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)

Exposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic guanosine-3',-5'-monophosphate (cyclic GMP). We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3mg/h for 5 days). Myocyte function was determined at baseline, after C-type natriuretic peptide (CNP, 10(-8) and 10(-7)M) or brain natriuretic peptide (BNP, 10(-8) and 10(-7)M) or S-nitroso-N-acetyl-penicilliamine (SNAP, a NO donor, 10(-6) and 10(-5)M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10(-6)M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10(-8)M (5.14+/-0.5%) and 10(-7)M (4.4+/-0.7%) significantly reduced percentage shortening from baseline (6.1+/-1.6%). KT5823 restored percentage shortening to 4.9+/-0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.
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PMID:Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes. 1748 33

We have recently demonstrated that nitric oxide (NO) produced by neuronal NO synthase (nNOS) in the spinal cord is involved in the maintenance of neuropathic pain. To clarify whether NO itself affected nNOS activity in the spinal cord as a retrograde messenger, we examined the involvement of the NO/cGMP signaling pathway in the regulation of nNOS activity by NADPH-diaphorase histochemistry. NO-generating agents NOR3 (t(1/2)=30min) and SNAP (t(1/2)=5h), but not NOR1 (t(1/2)=1.8min), significantly enhanced NADPH-diaphorase staining in the spinal cord. 8-Br-cGMP also enhanced it similar to that by NOR3, and 8-Br-cAMP and forskolin, an activator of adenylate cyclase, enhanced it moderately. NOR1 and NOR3 markedly increased the cGMP level in the spinal cord. The enhancement of NADPH-diaphorase staining by NOR3 was significantly inhibited by CPTIO, an NO scavenger, ODQ, a soluble guanylate cyclase inhibitor, and KT5823, an inhibitor of cGMP-dependent protein kinase. Additionally, the NOR3-enhanced nNOS activity was completely inhibited by NMDA antagonists MK-801 and d-AP5, partially by the GluRepsilon2-selective antagonist CP-101,606, and was attenuated in GluRepsilon1(-/-) and GluRepsilon1(-/-)/epsilon4(-/-) mice. These results suggest that NO may regulate nNOS activity as a retrograde messenger in the spinal cord via activation of NMDA receptor containing GluRepsilon1 and GluRepsilon2 subunits.
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PMID:Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors. 1754 18

Nitric oxide (NO) and 5'-AMP-activated protein kinase (AMPK) are involved in glucose transport and mitochondrial biogenesis in skeletal muscle. Here, we examined whether NO regulates the expression of the major glucose transporter in muscle (GLUT4) and whether it influences AMPK-induced upregulation of GLUT4. At low levels, the NO donor S-nitroso-N-penicillamine (SNAP, 1 and 10 microM) significantly increased GLUT4 mRNA ( approximately 3-fold; P < 0.05) in L6 myotubes, and cotreatment with the AMPK inhibitor compound C ablated this effect. The cGMP analog 8-bromo-cGMP (8-Br-cGMP, 2 mM) increased GLUT4 mRNA by approximately 50% (P < 0.05). GLUT4 protein expression was elevated 40% by 2 days treatment with 8-Br-cGMP, whereas 6 days treatment with 10 microM SNAP increased GLUT4 expression by 65%. Cotreatment of cultures with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one prevented the SNAP-induced increase in GLUT4 protein. SNAP (10 microM) also induced significant phosphorylation of alpha-AMPK and acetyl-CoA carboxylase and translocation of phosphorylated alpha-AMPK to the nucleus. Furthermore, L6 myotubes exposed to 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) for 16 h presented an approximately ninefold increase in GLUT4 mRNA, whereas cotreatment with the non-isoform-specific NOS inhibitor N(G)-nitro-l-arginine methyl ester, prevented approximately 70% of this effect. In vivo, GLUT4 mRNA was increased 1.8-fold in the rat plantaris muscle 12 h after AICAR injection, and this induction was reduced by approximately 50% in animals cotreated with the neuronal and inducible nitric oxide synthases selective inhibitor 1-(2-trifluoromethyl-phenyl)-imidazole. We conclude that, in skeletal muscle, NO increases GLUT4 expression via a cGMP- and AMPK-dependent mechanism. The data are consistent with a role for NO in the regulation of AMPK, possibly via control of cellular activity of AMPK kinases and/or AMPK phosphatases.
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PMID:Nitric oxide increases GLUT4 expression and regulates AMPK signaling in skeletal muscle. 1766 90

We investigated the role of nitric oxide (NO) in pacemaker activity and signal mechanisms in cultured interstitial cells of Cajal (ICC) of the mouse small intestine using whole cell patch-clamp techniques at 30 degrees C. ICC generated pacemaker potential in the current clamp mode and pacemaker currents at a holding potential of -70 mV. (+/-)-S-nitroso-N-acetylpenicillamine (SNAP; a NO donor) produced membrane hyperpolarization and inhibited the amplitude and frequency of the pacemaker currents, and increased resting currents in the outward direction. These effects were blocked by the use of glibenclamide (an ATP-sensitive K+ channel blocker), but not by the use of 5-hydroxydecanoic acid (a mitochondrial ATP-sensitive K+ channel blocker). Pretreatment with ODQ (a guanylate cyclase inhibitor) almost blocked the NO-induced effects. The use of cell-permeable 8-bromo-cyclic GMP also mimicked the action of SNAP. However, the use of KT-5823 (a protein kinase G inhibitor) did not block the NO-induced effects. Spontaneous [Ca2+]i oscillations in ICC were inhibited by the treatment of SNAP, as seen in recordings of intracellular Ca2+ ([Ca2+]i). These results suggest that NO inhibits pacemaker activity by the activation of ATP-sensitive K+ channels via a cyclic GMP dependent mechanism in ICC, and the activation of ATP-sensitive K+ channels mediates the inhibition of spontaneous [Ca2+]i oscillations.
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PMID:Inhibition of pacemaker currents by nitric oxide via activation of ATP-sensitive K+ channels in cultured interstitial cells of Cajal from the mouse small intestine. 1793 55

The role of nitric oxide (NO) in cardiac contractility is complex and controversial. Several NO donors have been reported to cause positive or negative inotropism. NO can bind to guanylate cyclase, increasing cGMP production and activating PKG. NO may also directly S-nitrosylate cysteine residues of specific proteins. We used the isolated rat heart preparation to test the hypothesis that the differential inotropic effects depend on the degree of NO production and the signaling recruited. SNAP (S-nitroso-N-acetylpenicillamine), a NO donor, increased contractility at 0.1, 1 and 10 microM. This effect was independent of phospholamban phosphorylation, was not affected by PKA inhibition with H-89 (N-[2((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide), but it was abolished by the radical scavenger Tempol (4-hydroxy-[2,2,4,4]-tetramethyl-piperidine-1-oxyl). However, at 100 microM SNAP reduced contractility, effect reversed to positive inotropism by guanylyl cyclase blockade with ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), and abolished by PKG inhibition with KT5823, but not affected by Tempol. SNAP increased tissue cGMP at 100 microM, but not at lower concentrations. Consistently, a cGMP analog also reduced cardiac contractility. Finally, SNAP at 1 microM increased the level of S-nitrosylation of various cardiac proteins, including the ryanodine receptor. This study demonstrates the biphasic role for NO in cardiac contractility in a given preparation; furthermore, the differential effect is clearly ascribed to the signaling pathways involved. We conclude that although NO is highly diffusible, its output determines the fate of the messenger: low NO concentrations activate redox processes (S-nitrosylation), increasing contractility; while the cGMP-PKG pathway is activated at high NO concentrations, reducing contractility.
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PMID:Differential role of S-nitrosylation and the NO-cGMP-PKG pathway in cardiac contractility. 1802 73

In locusts, a central pattern generator underlies the rhythmic movements of the ovipositor valves that serve to drive the abdomen into damp soil in order to lay eggs. We have investigated the role of nitric oxide (NO) in the control of this oviposition digging rhythm. NO increases the frequency of the rhythm by acting via sGC to elevate cGMP, which in turn acts via PKG. Increasing exogenous NO levels using the NO donors SNAP and PAPANONOate increased the cycle frequency of the fictive digging rhythm, as did increasing endogenous NO by bath application of the substrate for NOS, l-arginine. On the other hand, application of the NO scavenger PTIO decreased the cycle frequency, indicating that NO must normally exert a continuous and dynamic role on the central pattern generator underlying the oviposition rhythm. Inhibiting the main molecular target of NO, soluble guanylate cyclase, with ODQ reduced the cycle frequency of the rhythm, suggesting that NO mediated its effects via sGC and cyclic GMP. Further evidence for this was produced by bath application of 8-Br-cGMP, which increased the frequency of the rhythm. Bath application of the generic protein kinase inhibitor and a selective PKG inhibitor, H-7 and KT-5823, respectively, reduced the frequency of the rhythm, suggesting that PKG acted as a target for cGMP. Thus, we conclude that NO plays a key role in regulating the frequency of the central pattern generator controlling rhythmic egg-laying movements in locusts by acting via sGC/cGMP-PKG.
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PMID:Nitrergic modulation of an oviposition digging rhythm in locusts. 1805 33

South American (SA) opossum lower esophageal sphincter (LES) circular smooth muscle relaxes by activation of enteric nerves elicited by EFS (electrical field stimulation, 0.5 ms, 48 V, 0.5-8 Hz for 10 s). The identity of the mediator released and the cellular mechanism, however, remain to be fully elucidated. The purpose of this study was to determine the effect of the enzyme soluble guanylate cyclase (cGC) inhibitors, cystamine (100 microM), methylene blue (30 microM), LY 83583 (6-anilino-5,8 quinoledione, 10 microM) and ODQ (H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one, 1 microM) on the relaxations induced by EFS and by exogenous NO (nitric oxide, 0.5 mM) or NO-donors on SA opossum LES smooth muscle strips. EFS caused frequency-dependent relaxations, which were inhibited by NO-synthase inhibitors and abolished by tetrodotoxin. Cystamine did not affect relaxations caused by EFS and NO or NO-donor. Methylene blue also failed to affect EFS-caused relaxations, although it was capable of inhibiting relaxation induced by NO. LY 83583 inhibited relaxations induced by NO, but did not affect those induced by EFS or by SNAP and HXA. ODQ abolished relaxations caused by EFS at lower frequencies and by HXA (hydroxylamine, 10 microM) and SNAP (S-nitroso-N-acetyl penicillamine, 10 microM). Relaxations at higher frequencies of EFS and induced by SNP (sodium nitroprusside, 30 microM) and NO were only reduced by ODQ. These findings indicate that activation of the cGC can be involved in relaxations induced by EFS at lower frequencies, but other mechanisms can be involved at higher frequencies of EFS and caused by SNP or NO.
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PMID:The effect of guanylate cyclase inhibitors on non-adrenergic and non-cholinergic neurogenic relaxations of the South American opossum lower esophageal sphincter. 1848 48

Organotypic cerebellar cultures were maintained on multi-electrode dishes (MED) with an 8x8 array of electrodes and examined for physiological activity. The cultures remained viable for up to seven months and exhibited spontaneous discharges most likely originating from Purkinje cells. Spike frequencies varied but were mostly around 10-30 Hz and were often stable over weeks with average drifts of <20% per week. Spontaneous firing was significantly reduced by blockers of sodium channels (riluzole) and several potassium channels (iberiotoxin, TEA, 4-amino-pyridine), but blockers of calcium channels, GIRK channels, and SK-type potassium channels were ineffective. Inhibitors of excitatory and inhibitory synaptic transmission made spike discharges more regular. Particularly robust changes in spike frequency were produced by agents that increase cGMP. Bromo-cGMP, the NO donor SNAP, the guanylate cyclase activator YC-1, and the phosphodiesterase inhibitor zaprinast greatly reduced spike frequency. Activation of the metabotropic receptor mGluR1 and inhibition of I(h) channels caused a majority of cells to switch from tonic firing to a cyclic activity mode in which intense firing alternated with silence. Agonists for cholinergic, serotonergic, histamine, opiate, and CRF receptors had no effect, but those for adrenergic and adenosine A1 receptors reduced firing. Moreover, brief application of bromocriptine caused a delayed decrease in firing that reached a minimum after 24 to 48 h and recovered after 1-2 weeks. Taken together, our results demonstrate that long-term cultures maintained on multi-electrode arrays retain many essential features of cerebellar physiology and that they provide a test system that is well suited for broad screening of pharmacological agents as well as for studying long-term effects of drugs, tissue factors, and pathogens.
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PMID:Spontaneous activity in Purkinje cells: multi-electrode recording from organotypic cerebellar slice cultures. 1853 33

The dorsal lateral geniculate nucleus (dLGN) not only serves as the obligatory pathway for visual information transfer from the retina to neocortex but can also generate intrathalamic rhythmic activities associated with different arousal states and certain pathological conditions. The gating activity of thalamocortical circuits is under neuromodulatory control by various brainstem nuclei as well as intrinsic thalamic neurons (e.g. thalamic reticular nucleus (TRN) neurons and dLGN interneurons). In this study, we examined the effect of the putative neuromodulator nitric oxide (NO) on thalamic neuron excitability. There are multiple potential sources of NO in thalamus: cholinergic terminals originating from brainstem nuclei, GABAergic TRN neurons, and local GABAergic interneurons. Using whole cell recording techniques in in vitro thalamic slices, we found that the NO donor SNAP produced a robust, long-lasting depolarization in TRN neurons, a weaker depolarization in thalamocortical relay neurons, and no effect in local interneurons. SNAP preferentially depolarized stereotypical TRN neurons that could produced strong burst discharge. In contrast, SNAP had little effect on atypical burst and non-burst TRN cells. The NO donor SIN-1 and the endogenous NO precursor, L-arginine, mimicked the SNAP-mediated actions. The NO-mediated depolarizations were blocked by the guanylyl cyclase inhibitor ODQ indicating involvement of the cGMP pathway. In addition, the phosphodiesterase (PDE) inhibitor zaprinast depolarized and occluded the NO-mediated depolarization in TRN neurons. At the circuit level, NO activation significantly attenuated intrathalamic rhythmic activities likely resulting from the shifting of the firing mode of thalamic neurons, perhaps both TRN and thalamocortical neurons, from burst- to tonic-discharge mode. These alterations in thalamic neuron excitability not only change rhythmic circuit activity, but could also influence sensory information processing through thalamocortical circuits.
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PMID:Excitatory and anti-oscillatory actions of nitric oxide in thalamus. 1853 92

We investigated the inhibitory role of the nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway on receptor-activated TRPC6 channels in both a heterologous expression system (HEK293 cells) and A7r5 vascular myocytes. Cationic currents due to TRPC6 expression were strongly suppressed (by approximately 70%) by a NO donor SNAP (100 microm) whether it was applied prior to muscarinic receptor stimulation with carbachol (CCh; 100 microm) or after G-protein activation with intracellular perfusion of GTPgammaS (100 microm). A similar extent of suppression was also observed with a membrane-permeable analogue of cGMP, 8Br-cGMP (100 microm). The inhibitory effects of SNAP and 8Br-cGMP on TRPC6 channel currents were strongly attenuated by the presence of inhibitors for guanylyl cyclase and PKG such as ODQ, KT5823 and DT3. Alanine substitution for the PKG phosphorylation candidate site at T69 but not at other sites (T14A, S28A, T193A, S321A) of TRPC6 similarly attenuated the inhibitory effects of SNAP and 8Br-cGMP. SNAP also significantly reduced single TRPC6 channel activity recorded in the inside-out configuration in a PKG-dependent manner. SNAP-induced PKG activation stimulated the incorporation of (32)P into wild-type and S321A-mutant TRPC6 proteins immunoprecipitated by TRPC6-specific antibody, but this was greatly attenuated in the T69A mutant. SNAP or 8Br-cGMP strongly suppressed TRPC6-like cation currents and membrane depolarization evoked by Arg(8)-vasopressin in A7r5 myocytes. These results strongly suggest that TRPC6 channels can be negatively regulated by the NO-cGMP-PKG pathway, probably via T69 phosphorylation of the N-terminal. This mechanism may be physiologically important in vascular tissues where NO is constantly released from vascular endothelial cells or nitrergic nerves.
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PMID:Nitric oxide-cGMP-protein kinase G pathway negatively regulates vascular transient receptor potential channel TRPC6. 1861 65


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