimulation of pineal cyclic GMP accumulation, it does not appear to play a critical role in the adrenergic stimulation of cyclic AMP, N-acetyltransferase activity or melatonin production.
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PMID:Pineal nitric oxide synthase: characteristics, adrenergic regulation and function. 752 30

Ever since the identification of two distinct Ang II receptor subtypes, the function of the AT2 receptor has been a subject of debate. As opposed to the AT1 subtype, this receptor does not interact with G-proteins in most cell lines and tissues. We show here that, in intact PC12W cells which express only AT2 receptors, Ang II significantly decreases basal and atrial natriuretic peptide (ANP)-stimulated cGMP concentration. This effect is mimicked by the AT2 selective agonist CGP 42112, and is not prevented by the AT1 selective antagonist losartan, indicating that this is an AT2 receptor mediated response. The lack of effect of the phosphodiesterase (PDE) inhibitor IBMX shows that this mechanism does not involve PDE stimulation. This is confirmed by the finding that neither Ang II or CGP 42112 affect the Ca++/calmodulin dependent cGMP PDE activity. Furthermore Ang II and CGP 42112 have no effect on nitroprusside-stimulated cGMP levels in these cells, thus ruling out interactions between the AT2 receptor and soluble guanylate cyclase. These data indicate that the AT2 receptor mediated decrease of cGMP is due to the selective inhibition of particulate guanylate cyclase (pGC) activity. In an accompanying paper we report that interaction of Ang II with the AT2 receptor in the same cells results in the stimulation of phosphotyrosine phosphatase (PTPase) activity. Interestingly, the PTPase inhibitors sodium orthovanadate and phenylarsine oxyde, but not the Ser/Thr phosphatase inhibitor okadiac acid, inhibitthe Ang II and CGP 42112 induced decreases in cellular cGMP concentration. These findings suggest that stimulation of PTPase activity may be involved in the regulation of pGC activity via AT2 receptors.
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PMID:Angiotensin AT2 receptor mediated inhibition of particulate guanylate cyclase: a link with protein tyrosine phosphatase stimulation? 752 2

Regulation of guanosine 3',5'-cyclic monophosphate (cGMP) formation by calcium and calcium-binding proteins was studied at the levels of nitric oxide synthase (NOS) and guanylyl cyclase (GC) in dispersed pancreatic acini isolated from guinea pig. In intact cells, in the cytosol, and on diethylaminoethyl fractions from cytosolic proteins, GC activity was negatively regulated by Ca2+. An increase in Ca2+ concentration ([Ca2+]) from 25 to 950 nM suppressed cGMP formation by 85%. On the other hand, NOS was stimulated by agents increasing cytosolic [Ca2+] and inhibited by intracellular Ca2+ chelators. Thus Ca2+ regulates cGMP production in opposite directions by activating NOS and inhibiting GC. Calmodulin antagonists W-7, trifluoperazine, and R-24571 inhibited NOS, suggesting that the enzyme is regulated by calmodulin as in other cell types. Calmodulin antagonists appeared to inhibit GC. In particular, 200 microM W-7 completely abolished the cGMP rise evoked by the nitric oxide donor, nitroprusside. The effect was not reversed by addition of excess calmodulin. The findings suggest that the negative regulation of GC by Ca2+ is due to factors other than calmodulin but affected by calmodulin antagonists.
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PMID:Dual regulation of cGMP formation by calcium in pancreatic acinar cells. 754 46

A nitric oxide synthase was partially purified from soluble extracts of Trypanosoma cruzi epimastigote forms. The conversion of L-arginine to citrulline by this enzyme activity required NADPH and was blocked by EGTA. The reaction was activated by Ca2+, calmodulin, tetrahydrobiopterin, and FAD, and inhibited by N omega-methyl-L-arginine. L-Glutamate and N-methyl-D-aspartate stimulated in vivo conversion of L-arginine to citrulline by epimastigote cells. These stimulations could be blocked by EGTA, MK-801, and ketamine and enhanced by glycine. A sodium nitroprusside-activated guanylyl cyclase activity was detected in cell-free, soluble preparations of T. cruzi epimastigotes. L-Glutamate, N-methyl-D-aspartate, and sodium nitroprusside increased epimastigote cyclic GMP levels. MK-801 bound specifically to T. cruzi epimastigote cells. This binding was competed by ketamine and enhanced by glycine or L-serine. Evidence thus indicates that in T. cruzi epimastigotes, L-glutamate controls cyclic GMP levels through a pathway mediated by nitric oxide.
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PMID:The nitric oxide transduction pathway in Trypanosoma cruzi. 754 49

In the present study we demonstrated that human erythrocytes possess a NO synthase (NOS) that can be activated by oxidative stress and Ca2+ accumulation to produce nitric oxide (NO), and that this activation could be involved in the pathogenesis of toxic anaemia in breast cancer patients. By causing oxidative stress in human erythrocytes with hydrogen peroxide (H2O2) (100 microM), or by increasing the intracellular calcium concentration using various doses (up to 100 microM) of the calcium ionophore A23187, a gradual increase in both NO and peroxynitrite (ONOO-) release that was inhibited by N-monomethyl-L-arginine (L-NMMA) (1mM) was observed. Time-dependent experiments using hemolysates showed a linear rise of NO production which was elevated by 60% in the presence of superoxide dismutase (SOD) (100 U). NOS isolated from hemolysates was constitutively expressed and was dependent on NADPH, Ca2+/calmodulin, tetrahydrobiopterin and flavins. In reconstitution experiments, when purified NOS, isolated from erythrocytes, was added to purified soluble guanylate cyclase (sGC), isolated from endothelial cells, in the presence of the appropriate cofactors and substrates, a linear increase in cGMP production at various concentrations (up to 50 microM) of H2O2 was observed. Furthermore, it was shown that erythrocytes from breast cancer patients were subjected to higher oxidative stress by ONOO- (100 microM), with a consequential increase of membrane rigidity, than erythrocytes from healthy individuals. Such mechanic changes may result in shortening of the lifespan of erythrocytes, a feature of toxic anemia in cancer patients.
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PMID:Nitric oxide and peroxynitrite production by human erythrocytes: a causative factor of toxic anemia in breast cancer patients. 754 67

The N-methyl-D-aspartate (NMDA) receptor plays a key role in synaptic plasticity and is thought to underlie memory, learning and development of the nervous system. The NMDA receptor is a ligand-gated ion channel complex that contains distinct recognition sites for endogenous and exogenous ligands, including glutamate, glycine, Mg2+, Zn2+ and noncompetitive blockers such as MK-801. In the central nervous system, nitric oxide (NO) is produced in some neurons following activation of excitatory amino acids receptors, particularly those of the NMDA receptor. Nitric oxide is synthesized from a L-arginine by the cytoplasmic enzyme nitric oxide synthase (NOS) which is a calcium dependent enzyme, and this pathway is inhibited by the analogues of L-arginine such as NG-monomethyl-L-arginine (L-NMMA) and is augmented by NMDA receptor activation. Activation of the NMDA receptor results in the elevation of intracellular calcium ([Ca2+]i) which in turn activates NOS via the calcium-calmodulin complex. Nitric oxide is not a classical neurotransmitter in the central nervous system since it is not released by exocytosis and does not interact with a receptor protein but rather diffuses rapidly across the membrane and binds with the iron in heme-containing proteins. Nitric oxide can serve as both an oxidizing and reducing agent. It has strong affinity for heme proteins such as guanylyl cyclase, but there is evident that NO may have a regulatory role by oxidizing sulfhydryl groups of non-heme proteins such as those on the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The generation of nitric oxide and its roles in neurotransmission and neurotoxicity. 754 46

In this paper we show that isolated rat atria synthetized nitric oxide (NO) and its acts as intracellular messenger, increasing cGMP production that in turn modulates the muscarinic cholinergic dependent inhibition of contractility. Carbachol activating M2 muscarinic acetylcholine receptors (M2 mAchR) activated phosphoinositide turnover, stimulated nitric oxide synthase and increased production of NO. Inhibitors of phospholipase C, protein kinase C, calcium/calmodulin, nitric oxide synthase and guanylate cyclase activities, shifted to the right the dose-response curve of carbachol upon contractility. Moreover, sodium nitroprusside and 8-bromo cGMP, induced negative inotropic effect. These results suggest that carbachol activating M2 mAchR exerts inotropic negative effect associated to an increase production of NO. The mechanism appears to occur secondarily to stimulation of phosphoinositide turnover via phospholipase C activation. This in turn, triggers cascade reactions leading to the production of NO, that contribute to the inotropic negative action of low concentrations of carbachol.
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PMID:Negative inotropic effect of carbachol on rat atria mediated by nitric oxide. 754 28

The production of cyclic GMP (cGMP) induced by acetylcholine and other stimuli was studied in bovine chromaffin cells. Acetylcholine increased intracellular cGMP in a transitory (peak at 2 min) and concentration-dependent manner (estimated half maximal increase, EC50 = 61 +/- 5 microM). NG-nitro-L-arginine methyl ester (NAME) inhibited such a rise in cGMP with a half maximal inhibitory concentration (IC50) of 231 +/- 55 microM. The acetylcholine-induced increase in cGMP was also inhibited by a calmodulin antagonist (calmidazolium, 30 microM) and by the absence of extracellular calcium. Other agents that strongly increased cytosolic calcium concentration ([Ca2+]i) as acetylcholine did, such as the nicotinic-agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP), high-KCl (50 mM), and ionomycin, also caused a rise in cGMP in cultured bovine chromaffin cells. Veratridine, an activator of sodium channels, produced a slowly developing calcium increase and no significant cGMP production. The muscarinic-agonist, muscarine, failed to increase cytosolic calcium, and was the weakest stimulator of cGMP production. cGMP formation, induced by sodium nitroprusside (SNP, 100 microM) and by C-type natriuretic peptide (CNP, 100 nM), was inhibited by 30-40% by increasing [Ca2+]i with ionomycin. This inhibition was abolished by calmidazolium (30 microM) and by the absence of calcium in the extracellular medium. In conclusion, bovine chromaffin cells synthesize nitric oxide (NO) to activate guanylate cyclase in response to several stimuli, which increase [Ca2+]i. Moreover, the increase in [Ca2+]i also stimulates a Ca2+/calmodulin phosphodiesterase, which could down-regulate the levels of cGMP in these cells.
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PMID:Activation of NO:cGMP pathway by acetylcholine in bovine chromaffin cells. Possible role of Ca2+ in the down-regulation of cGMP signaling. 757 35


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