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 mechanism of modulation of cyclic guanosine monophosphate (cGMP) accumulation by methylene blue (MB), a putative inhibitor of soluble guanylate cyclase, was investigated in cultured rabbit pulmonary arterial smooth muscle cells (RPASM). Control or MB-pretreated RPASM were stimulated with sodium nitroprusside (SNP), nitrosothiols or endothelium-derived relaxing factor (EDRF) released basally from bovine pulmonary arterial endothelial cells, in short-term co-cultures. The putative EDRF, S-nitroso-L-cysteine (CYSNO), a stable deaminated analog of CYSNO, S-nitroso-3-mercaptoproprionic acid (MPANO) and SNP produced concentration-dependent (1-100 microM) increase (1.5- to 12-fold) in RPASM cGMP levels. MB pretreatment inhibited CYSNO and SNP-induced cGMP accumulation by 51% to 100%, but MPANO-mediated responses were not altered by MB. The inhibition profile of MB on nitrovasodilator-induced cGMP accumulation was quantitatively reproduced by extracellular generation of superoxide anion with xanthine (100 microM) and xanthine oxidase (5 mU). Similarly to MB pretreatment, superoxide anion generation had no effects on base-line cGMP levels or cGMP responses elicited by MPANO. Furthermore, MB induced a dose- and time-dependent generation of superoxide anion from RPASM, as evidenced from spectrophotometric determination of cytochrome c reduction. Inhibition of cGMP accumulation in response to CYSNO and SNP by MB was completely prevented by superoxide dismutase but not catalase. Selective pretreatment of endothelial cells with MB before co-culture with untreated RPASM produced a reduction in RPASM cGMP levels of a magnitude comparable with that seen in co-cultures of MB-pretreated RPASM with untreated endothelial cells, and which was partially prevented by superoxide dismutase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Methylene blue inhibits nitrovasodilator- and endothelium-derived relaxing factor-induced cyclic GMP accumulation in cultured pulmonary arterial smooth muscle cells via generation of superoxide anion. 132 4

High levels of endothelin-like immunoreactivity were detected in red blood cells from rat, pig and man. When characterized on HPLC the immunoreactivity coeluted with haemoglobin, however. Thus, the high levels of endothelin-like immunoreactivity did not reflect occurrence of endothelin peptides but rather the interference of haemoglobin in the RIA. Free haemoglobin > 0.8 g/l (which may occur in haemolytic samples) increased measured plasma "endothelin-like immunoreactivity". SepPak extraction of plasma samples markedly reduced this interference, although some effect still remained at high haemoglobin concentrations. The influence of microperoxidase in the RIA suggests that the interference is related to the haeme portion of haemoglobin and thus may be extended to other haeme-containing proteins, e.g. cytochrome c or guanylate cyclase. The present findings emphasize the importance of characterizing endothelin-like immunoreactivity with HPLC, especially in haemolytic samples.
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PMID:Free haemoglobin interferes with detection of endothelin peptides. 147 49

We have previously reported that nitric oxide (NO) synthase activity, protein, and mRNA are increased in proliferating compared with postconfluent bovine aortic endothelial cells (BAEC). Because superoxide anion inactivates NO, in the present study, we have assessed the effect of proliferation on superoxide anion production by use of cytochrome c reduction. The superoxide anion production in proliferating cells was increased about threefold compared with postconfluent cells in both basal and calcium ionophore-stimulated conditions and exceeded the amount of released nitrite and nitrate (NOx) in all cases. A-23187 (1 microM) stimulated the superoxide anion production about twofold at all stages of confluence. Because superoxide anion can inactivate NO, we then assessed the effect of proliferation on NO bioactivity released in the conditioned medium, by use of RFL-6 cells (reporter cells very rich in guanylate cyclase, which on activation by NO generates guanosine 3',5'-cyclic monophosphate, second messenger of NO). In the absence of added superoxide dismutase (SOD) in the conditioned medium, the guanylate cyclase-stimulating activities evoked by A-23187 from proliferating and growth-arrested cells were similar, despite a greater NOx release in the former. When SOD (100 U/ml) was added in the conditioned medium, the guanylate cyclase-stimulating activity evoked by 1 microM A-23187 was increased approximately 10-fold and closely paralleled NOx release (i.e., was greater in supernatant of proliferating cells than in that of growth-arrested cells). Thus BAEC release more superoxide anion extracellularly than NO at all stages of confluence. Endothelium-derived superoxide anion is a major determinant of the breakdown of NO.
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PMID:Nitric oxide and superoxide anion production during endothelial cell proliferation. 894 35

Nitric oxide (NO) binds to metalloproteins, and particularly to hemoproteins in both ferrous and ferric states, with association and dissociation rate constants which cover many orders of magnitude. These chemical properties often provide clear explanations of enzymatic specificity. A basic and straightforward description of the versatility of NO chemistry and of the biological relevance of NO effects, as understood by biochemists as opposed to physiologists, is presented. NO effects on hemoglobin and soluble guanylate cyclase, two proteins directly involved in arterio-venous oxygen transport at quite different biological levels, are compared. NO and other N-oxides also play primary roles in several mitochondrial functions. Specific interactions with cytochrome c oxidase and cytochrome c are reviewed, and the effects of NO and other N-oxides on other iron-cluster-containing components of mitochondrial respiration are discussed.
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PMID:Interactions of nitric oxide with hemoproteins: roles of nitric oxide in mitochondria. 1044 85

Exposure of RINm5F cells to interleukin-1beta and to several chemical NO donors such as sodium nitroprusside (SNP), SIN-1 and SNAP induce apoptotic events such as the release of cytochrome c from mitochondria, caspase 3 activation, Bcl-2 downregulation and DNA fragmentation. SNP exposure led to transient activation of soluble guanylate cyclase (sGC) and prolonged protein kinase G (PKG) activation but apoptotic events were not attenuated by inhibition of the sGC/PKG pathway. Prolonged activation of the cGMP pathway by exposing cells to the dibutyryl analogue of cGMP for 12 h induced both apoptosis and necrosis, a response that was abolished by the PKG inhibitor KT5823. These results suggest that NO-induced apoptosis in the pancreatic beta-cell line is independent of acute activation of the cGMP pathway.
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PMID:NO induces a cGMP-independent release of cytochrome c from mitochondria which precedes caspase 3 activation in insulin producing RINm5F cells. 1051 27

Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature. This will include the induction of antioxidant defenses such as glutathione, activation of mitogen-activated protein kinases in response to blood flow, and modulation of mitochondrial function and its impact on apoptosis. Models are presented that show the increased synthesis of glutathione in response to shear stress and inhibition of cytochrome c release from mitochondria. It appears that in the vasculature NO-dependent signaling pathways are of three types: (i) those involving NO itself, leading to modulation of mitochondrial respiration and soluble guanylate cyclase; (ii) those that involve S-nitrosation, including inhibition of caspases; and (iii) autocrine signaling that involves the intracellular formation of peroxynitrite and the activation of the mitogen-activated protein kinases. Taken together, NO plays a major role in the modulation of redox cell signaling through a number of distinct pathways in a cellular setting.
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PMID:Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases. 1139 77

Intracellular signaling pathways involved in the survival of proliferating L1210 leukemia cells were investigated by using specific modulators. Among the various inhibitors tested, only 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor, was found to induce a marked increase in caspase activity, which was associated with a loss of cell viability and a reduction in cGMP content. ODQ also provoked the processing of caspases-3 and -9, release of cytochrome c and, as early events, reduction of Bcl-2 content and dephosphorylation of Bad at Ser 112. Furthermore, YC-1, an sGC activator, and 8-Br-cGMP, a cell-permeant analogue of cGMP, exerted some protection against various apoptotic stimuli, such as serum deprivation or spermine accumulation. Although PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, did not increase basal caspase activity, and ODQ did not affect p44/42 MAPK phosphorylation significantly, phorbol myristate acetate stimulated p44/42 MAPK and reduced caspase activation induced by ODQ, serum deprivation, and spermine in a p44/42-dependent manner. SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)1H-imidazole), a p38 MAPK inhibitor, also partially protected against ODQ-induced apoptosis by increasing p44/42 MAPK phosphorylation. In conclusion, these results suggest that sGC may be relevant both for survival of L1210 cells under basal growing conditions and for protection against various apoptotic stimuli. p44/42 MAPK activation may also confer some protection from apoptosis, but apparently through a pathway largely independent of cGMP.
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PMID:Control of survival of proliferating L1210 cells by soluble guanylate cyclase and p44/42 mitogen-activated protein kinase modulators. 1143 4

The mechanism by which nitric oxide (NO) protects from apoptosis is a matter of debate. We have shown previously that phosphorylation of tyrosine residues participates in the protection from apoptosis in insulin-producing RINm5F cells (Inorg. Chem. Commun. 3 (2000) 32). Since NO has been reported to activate the tyrosine kinase c-Src and this kinase is involved in the activation of protein kinase G (PKG) in some cell systems, we aimed at studying the contribution of c-Src and PKG systems in anti-apoptotic actions of NO in serum-deprived RINm5F cells. Here we report that exposure of serum-deprived cells to 10 microM DETA/NO results in protection from degradation of the anti-apoptotic protein Bcl-2, together with a reduction of cytochrome c release from mitochondria and caspase-3 inhibition. Studies with the inhibitors ODQ and KT-5823 revealed that these actions are dependent on both activation of guanylate cyclase and PKG. DETA/NO was also able to induce autophosphorylation and activation c-Src protein both in vivo and in vitro and active c-Src was able to induce tyrosine phosphorylation of Bcl-2 in vitro. The c-Src kinase inhibitor PP1 abrogated the actions of DETA/NO on cGMP formation, PKG activation, caspase activation, cytochrome c release from mitochondria, and Bcl-2 phosphorylation and degradation in serum-deprived cells. We thus propose that activation of c-Src is an early step in the chain of events that signal cGMP-dependent anti-apoptotic actions of NO in mitocohondria.
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PMID:Evidence for involvement of c-Src in the anti-apoptotic action of nitric oxide in serum-deprived RINm5F cells. 1158 16

The 5-coordinate ferrous heme of Alcaligenes xylosoxidans cytochrome c' reacts with NO to form a 6-coordinate nitrosyl intermediate (lambdaSoret at 415 nm) which subsequently converts to a 5-coordinate nitrosyl end product (lambdaSoret at 395 nm) in a rate-determining step. Stopped-flow measurements at pH 8.9, 25 degrees C, yield a rate constant for the formation of the 6-coordinate nitrosyl adduct, k(on) = (4.4 +/- 0.5) x 10(4) M(-1) x s(-1), which is 3-4 orders of magnitude lower than the values for other pentacoordinate ferrous hemes and is consistent with NO binding within the sterically crowded distal heme pocket. Resonance Raman measurements of the freeze-trapped 6-coordinate nitrosyl intermediate reveal an unusually high Fe-NO stretching frequency of 579 cm(-1), suggesting a distorted Fe-N-O coordination geometry. The rate of 6- to 5-coordinate heme nitrosyl conversion is also dependent upon NO concentration, with a rate constant, k(6-5) = (8.1 +/- 0.7) x 10(3) M(-1) x s(-1), implying that an additional molecule of NO is required to form the 5c-NO adduct. Since crystallographic studies have shown that the 5-coordinate nitrosyl complex of cytochrome c' binds NO to the proximal (rather than distal) face of the heme, the NO dependence of the 6- to 5-coordinate NO conversion supports a mechanism in which the weakened His ligand, as well as the distally bound NO, is displaced by a second NO molecule which attacks and is retained in the proximal coordination position. The fact that a dependent 6- to 5-coordinate nitrosyl conversion has been previously reported for soluble guanylate cyclase suggests that the mechanism of Fe-His bond cleavage may be similar to that of cytochrome c' and strengthens the recent proposal that both proteins exhibit proximal NO binding in their 5-coordinate nitrosyl adducts.
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PMID:Six- to five-coordinate heme-nitrosyl conversion in cytochrome c' and its relevance to guanylate cyclase. 1184 Dec 28

1. We investigated the cytoprotective effect of low-dose nitric oxide (NO) on NO-induced cell death in mouse macrophage-like cell line RAW264. 2. Sodium nitroprusside (SNP), an NO donor, at a high concentration (4 mM) released cytochrome c from mitochondria and induced death in RAW264 cells. Acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspart-1-al (Ac-DEVD-CHO, 100-200 microM), a caspase-3 inhibitor, attenuated the SNP-induced cell death in a concentration-dependent manner. 3. Pretreatment with 100 microM SNP for 24 h, which had no effect on cell viability, attenuated the cell death and reduced cytochrome c release from mitochondria to the cytosol induced by 4 mM SNP. 4. LY83583 (1-3 microM) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 30-100 microM), soluble guanylate cyclase inhibitors, negated the protective effect of the 100 microM SNP pretreatment. 5. Pretreatment with 1 mM dibutylyl guanosine-3',5'-cyclic monophosphate (DBcGMP), a cell-permeable guanosine-3',5'-cyclic monophosphate (cGMP) analogue, for 24 h inhibited both cytochrome c release and cell death induced by SNP. 6. Protein kinase G inhibitor KT5823 (10 microM) significantly reduced the cytoprotective effects of low-dose SNP and DBcGMP. 7. These results indicate that low-dose NO protects RAW264 cells from NO-induced apoptosis through cGMP production and activation of protein kinase G.
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PMID:Nitric oxide at a low concentration protects murine macrophage RAW264 cells against nitric oxide-induced death via cGMP signaling pathway. 1274 20


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