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)

This study examined the signal transduction pathway(s) leading to phosphorylation of p38 in human neutrophils stimulated with lipopolysaccharide and formyl peptides. Blockade of the nitric oxide (NO) pathway in neutrophils with the NO synthase inhibitor N-nitro-L-arginine methyl ester or by treatment with the NO scavenger 2-phenyl-tetramethylimidazoline-1-oxyl-3-oxide attenuated phosphorylation of the mitogen-activated protein kinase p38 in response to lipopolysaccharide but not fMet-Leu-Phe. Using the NO releasing agents S-nitroso-N-acetylpenicillamine and sodium nitroprusside it was determined that nitric oxide is sufficient to cause an increase in phosphorylation of p38. Increasing cellular cGMP with phosphodiesterase inhibitors, by stimulation of soluble guanylyl cyclase with YC-1 or with exogenous dibutyryl cGMP resulted in mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 3,6 (MEK3,6) activation and phosphorylation of p38. This phenomenon was specific for MEK3,6, because these agents had no effect on the phosphorylation state of MEK1,2. A role for protein kinase G but not protein kinase A downstream of lipopolysaccharide but not formylmethionylleucylphenylalanine was shown using the specific inhibitors KT5823 and H89, respectively. These data indicate that activation of p38 by fMet-Leu-Phe and lipopolysaccharide involve different mechanisms, and that activation of protein kinase G by NO-dependent stimulation of guanylyl cyclase is necessary and sufficient for phosphorylation of p38 downstream of lipopolysaccharide.
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PMID:Activation of p38 mitogen-activated protein kinase by lipopolysaccharide in human neutrophils requires nitric oxide-dependent cGMP accumulation. 986 77

Previously characterized soluble guanylyl cyclases form alpha-beta heterodimers that can be activated by the gaseous messenger, nitric oxide. In mammals, four subunits have been cloned, named alpha1, alpha2, beta1, and beta2. We have identified a novel soluble guanylyl cyclase isoform from the nervous system of the insect Manduca sexta that we have named M. sexta guanylyl cyclase beta3 (MsGC-beta3). It is most closely related to the mammalian beta subunits but has several features that distinguish it from previously identified soluble cyclases. Most importantly, MsGC-beta3 does not need to form heterodimers to form an active enzyme because guanylyl cyclase activity can be measured when it is expressed alone in COS-7 cells. Moreover, this activity is only weakly enhanced in the presence of the nitric oxide donor, sodium nitroprusside. Several of the amino acids in rat beta1 subunits, previously identified as being important in heme binding or necessary for nitric oxide activation, are substituted with nonsimilar amino acids in MsGC-beta3. There are also an additional 315 amino acids C-terminal to the catalytic domain of MsGC-beta3 that have no sequence similarity to any known protein. Northern blot analysis shows that MsGC-beta3 is primarily expressed in the nervous system of Manduca.
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PMID:Identification and characterization of a novel beta subunit of soluble guanylyl cyclase that is active in the absence of a second subunit and is relatively insensitive to nitric oxide. 989 Oct 24

We examined potential mechanisms by which angiotensin subtype-2 (AT2) receptor stimulation induces net fluid absorption and serosal guanosine cyclic 3',5'-monophosphate (cGMP) formation in the rat jejunum. L-arginine (L-ARG) given intravenously or interstitially enhanced net fluid absorption and cGMP formation, which were completely blocked by the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methylester (L-NAME), but not by the specific AT2 receptor antagonist, PD-123319 (PD). Dietary sodium restriction also increased jejunal interstitial fluid cGMP and fluid absorption. Both could be blocked by PD or L-NAME, suggesting that the effects of sodium restriction occur via ANG II at the AT2 receptor. L-ARG-stimulated fluid absorption was blocked by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo[4, 2-alpha]quinoxalin-1-one (ODQ). Cyclic GMP-specific phosphodiesterase in the interstitial space decreased extracellular cGMP content and prevented the absorptive effects of L-ARG. Angiotensin II (ANG II) caused an increase in net Na+ and Cl- ion absorption and 22Na+ unidirectional efflux (absorption) from the jejunal loop. In contrast, intraluminal heat-stable enterotoxin of Escherichia coli (STa) increased loop cGMP and fluid secretion that were not blocked by either L-NAME or ODQ. These findings suggest that ANG II acts at the serosal side via AT2 receptors to stimulate cGMP production via soluble guanylyl cyclase activation and absorption through the generation of NO, but that mucosal STa activation of particulate guanylyl cyclase causes secretion independently of NO, thus demonstrating the opposite effects of cGMP in the mucosal and serosal compartments of the jejunum.
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PMID:Compartmentalization of extracellular cGMP determines absorptive or secretory responses in the rat jejunum. 991 28

The effects of various spontaneous nitric oxide (NO) donors and NO synthase inhibitors on endothelin- production were examined using porcine cultured aortic endothelial cells. NO donors such as (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 2), (+/-)-(E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 3) and (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridine carboxamide (NOR 4) suppressed effectively the release of endothelin-1 from the cells. Endothelin-1 mRNA expression was also attenuated by these compounds. Other NO donors such as 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamin e (NOC 5), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC 18), s-nitroso-n-acetyl-DL-penicillamine, N-morpholino sydnonimine (SIN-1) had no effects on endothelin-1 production. Endothelial intracellular cyclic guanosine monophosphate (cGMP) levels were significantly increased by all NO donors. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective soluble guanylyl cyclase inhibitor, had no effect on the NOR 3-induced decrease in endothelin-1 secretion, although cGMP production was abolished by ODQ. NOR 3 also inhibited endothelin-1 secretion even in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetrametylimidazole-1-oxyl 3-oxide (carboxy-PTIO), a NO scavenger. NOR 3-induced inhibitory effects on endothelin-1 secretion were abolished by preincubation of the compound in phosphate-buffered saline (37 degrees C, 4 h), a procedure by which about 98% of the parent compound's ability to release NO was lost. NO synthase inhibitors such as N(G)-nitro-L-arginine, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced prepro endothelin-1 mRNA expression and significantly increased endothelin-1 release from endothelial cells. Endothelin-1 secretion was also increased effectively by carboxy-PTIO or ODQ. When the cells were exposed to L-NAME with carboxy-PTIO or ODQ, no significant further increase in endothelin-1 release was observed. These results suggest that endogenous NO inhibits endothelin-1 production through guanylyl cyclase/cGMP-dependent mechanisms. In contrast, it seems unlikely that exogenous NO has an inhibitory effect on endothelin-1 production in endothelial cells. NOR compounds inhibit endothelin-1 production perhaps through NO/cGMP-independent mechanisms, i.e., through an unknown effect of the parent compound itself.
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PMID:Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. 992 Jan 86

Genomic DNA corresponding to the soluble guanylyl cyclase beta-subunit (GCSbeta) gene was cloned and sequenced from Anopheles gambiae. The sequence was 8103 bp long and presumably included the entire coding region. The deduced amino acid sequence was 71% and 62% similar to previously known Drosophila and vertebrate GCSbeta, while the C-terminus of A. gambiae GCSbeta was shorter. Because of the conserved characteristics in each functional domain, the high G+C% in the third codon positions compared to the introns, the lack of internal stop codons, and the fact that we identified the gene from a cDNA, we conclude that this A. gambiae gene is functional. This is the first detailed description of a guanylyl cyclase gene structure (e.g. intron-exon boundaries). Interestingly, within the fifth intron we found high similarity to the flanking regions of the Pegasus-27 transposable element and other noncoding regions of the A. gambiae genome.
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PMID:Characterization of the soluble guanylyl cyclase beta-subunit gene in the mosquito Anopheles gambiae. 992 71

PC12 cells are used as a model system to study neuronal differentiation. Nerve growth factor (NGF) triggers a differentiation pathway in PC12 cells. Neurite outgrowth (a morphological marker of differentiation) in PC12 cells is significantly reduced in the presence of the NOS inhibitor l-NAME, but not d-NAME, implicating NOS in the differentiation process. Previously we have shown that the neuronal NO synthase (nNOS) isoform is induced in PC12 cells in the presence of NGF. Thus, we wished to further evaluate the role of nNOS and NO in PC12 cell differentiation. When a dominant negative mutant nNOS expression vector was transiently transfected into NGF-treated PC12 cells, it significantly reduced PC12 cell neurite outgrowth. Thus, we concluded that the NO required for PC12 cell differentiation, in response to NGF, is produced by nNOS. NO alone was insufficient to induce differentiation as cells treated with the NO donor, sodium nitroprusside did not produce neurites. Treatment of PC12 cells with oxyhemoglobin (an NO scavenger) was also found to significantly reduce the number of neurites produced by PC12 cells treated with NGF. Thus, NO appears to be necessary, but not sufficient, to induce differentiation, and its mode of action appears to be extracellular. A well documented action of NO is to activate soluble guanylate cyclase. Thus, we determined the role of soluble guanylate cyclase activation as a means by which NO induces PC12 cell differentiation. However, in the presence of NGF (to prime PC12 cells for differentiation) and l-NAME (to specifically remove the NO component), 8Br-cGMP (a cGMP analog) failed to induce PC12 cell differentiation. In addition, blockade of sGC activity with specific inhibitors failed to block NGF-induced PC12 cell differentiation. We conclude that the NO required for PC12 cell differentiation is produced by nNOS and that the NO exerts its effects on surrounding PC12 cells in a sGC/cGMP independent manner.
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PMID:Both neuronal NO synthase and nitric oxide are required for PC12 cell differentiation: a cGMP independent pathway. 993 81

Recently we reported that Vibrio vulnificus hemolysin, an exotoxin produced by V. vulnificus, dilates rat thoracic aorta via elevated cGMP levels without affecting nitric oxide synthase. We investigated the mechanism further by observing the guanylyl cyclase activities in cytosolic, membrane, unfractionated, or reconstituted preparations. Hemolysin did not activate guanylyl cyclase in the membrane or cytosolic fraction, while it activated guanylyl cyclase in unfractionated or reconstituted preparation. The increased activity was not inhibited by the HS-142-1, a microbial polysaccharide which antagonizes atrial natriuretic peptide receptor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor. However, it was attenuated by 6-(phenylamino)-5,8-quinolinedione (LY 83.583), which inhibits the catalytic domain of both guanylyl cyclases, and by cholesterol, which blocks hemolysin-incorporation into the membrane. Removing ATP, a cofactor of particulate guanylyl cyclase, attenuated the activation and ATPgammaS, a non-phosphorylating analog, restored it. These results suggest that V. vulnificus hemolysin activates particulate guanylyl cyclase via hemolysin incorporation into the vascular smooth muscle cell membrane in cooperation with certain unidentified cytosolic component(s).
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PMID:Activation of particulate guanylyl cyclase by Vibrio vulnificus hemolysin. 998 11

We investigated the effects of cGMP-elevating agents, including atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and sodium nitroprusside (SNP), on cGMP accumulation and on carbachol (CCh)-stimulated intracellular calcium ([Ca2+]i) mobilisation in SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells and in primary cultured cat iris sphincter smooth muscle (CISM) cells. The stimulatory effects of the natriuretic peptides on cGMP production correlated well with their inhibitory effects on CCh-induced [Ca+1]i mobilisation, and these effects were significantly more pronounced in the SV-CISM-2 cells than in the CISM cells. Thus, ANP (1 microM) increased cGMP production in the SV-CISM-2 cells and CISM cells by 487- and 1.7-fold, respectively, and inhibited CCh-induced [Ca2+]i mobilisation by 95 and 3%, respectively. In the SV-CISM-2 cells, ANP and CNP dose dependently inhibited CCh-induced [Ca2+]i mobilisation with IC50 values of 156 and 412 nM, respectively, and dose dependently stimulated cGMP formation with EC50 values of 24 and 88 nM, respectively, suggesting that the inhibitory actions of the peptides are mediated through cGMP. Both ANP and CNP stimulated cGMP accumulation in a time-dependent manner. The potency of the cGMP-elevating agents were in the following order: ANP>>CNP>>SNP; these agents had no effect on cAMP accumulation. The inhibitory effects of the natriuretic peptides were mimicked by 8-Br-cGMP, a selective activator of cGMP-dependent protein kinase. LY83583, a soluble guanylyl cyclase inhibitor, significantly inhibited SNP-induced cGMP formation but had no effect on those of ANP and CNP. The basal activities of the guanylyl cyclase and the dissociation constant (Kd) and total receptor density (Bmax) values of the natriuretic peptide receptor for [125I]ANP binding were not significantly different between the two cell types. The cGMP system, as with the cAMP system, has a major inhibitory influence on the muscarinic responses in the iris sphincter smooth muscle cells, and SV-CISM-2 cells can serve as an excellent model for investigating the cross talk between cGMP and the Ca2+ signalling system.
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PMID:Atrial natriuretic peptide provokes a dramatic increase in cyclic GMP formation and markedly inhibits muscarinic-stimulated Ca2+ mobilisation in SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. 1004 85

Overwhelming evidence indicates that the glutamate/nitric oxide (NO) synthase/soluble guanylyl cyclase system is of primary importance in a variety of physiological and pathological processes of the brain. Most of our knowledge on this neurochemical pathway derives from in vitro and ex vivo studies but the recent improvement of microdialysis techniques combined with extremely sensitive measurements of the amplified end-product cyclic GMP (cGMP) has given new impulses to the investigation of this cascade of events, its modulation by neurotransmitters and its functional relevance, in a living brain. The first reports, appeared in the early 90's, have demonstrated that microdialysis monitoring of cGMP in the extracellular environment of the cerebellum and hippocampus exactly reflects what is expected to occur at the intracellular level; thus, in vivo extracellular cGMP is sensitive to NO-synthase and soluble guanylyl cyclase inhibitors, can be increased by NO-donors or phosphodiesterase blockers and is modulated by glutamate receptor stimulation in a NO-dependent fashion. Since then, other microdialysis studies have been reported showing that the brain NO synthase/guanylyl cyclase pathway is mainly controlled by NMDA, AMPA and metabotropic glutamate receptors but can be also influenced by other transmitters (GABA, acetylcholine, neuropeptides) through polysynaptic circuits interacting with the glutamatergic system. The available data indicate that this technique, applied to freely-moving animals and combined with behavioural tests, could be useful to get a better insight into the functional roles played by NO and cGMP in physiological and pathological situations such as learning, memory formation, epilepsy, cerebral ischemia and neurodegenerative diseases.
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PMID:In vivo studies of the cerebral glutamate receptor/NO/cGMP pathway. 1032 98

The effects in bovine coronary arteries of the soluble guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) were examined in order to establish the relative importance of the enzyme (a) in the vasodilator actions of glyceryl trinitrate and S-nitroso-N-acetylpenicillamine and (b) in induction of tolerance to these agents. ODQ strongly inhibited responses to both relaxants with IC50's of the order of 0.5 microM; in contrast, the protein kinase G inhibitor, 8-bromoguanosine-3',5'-monophosphorothioate (Rp-8-Br-cGMPS) had little effect on the responses. Tolerance after pre-incubation with glyceryl trinitrate (10 microM) was unaffected by co-pre-incubation with ODQ (1.0 microM), but similar experiments with S-nitroso-N-acetylpenicillamine were inconclusive because tolerance was associated with depressed contractile activity. It is concluded that in bovine coronary arteries soluble guanylyl cyclase is essential for vasorelaxation to both glyceryl trinitrate and S-nitroso-N-acetylpenicillamine but is unimportant for induction of tolerance to glyceryl trinitrate. Our results add weight to the hypothesis of impaired biotransformation rather than guanylyl cyclase desensitisation as the mechanism of in vitro nitrate tolerance.
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PMID:Effects of guanylyl cyclase and protein kinase G inhibitors on vasodilatation in non-tolerant and tolerant bovine coronary arteries. 1032 78


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