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)

Random migration of rabbit peritoneal neutrophils was enhanced in a chemokinetic way by N-acetylcysteine (NAC) in a small concentration range (10-400 microM). The enhancement was due to the cysteine moiety in the molecule, because cysteine equally caused a stimulation of random migration. The stimulating effect of NAC or cysteine largely disappeared when cells were preincubated with NAC or cysteine for 30 min before submission to chemotaxis, indicating that desensitization occurs. The stimulating effect of NAC was dependent on extracellular calcium. Because the Ca2+-dependence of migration by electroporated cells differed from that of intact cells, and because calcium channel blockers inhibited the effect of NAC, the calcium-dependent target is probably located inside the cell rather than on the cell surface. In contrast with fMLP, NAC did not cause an upregulation of CD11b expression of cells in suspension. Inhibitors of guanylate cyclase and of cGMP-dependent protein kinase (G-kinase) inhibited stimulation of migration by NAC, suggesting that cGMP played a decisive role in the stimulatory effect of NAC.
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PMID:N-acetylcysteine causes a transient stimulation of neutrophil migration. 950 22

The cyclic guanosine-3',5'-monophosphate (cGMP) analogue, 8-bromo-cGMP (1 mM), increased glucose oxidation in isolated soleus muscle. The nitric oxide (NO) donor, sodium nitroprusside (SNP) (15 mM), increased glucose, pyruvate, palmitate and leucine oxidation. Removal of extracellular Ca2+ did not affect SNP-stimulated glucose oxidation (or other glucose utilization parameters), thus eliminating the influx of Ca2+ as a mechanism for the increases. The guanylate cyclase inhibitor, LY-83583 (10 microM), inhibited SNP-stimulated palmitate oxidation and activation of cGMP-dependent protein kinase (PKG). Activation of PKG might supersede any inhibitory effects of NO on respiration to stimulate metabolic fuel oxidation in skeletal muscle.
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PMID:Fuel oxidation in skeletal muscle is increased by nitric oxide/cGMP--evidence for involvement of cGMP-dependent protein kinase. 953 19

The second messengers cAMP and inositol-1,4,5-triphosphate have been implicated in olfaction in various species. The odorant-induced cGMP response was investigated using cilia preparations and olfactory primary cultures. Odorants cause a delayed and sustained elevation of cGMP. A component of this cGMP response is attributable to the activation of one of two kinetically distinct cilial receptor guanylyl cyclases by calcium and a guanylyl cyclase-activating protein (GCAP). cGMP thus formed serves to augment the cAMP signal in a cGMP-dependent protein kinase (PKG) manner by direct activation of adenylate cyclase. cAMP, in turn, activates cAMP-dependent protein kinase (PKA) to negatively regulate guanylyl cyclase, limiting the cGMP signal. These data demonstrate the existence of a regulatory loop in which cGMP can augment a cAMP signal, and in turn cAMP negatively regulates cGMP production via PKA. Thus, a small, localized, odorant-induced cAMP response may be amplified to modulate downstream transduction enzymes or transcriptional events.
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PMID:Calcium-sensitive particulate guanylyl cyclase as a modulator of cAMP in olfactory receptor neurons. 954 28

We used the patch-clamp technique to study the effect of nitric oxide (NO) on a cation channel in rat type II pneumocytes [alveolar type II (AT II) cells]. Single-channel recordings from the apical surface of AT II cells in primary culture showed a predominant cation channel with a conductance of 20.6 +/- 1.1 (SE) pS (n = 9 cell-attached patches) and Na(+)-to-K+ selectivity of 0.97 +/- 0.07 (n = 7 cell-attached patches). An NO donor, S-nitrosoglutathione (GSNO; 100 microM), inhibited the basal cation-channel activity by 43% [open probability (Po), control 0.28 +/- 0.05 vs. GSNO 0.16 +/- 0.03; P < 0.001; n = 16 cell-attached patches], with no significant change in the conductance. GSNO reduced the Po by reducing channel mean open and increasing mean closed times. GSNO inhibition was reversed by washout. The inhibitory effect of NO was confirmed by using a second donor of NO, S-nitroso-N-acetylpenicillamine (100 microM; Po, control 0.53 +/- 0.05 vs. S-nitroso-N-acetylpenicillamine 0.31 +/- 0.04; -42%; P < 0.05; n = 5 cell-attached patches). The GSNO effect was blocked by methylene blue (a blocker of guanylyl cyclase; 100 microM), suggesting a role for cGMP. The permeable analog of cGMP, 8-bromo-cGMP (8-BrcGMP; 1 mM), inhibited the cation channel in a manner similar to GSNO (Po, control 0.38 +/- 0.06 vs. 8-BrcGMP 0.09 +/- 0.02; P < 0.05; n = 7 cell-attached patches). Pretreatment of cells with 1 microM KT-5823 (a blocker of protein kinase G) abolished the inhibitory effect of GSNO. The NO inhibition of channels was not due to changes in cell viability. Intracellular cGMP was found to be elevated in AT II cells treated with NO (control 13.4 +/- 3.6 vs. GSNO 25.4 +/- 4.1 fmol/ml; P < 0.05; n = 6 cell-attached patches). We conclude that NO suppresses the activity of an Na(+)-permeant cation channel on the apical surface of AT II cells. This action appears to be mediated by a cGMP-dependent protein kinase.
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PMID:Nitric oxide inhibits lung sodium transport through a cGMP-mediated inhibition of epithelial cation channels. 957 65

The influence of arachidonic acid (AA) on the feedback regulation of mesangial contraction by large Ca(2+)-activated K+ channels (BKCa) was determined through single-channel analysis using the patch clamp method. The mesangial BKCa is a low-gain negative feedback inhibitor of contraction that is activated in response to agonist-induced Ca2+ transients and membrane depolarization. AA activated BKCa in cell-attached patches in a dose-dependent manner with a maximal effect at 400 nM and a half-maximal response at 49 nM. In inside-out patches, AA directly activated BKCa with a maximal effect at 400 nM. BKCa was activated significantly in response to addition of 100 nM ANG II in the presence but not the absence of AA. Since it was shown previously that fatty acids stimulated both soluble and membrane-bound guanylyl cyclase, we determined whether AA activated BKCa by interfering with cGMP-mediated signal transduction pathways. It was previously shown that 10 microM cGMP, via cGMP-dependent protein kinase, activated BKCa in a biphasic manner with an early increase in probability of a channel existing in an open state (Po) and a subsequent inactivation mediated by protein phosphatase 2A (PP2A). We found that 10 microM dibutyryl-cGMP enhanced BKCa activity in an additive manner with saturating concentrations (400 nM) of AA. Moreover, the inactivation phase mediated by PP2A was not abolished. Thus AA does not affect the phosphorylation/dephosphorylation regulatory cycle for BKCa. It is concluded that AA potentiates the ANG II feedback response of BKCa by a mechanism that is independent of the phosphorylation cycle.
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PMID:Arachidonic acid potentiates the feedback response of mesangial BKCa channels to angiotensin II. 957 88

We have previously shown that C-type natriuretic peptide (CNP), a guanylate cyclase agonist, can stimulate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion in murine airway epithelial cells via protein kinase (PK) A activation through the inhibition of cGMP-inhibited phosphodiesterases. In this paper, we show that CNP is also capable of reducing amiloride-sensitive sodium absorption in murine airway epithelium through a cGMP-dependent mechanism that is separate from the CFTR regulatory signaling pathway. Both murine tracheal and nasal tissues exhibit sensitivity to amiloride-sensitive sodium regulation by exogenously added CNP. CNP depolarized the nasal transepithelial potential difference by 6.3 +/- 0.5 mV, whereas the cGMP-inhibited phosphodiesterase inhibitor milrinone actually hyperpolarized the nasal transepithelial potential difference by 2.0 +/- 1.2 mV in mice homozygous for a CFTR stop mutation [CFTR(-/-)]. Inhibition of guanylate cyclase activity and PKG activity in normal mice resulted in an increase in amiloride-sensitive sodium absorption, suggesting that tonic regulation of amiloride-sensitive sodium absorption is in part due to basal cGMP levels and PKG activity.
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PMID:Regulation of amiloride-sensitive sodium absorption in murine airway epithelium by C-type natriuretic peptide. 960 38

The effects of sodium nitroprusside (SNP) on Ca2+-dependent K+ (KCa) channels in cultured bovine adrenal chromaffin cells were investigated using single channel recording patch-clamp techniques. KCa channels were activated by application of 100 microM SNP to the extracellular side of cell-attached patches. Methylene blue (300 microM), an inhibitor of soluble guanylate cyclase, or H-8 (1 microM), a protein kinase inhibitor with relative specificity for cGMP-dependent protein kinase, diminished but did not completely abolish the SNP-induced KCa channel activation. Diethylamine/NO complex (DEA/NO), an NO donor, also activated KCa channels in cell-attached patches. Furthermore, application of 100 microM SNP or 100 nM DEA/NO to the intracellular surface of excised inside-out patches also activated KCa channels in the bath solution which contained 1 microM Ca2+. These results indicate that SNP is capable of activating the KCa channel via cGMP-dependent and -independent mechanisms. These studies demonstrate that NO may serve as an important regulatory mechanism for catecholamine secretion in chromaffin cells via the activation of KCa channels.
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PMID:Nitric oxide activates Ca2+-activated K+ channels in cultured bovine adrenal chromaffin cells. 965 59

Azide, in the absence of other stimuli, enhanced neutrophil migration in a chemotactic way. The effect of azide on migration was significant at concentrations > or = 1 microM and maximal at 10 microM azide. Although azide itself could not induce exocytosis, at concentrations > or = 10 microM azide enhanced exocytosis induced by a combination of the chemotactic peptide f-methionyl-leucyl-phenylalanine (fMLP) and cytochalasin B (CB). Azide can be oxidized by catalase and myeloperoxidase in the presence of H2O2, resulting in the generation of nitric oxide (NO). Formation of NO from azide was detected by ESR spectroscopy with carboxy-PTIO as a NO-selective probe, and by measurement of nitrite formation. Azide-induced migration, and the enhancement by azide of fMLP/CB-induced exocytosis, were blocked by pre-incubating cells with aminotriazole, an inhibitor of catalase and myeloperoxidase, suggesting that the effect of azide was mediated by NO. Azide-induced migration, but not the enhancement by azide of fMLP/CB-induced exocytosis, was inhibited to a large extent by inhibitors of soluble guanylate cyclase and by inhibitors of cGMP-dependent protein kinase. These observations suggest that azide-induced migration is mediated via cGMP and cGMP-dependent protein kinase, while the enhancement of fMLP/CB-induced exocytosis is not. Azide caused a sustained elevation of the intracellular Ca2+-concentration of neutrophils stimulated with fMLP/CB, which was not affected by inhibitors of the cGMP-signalling cascade. Since neutrophil exocytosis has been shown to be closely correlated with increases in intracellular Ca2+, a further increase by azide of the intracellular Ca2+-level of cells stimulated with fMLP/CB provides a likely mechanism for the enhancement of fMLP/CB-induced exocytosis by azide.
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PMID:Sodium azide enhances neutrophil migration and exocytosis: involvement of nitric oxide, cyclic GMP and calcium. 971 94

The present study examined the contribution of elevations in cGMP versus inhibition of cytochrome P-4504A enzymes and the production of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) to the vasodilator actions of NO in renal arterioles. The NO donor sodium nitroprusside (SNP) at 10(-5), 10(-4), and 10(-3) M reduced the production of 20-HETE in microsomes prepared from renal arterioles to 80 +/- 2, 43 +/- 5, and 7 +/- 1% of control, respectively (n = 4). In other experiments, the vasodilator response to SNP (10(-7) to 10(-3) M) was examined in rat renal interlobular arteries (<90 micron ID), preconstricted with phenylephrine (1 microM) under control conditions and after blockade of the cGMP and P-4504A pathways. Inhibition of guanylyl cyclase with 1H-[1,2, 4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (10 microM, n = 6) or of cGMP-dependent protein kinase with 8R,9S, 11S-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8, 11-epoxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cycloocta-(c, d, e)-trinden-1-one (KT-5823, 1 microM; n = 5) attenuated the vasodilator response to SNP by 26 and 30%, respectively. In contrast, inhibition of the endogenous production of 20-HETE with a suicide substrate, irreversible inhibitor [17-octadecynoic acid (17-ODYA), 1 microM, n = 5], or a selective, competitive inhibitor of 20-HETE formation (dibromo-dodecenyl-methylsulfimide, 25 microM, n = 5) markedly impaired the vasodilator response to SNP by 76 and 78%, respectively. Similarly, when 20-HETE levels were fixed at 100 nM (n = 6), the response to SNP was attenuated by 73%. Blockade of both pathways with ODQ and 17-ODYA completely abolished the response to SNP (n = 6). These results indicate that the vasodilator response to NO is largely cGMP independent and that inhibition of 20-HETE formation contributes to the cGMP-independent effects of NO in the renal microcirculation.
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PMID:Contribution of 20-HETE to the vasodilator actions of nitric oxide in renal arteries. 972 9

We previously described the isolation of a variant subline of HL-60 cells that does not differentiate in response to nitric oxide (NO)-generating agents or to cGMP analogs. The variant cells have normal guanylate cyclase activity and normal NO-induced increases in the intracellular cGMP concentration. We now show that the variant cells have normal cGMP-dependent protein kinase (G-kinase) activity, both by an in vitro and in vivo assay, and using two-dimensional gel electrophoresis we have identified six G-kinase substrates in the parental cells. Of these six proteins, we found considerably less phosphorylation of one of the proteins in the variant cells than in parental cells, both in vitro and in intact cells, and by 35S-methionine/35S-cysteine incorporation we found much less of this protein in the variant cells than in parental cells. The protein is a shared substrate of cAMP-dependent protein kinase (A-kinase); since cAMP analogs still induce differentiation of the variant cells, it appears that the NO/cGMP/G-kinase and cAMP/A-kinase signal transduction pathways share some but not all of the same target proteins in inducing differentiation of HL-60 cells.
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PMID:Decreased phosphorylation of a low molecular weight protein by cGMP-dependent protein kinase in variant HL-60 cells resistant to nitric oxide- and cGMP-induced differentiation. 974 17


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