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 endothelial-derived relaxing factor, nitric oxide (NO.) has been shown to depress force in smooth and cardiac muscles through the activation of guanylyl cyclase and an increase in cGMP. In fast skeletal muscle, NO (i.e. NO-related compounds) elicits a modest decrease in developed force, but in contracting muscles NO increases force by a mechanism independent of cGMP. We now demonstrate an alternative mechanism whereby NO triggers Ca2+ release from skeletal and cardiac sarcoplasmic reticulum (SR). NO delivered in the form of NO gas, NONOates (a class of sulfur-free compounds capable of releasing NO), or S-nitrosothiols (R-SNO) oxidized or transnitrosylated regulatory thiols on the release channel (or ryanodine receptor, RyR), resulting in channel opening and Ca2+ release from skeletal and cardiac SR. The process was reversed by sulfhydryl reducing agents which promoted channel closure and Ca2+ reuptake by ATP-driven Ca2+ pumps. NO did not directly alter Ca(2+)-ATPase activity but increased the open probability of RyRs reconstituted in planar bilayers and inhibited [3H]-ryanodine binding to RyRs. The formation of peroxynitrite or thiyl radicals did not account for the reversible R-SNO-dependent activation of RyRs. Ca2+ release induced by nitric oxide free radicals (NO.) was potentiated by cysteine providing compelling evidence that NO. in the presence of O2 formed nitrosylated cysteine followed by the transnitrosation of regulatory thiols on the RyR to activate the channel. These findings demonstrate direct interactions of NO derivatives with RyRs and a new fundamental mechanism to regulate force in striated muscle.
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PMID:Nitric oxide activates skeletal and cardiac ryanodine receptors. 905 74

The present study was designed to investigate whether nitric oxide (NO) could interfere with intracellular Ca++ release through different pathways in vascular smooth muscle. Phasic contractions of rat aorta induced by phenylephrine or caffeine in Ca++-free solution were used as an indicator of intracellular Ca++ release through the inositol 1,4,5-triphosphate receptor pathway and the ryanodine receptor pathway, respectively. In addition, cytoplasmic Ca++ concentration ([Ca++]i) in vascular smooth muscle cells was determined by fluorescence measurement. Acetylcholine (ACh) inhibited the phenylephrine-evoked phasic contractions in Ca++-free solution in endothelium-intact but not -denuded aortic rings in a dose-dependent manner. However, ACh did not affect the action of caffeine. The inhibition by ACh was blocked completely by the NO synthase inhibitor Nomega-nitro-L-arginine, which could be reversed totally by L-arginine but not D-arginine. Methylene blue, a soluble guanylate cyclase inhibitor, also abolished the inhibition by ACh. Sodium nitroprusside, an NO donor, attenuated the phenylephrine- but not caffeine-induced phasic contractions in denuded aortic rings in Ca++-free solution. The effect of sodium nitroprusside was reversed substantially by methylene blue. Furthermore, sodium nitroprusside inhibited the elevation of [Ca++]i induced by phenylephrine in vascular smooth muscle cells isolated from rat aorta in the absence of extracellular Ca++, which could be abolished significantly by methylene blue. These results suggest that NO selectively inhibits intracellular Ca++ release stimulated by inositol 1,4,5-triphosphate, but not caffeine in vascular smooth muscle.
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PMID:Nitric oxide selectively inhibits intracellular Ca++ release elicited by inositol trisphosphate but not caffeine in rat vascular smooth muscle. 953 89

In this study, we highlight a role for the nitric oxide-cGMP-dependent protein kinase (NO-G-kinase) signaling pathway in glial intercellular Ca(2+) wave initiation and propagation. Addition of the NO donor molsidomine (100-500 microM) or puffing aqueous NO onto primary glial cell cultures evoked an increase in [Ca(2+)](i) in individual cells and also local intercellular Ca(2+) waves, which persisted after removal of extracellular Ca(2+). High concentrations of ryanodine (100-200 microM) and antagonists of the NO-G-kinase signaling pathway essentially abrogated the NO-induced increase in [Ca(2+)](i), indicating that NO mobilizes Ca(2+) from a ryanodine receptor-linked store, via the NO-G-kinase signaling pathway. Addition of 10 microM nicardipine to cells resulted in a slowing of the molsidomine-induced rise in [Ca(2+)](i), and inhibition of Mn(2+) quench of cytosolic fura-2 fluorescence mediated by a bolus application of 2 microM aqueous NO to cells, indicating that NO also induces Ca(2+) influx in glia. Mechanical stress of individual glial cells resulted in an increase in intracellular NO in target and neighboring cells and intercellular Ca(2+) waves, which were NO, cGMP, and G-kinase dependent, because incubating cells with nitric oxide synthase, guanylate cyclase, and G-kinase inhibitors, or NO scavengers, reduced Delta[Ca(2+)](i) and the rate of Ca(2+) wave propagation in these cultures. Results from this study suggest that NO-G-kinase signaling is coupled to Ca(2+) mobilization and influx in glial cells and that this pathway plays a fundamental role in the generation and propagation of intercellular Ca(2+) waves in glia.
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PMID:A fundamental role for the nitric oxide-G-kinase signaling pathway in mediating intercellular Ca(2+) waves in glia. 1068 78

Nitric oxide is a ubiquitous cell-signaling molecule involved in regulation of numerous homeostatic mechanisms and in mediation of tissue injury. Nitric oxide influences contraction, blood flow, and metabolism, as well as myogenesis. Nitric oxide exerts its influence by activation of guanylate cyclase and nitrosylation of proteins, which include glyceraldehyde-3-phosphate dehydrogenase, the ryanodine receptor and actomyosin ATPase. Skeletal muscle expresses all three isoforms of the nitric oxide synthase, including a muscle-specific splice variant; expression of the isoforms is fiber-type specific and influenced by age and disease. Nitric oxide produced with certain systemic conditions and local inflammation is likely toxic to skeletal muscle, either directly or in reactions with oxygen-derived radicals. Although nitric oxide impacts on many functions in muscle, its effects are subtle, and much work remains to be done to determine its importance in the pathogenesis of muscle diseases.
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PMID:Nitric oxide: biologic effects on muscle and role in muscle diseases. 1152 79

The present study was designed to determine whether nitric oxide (NO)-induced reduction of [Ca(2+)](i) is associated with Ca(2+)-induced Ca(2+) release (CICR) in coronary arterial smooth muscle cells (CASMCs). Caffeine was used as a CICR activator to induce Ca(2+) release in these cells. The effects of NO donor, sodium nitroprusside (SNP), on caffeine-induced Ca(2+) release were examined in freshly dissociated bovine CASMCs using single cell fluorescence microscopic spectrometry. The effects of NO donor on caffeine-induced coronary vasoconstriction were examined by isometric tension recordings. Caffeine, a CICR or ryanodine receptor (RYR) activator, produced a rapid Ca(2+) release with a 330 nM increase in [Ca(2+)](i). Pretreatment of the CASMCs with SNP, CICR inhibitor tetracaine or RYR blocker ryanodine markedly decreased caffeine-induced Ca(2+) release. Addition of caffeine to the Ca(2+)-free bath solution produced a transient coronary vasoconstriction. SNP, tetracaine and ryanodine, but not guanylyl cyclase inhibitor, ODQ, significantly attenuated caffeine-induced vasoconstriction. These results suggest that CICR is functioning in CASMCs and participates in the vasoconstriction in response to caffeine-induced Ca(2+) release and that inhibition of CICR is of importance in mediating the vasodilator response of coronary arteries to NO.
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PMID:Effect of nitric oxide on calcium-induced calcium release in coronary arterial smooth muscle. 1167 4

Transient increases, or oscillations, of cytoplasmic free Ca(2+) concentration, [Ca(2+)](i), occur during fertilization of animal egg cells. In sea urchin eggs, the increased Ca(2+) is derived from intracellular stores, but the principal signaling and release system involved has not yet been agreed upon. Possible candidates are the inositol 1,4,5-trisphosphate receptor/channel (IP(3)R) and the ryanodine receptor/channel (RyR) which is activated by cGMP or cyclic ADP-ribose (cADPR). Thus, it seemed that direct measurements of the likely second messenger candidates during sea urchin fertilization would be essential to an understanding of the Ca(2+) signaling pathway. We therefore measured the cGMP, cADPR and inositol 1,4,5-trisphosphate (IP(3)) contents of sea urchin eggs during the early stages of fertilization and compared these with the [Ca(2+)](i) rise in the presence or absence of an inhibitor against soluble guanylate cyclase. We obtained three major experimental results: (1) cytosolic cGMP levels began to rise first, followed by cADPR and IP(3) levels, all almost doubling before the explosive increase of [Ca(2+)](i); (2) most of the rise in IP(3) occurred after the Ca(2+) peak; IP(3) production could also be induced by the artificial elevation of [Ca(2+)](i), suggesting the large increase in IP(3) is a consequence, rather than a cause, of the Ca(2+) transient; (3) the measured increase in cGMP was produced by the soluble guanylate cyclase of eggs, and inhibition of soluble guanylate cyclase of eggs diminished the production of both cADPR and IP(3) and the [Ca(2+)](i) increase without the delay of Ca(2+) transients. Taken together, these results suggest that the RyR pathway involving cGMP and cADPR is not solely responsible for the initiating event, but contributes to the Ca(2+) transients by stimulating IP(3) production during fertilization of sea urchin eggs.
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PMID:Increase of cGMP, cADP-ribose and inositol 1,4,5-trisphosphate preceding Ca(2+) transients in fertilization of sea urchin eggs. 1171 67

The synthesis of the free radical gas nitric oxide (NO) is catalyzed by the enzyme NO synthase (NOS). NOS converts arginine and molecular oxygen to NO and citrulline in a reaction that requires NADPH, FAD, FMN, and tetrahydrobiopterin as cofactors. Three types of NOS have been identified by molecular cloning. The activity of the constitutively expressed neuronal NOS (nNOS) and endothelial NOS (eNOS) is Ca(2+)/calmodulin-dependent, whereas that the inducible NOS (iNOS) is Ca(2+)-insensitive. The predominant NOS isoform in skeletal muscle is nNOS. It is present at the sarcolemma of both extra- and intrafusal muscle fibers. An accentuated accumulation of nNOS is found in the endplate area. This strict sarcolemmal localization of nNOS is due its association with the dystrophin-glycoprotein complex, which is mediated by the syntrophins. The activity of nNOS in skeletal muscle is regulated by developmental, myogenic, and neurogenic influences. NO exerts several distinct effects on various aspects of skeletal muscle function, such as excitation-contraction coupling, mitochondrial energy production, glucose metabolism, and autoregulation of blood flow. Inside the striated muscle fibers, NO interacts directly with several classes of proteins, such as soluble guanylate cyclase, ryanodine receptor, sarcoplasmic reticulum Ca(2+)-ATPase, glyceraldehyde-3-phosphate dehydrogenase, and mitochondrial respiratory chain complexes, as well as radical oxygen species. In addition, NO produced and released by contracting muscle fibers diffuses to nearby arterioles where it acts to inhibit reflex sympathetic vasoconstriction.
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PMID:NO message from muscle. 1174 89

1. We previously demonstrated that a balance of Ca2+-activated Cl- current (ICl(Ca)) and K+ current activity sets the resting membrane potential of opossum lower esophageal sphincter (LES) circular smooth muscle at approximately -41 mV, which leads to continuous spike-like action potentials and the generation of basal tone. Ionic mechanisms underlying this basal ICl(Ca) activity and its nitrergic regulation remain unclear. Recent studies suggest that spontaneous Ca2+ release from sarcoplasmic reticulum (SR) and myosin light chain kinase (MLCK) play important roles. The current study investigated this possibility. Conventional intracellular recordings were performed on circular smooth muscle of opossum LES. Nerve responses were evoked by electrical square wave pulses of 0.5 ms duration at 20 Hz. 2. In the presence of nifedipine (1 microm), substance P (1 microm), atropine (3 microm) and guanethidine (3 microm), intracellular recordings demonstrated a resting membrane potential (MP) of -38.1+/-0.7 mV (n=25) with spontaneous membrane potential fluctuations (MPfs) of 1-3 mV. Four pulses of nerve stimulation induced slow inhibitory junction potentials (sIJPs) with an amplitude of 6.1+/-0.3 mV and a half-amplitude duration of 1926+/-147 ms (n=25). 3. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific guanylyl cyclase inhibitor, abolished sIJPs, but had no effects on MPfs. Caffeine, a ryanodine receptor agonist, hyperpolarized MP and abolished sIJPs and MPfs. Ryanodine (20 microm) inhibited the sIJP and induced biphasic effects on MP, an initial small hyperpolarization followed by a large depolarization. sIJPs and MPfs were also inhibited by cyclopiazonic acid, an SR Ca2+ ATPase inhibitor. Specific ICl(Ca) and MLCK inhibitors hyperpolarized the MP and inhibited MPfs and sIJPs. 4. These data suggest that (1). spontaneous release of Ca2+ from the SR activates ICl(Ca), which in turn contributes to resting membrane potential; (2). MLCK is involved in activation of ICl(Ca); (3). inhibition of ICl(Ca) is likely to underlie sIJPs induced by nitrergic innervation.
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PMID:Role of sarcoplasmic reticulum in control of membrane potential and nitrergic response in opossum lower esophageal sphincter. 1453 Feb 11

Nitric oxide (NO) has been well established as a molecule necessary for memory consolidation. Interestingly, the majority of research has focused on only a single mechanism through which NO acts, namely the up-regulation of guanylate cyclase (GC). However, since NO and NO-derived reactive nitrogen species are capable of interacting with a broad array of enzymes, ion channels and receptors, a singular focus on GC appears short-sighted. Although NO inhibits the action of a number of molecules there are four, in addition to GC, which are up-regulated by the direct presence of NO, or NO-derived radicals, and implicated in memory processing. They are: cyclic nucleotide-gated channels; large conductance calcium-activated potassium channels; ryanodine receptor calcium release (RyR) channels; and the enzyme mono(ADP-ribosyl) transferase. This review presents evidence that not only are these four molecules worthy of investigation as GC-independent mechanisms through which NO may act, but that behavioural evidence already exists suggesting a relationship between NO and the RyR channel.
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PMID:New perspectives on the mechanisms through which nitric oxide may affect learning and memory processes. 1718 48

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


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