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)

NO synthase (NOS; EC 1.14.23) catalyzes the conversion of L-arginine into L-citrulline and a guanylyl cyclase-activating factor (GAF) that is chemically identical with nitric oxide or a nitric oxide-releasing compound (NO). Similar to the other isozymes of NOS that have been characterized to date, the soluble and Ca2+/calmodulin-regulated type I from rat cerebellum (homodimer of 160-kDa subunits) is dependent on NADPH for catalytic activity. The enzyme also possesses NADPH diaphorase activity in the presence of the electron acceptor nitroblue tetrazolium (NBT). We investigated the requirements of NOS and its content of the proposed additional cofactors tetrahydrobiopterin (H4biopterin) and flavins, further characterized the NADPH diaphorase activity, and quantified the NADPH binding site(s). Purified NOS type I Ca2+/calmodulin-independently bound the [32P]2',3'-dialdehyde analogue of NADPH (dNADPH), which, at near Km concentrations during 3-min incubations was utilized as a substrate and at higher concentrations or after prolonged incubations and cross-linking inhibited NOS activity. The NADPH diaphorase activity was Ca2+/calmodulin-independent, required higher NADPH concentrations than NOS activity, and was affected by dNADPH to a lesser degree. Divalent cations interfered with the diaphorase assay. Per dimer, native NOS contained about 1 mol each of H4biopterin, FAD, and FMN, classifying it as a biopteroflavoprotein, and incorporated 1 mol of dNADPH. No dihydrobiopterin (H2biopterin), biopterin, or riboflavin was detected. These findings suggest that NOS may share cofactors between two identical subunits via high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+/calmodulin-dependent NO synthase type I: a biopteroflavoprotein with Ca2+/calmodulin-independent diaphorase and reductase activities. 137 27

Although nitric oxide (NO) appears to be one of the oxidation products of L-arginine catalyzed by NO synthase (NOS; EC 1.14.13.39), past studies on the measurement of NO in cell-free enzymatic assays have not been based on the direct detection of the free NO molecule. Instead, assays have relied on indirect measurements of the stable NO oxidation products nitrite and nitrate and on indirect actions of NO such as guanylate cyclase activation and oxyhemoglobin oxidation. Utilizing a specific chemiluminescence assay, we report here that the gaseous product of L-arginine oxidation, catalyzed by both inducible macrophage and constitutive neuronal NOS, is indistinguishable from authentic NO on the basis of their physicochemical properties. NO gas formation by NOS was dependent on L-arginine, NADPH, and oxygen and inhibited by NG-methyl-L-arginine and cyanide anion. Superoxide dismutase (SOD) caused a marked, concentration-dependent increase in the production of free NO by mechanisms that were unrelated to the dismutation of superoxide anion or activation of NOS. These observations indicate that free NO is formed as a result of NOS-catalyzed L-arginine oxidation and that SOD enhances the generation of NO without directly affecting NO itself. SOD appears to elicit a novel biological action, perhaps accelerating the conversion of an intermediate in the L-arginine-NO pathway such as nitroxyl (HNO) to NO.
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PMID:Formation of free nitric oxide from l-arginine by nitric oxide synthase: direct enhancement of generation by superoxide dismutase. 752 87

The spatial and temporal distribution of soluble guanylyl cyclase and nitric oxide synthase mRNA was determined during embryonic and postnatal development of the mouse brain. This was achieved by in situ hybridization of specific probes for soluble beta 1 guanylyl cyclase subunit and nitric oxide synthase mRNA on mouse brain sections at late fetal development (19-day embryo) and different stages of postnatal development (3, 7, 15 days, and adult). In the embryo, soluble guanylyl cyclase transcripts are weakly expressed in the central nervous system. Following birth their expression increases in the striatum and neocortex, and they are widely distributed in the adult brain (layer II and V-VI of the cortex, olfactory bulb, striatum, Purkinje cell layer of the cerebellum). In contrast, nitric oxide synthase mRNA was expressed in several embryonic structures of the brain (different layers of the cortical neuroepithelium, colliculi neuroepithelium, pons), and markedly reduced at early postnatal stage, except in the accessory olfactory bulb and pediculopontine nuclei. Nitric oxide synthase transcripts progressively appear, within two weeks following birth, in the striatum and the cerebral cortex but they were specifically confined to isolated cells. During this period, this mRNA also increased in hippocampus, in discrete nuclei (hypothalamus, pontine) and in the molecular layer of the cerebellum. The situation in the adult was similar to the one observed at 15 days. These results show a general lack of regional colocalization of soluble guanylyl cyclase and NOS mRNA during ontogeny, thus suggesting an independent regulation of the related genes.
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PMID:Expression of mouse brain soluble guanylyl cyclase and NO synthase during ontogeny. 752 43

1. Vascular responses to acetylcholine and sodium nitroprusside in vivo and in vitro, in the isolated perfused kidney and in rings of rat thoracic aorta, were measured in rats treated chronically with NG-nitro-L-arginine methyl ester (L-NAME; approx, 70 mg kg-1) and compared to responses in age-matched control animals, and age-matched animals after the acute administration of L-NAME (3-100 mumol kg-1). Parallel experiments examined alterations in responsiveness in rings of trachea and anococcygeus muscles taken from the same animals. 2. Chronic oral administration of L-NAME elevated the blood pressure in anaesthetized animals from 114 +/- 5 mmHg to 153 +/- 11 mmHg (n = 5). The hypotensive responses to both acetylcholine (1 nmol kg-1) and sodium nitroprusside (10 nmol kg-1) were enhanced by chronic L-NAME treatment (n = 5-7) whereas acute L-NAME administration enhanced only the response to sodium nitroprusside (n = 5). 3. After chronic treatment with L-NAME, the basal perfusion pressure in the isolated perfused kidney was elevated. However, vasodilator responses to either acetylcholine (1 nmol) or sodium nitroprusside (3 nmol) were unaltered (n = 5-7). The vasodilatation induced by acetylcholine was inhibited in a concentration-dependent manner by the administration of acute L-NAME (0.1 - 100 microM; n = 5), such that significant inhibition was seen at 10 microM L-NAME. The response to sodium nitroprusside was unaffected by L-NAME. 4. The relaxations of isolated rings of rat thoracic aorta induced by acetylcholine were inhibited in tissues prepared from rats treated chronically with L-NAME (n = 5-7). Acute administration of L-NAME (0.1-100 microM) concentration-dependently inhibited the relaxations induced by acetylcholine in this preparation, with significant inhibition occurring at 1 microM L-NAME (n = 5). Responses to sodium nitroprusside were unaffected by either chronic or acute exposure to L-NAME (n = 5-7).5. Relaxations of precontracted anococcygeus muscles induced by electrical field stimulation, or contractions of rings of trachea induced by carbachol or endothelin-1, were unaffected by chronic oral administration of L-NAME (n = 4-6). Acute addition of L-NAME (0.1-100 microM) to the organ baths inhibited in a concentration-dependent manner the relaxations of anococcygeus muscles taken from control animals, with a significant effect being seen at a concentration of 10 micro.M (n = 4-6).6. Our cardiovascular data are consistent with chronic oral administration of L-NAME inhibiting the production of nitric oxide (NO) within the vasculature, although the pattern of inhibition is not uniform between different tissues. Despite the inhibition of endothelial NO production, chronic L-NAME does not alter the vasodepressor activity of acetylcholine in vivo or in the isolated perfused kidney. This maybe explained by an enhanced responsiveness of guanylyl cyclase pathways, the increased release of vasodilators other than nitric oxide or a decreased importance of nitric oxide in resistance vessels compared with conductance vessels. The resistance of peripheral neuronal NO responses to chronic treatment with L-NAME indicates that selective inhibition of different isoforms of NOS may be achieved in vivo.
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PMID:Comparison of effects of chronic and acute administration of NG-nitro-L-arginine methyl ester to the rat on inhibition of nitric oxide-mediated responses. 754 Dec 83

We compared inhibitory nonadrenergic noncholinergic (i-NANC) neural relaxations, evoked by electrical field stimulation (EFS), at three levels (main [MA], proximal [PA], and distal [DA] airways) of isolated human airways and correlated these with nitric oxide synthase-immunoreactive (NOS-IR) nerves, using antiserum raised to rat cerebellar NOS. Maximal relaxations to papaverine (100 microM) were reduced in PA and DA (MA: 1,712 +/- 219 mg, n = 12; DA: 862 +/- 69 mg, n = 5, P < 0.05 versus MA); hence, subsequent relaxations were expressed as a percentage of the papaverine maximum. EFS elicited frequency-dependent relaxations that were largest in MA and reduced in PA and DA, especially at high stimulation frequencies (10 Hz EFS: MA: 51.6 +/- 3.7%, n = 12; PA: 30.5 +/- 6.0%, n = 6, P < 0.01 versus MA; DA: 17.8 +/- 3.6%, n = 5, P < 0.001 versus MA). The NOS inhibitor L-NG-nitroarginine methyl ester (L-NAME) (100 microM) and tetrodotoxin (3 microM) significantly inhibited i-NANC responses at all frequencies, leaving an L-NAME-resistant non-neural relaxation at frequencies > 5 Hz which was reduced in PA and DA. Cumulative concentration-response studies to sodium nitroprusside (1 nM to 0.1 mM) and the NO donor 3-morpholinosydnonimine (1 nM to 1 mM) were not significantly different in PA and DA, suggesting impaired relaxation is not caused by impaired guanylyl cyclase activity. Total nerve density, shown by protein gene product 9.5 staining, was not significantly different in PA and DA; however, NOS-IR nerve density was reduced in PA and DA (NOS-IR [intercepts/mm2]: MA: 705 +/- 98, n = 6; DA: 284 +/- 32, n = 6, P < 0.01 versus MA). These studies demonstrate that i NANC neural relaxations are reduced in DA, apparently due to a decrease in the density of nitrergic innervation.
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PMID:Distribution of human i-NANC bronchodilator and nitric oxide-immunoreactive nerves. 754 97

Nitric oxide (NO), produced by either constitutive or inducible isoforms of NO synthase (cNOS or iNOS), influences myocardial inotropic and chronotropic responses. This pathway has been studied using NO donors or NOS inhibitors or by immune-mediated stimulation of iNOS. Although inhibition of constitutive NO activity in the heart does not influence indices of myocardial contractility, NO donors, in some species and preparations, may exert a negative inotropic effect as well as an enhancement of diastolic relaxation. The best documented cardiac action of NO is inhibition of the positive inotropic and chronotropic responses to beta-adrenergic receptor stimulation. Basal NO production, presumable via cNOS, appears to exert a mild tonic inhibition of beta-adrenergic responses. On the other hand, excessive NO production mediated by iNOS may contribute to the myocardial depression and beta-adrenergic hyporesponsiveness associated with conditions such as sepsis, myocarditis, cardiac transplant rejection, and dilated cardiomyopathy. Muscarinic cholinergic stimulation of the heart appears to stimulate NO production that mediates, at least partially, parasympathetic slowing of heart rate and inhibition of beta-adrenergic contractility. NO-stimulated production of 3',5'-cyclic guanosine monophosphate via guanylyl cyclase accounts for many of the observed physiological actions of NO. 3',5'-Cyclic guanosine monophosphate inhibits the beta-adrenergic-stimulated increase in the slow-inward calcium current and reduces the calcium affinity of the contractile apparatus, actions that could contribute to a negative inotropic effect, an abbreviation of contraction, and an enhancement of diastolic relaxation. Biochemical, immunocytochemical, and molecular biological techniques have been used to show the presence of both cNOS and iNOS within the myocardium. cNOS is expressed in myocytes, endothelial cells, and neurons in the myocardium, and there is evidence for iNOS in myocytes, small vessel endothelium, vascular smooth muscle cells, and immune cells that infiltrate the heart. Taken together, these observations suggest that NO influences normal cardiac physiology and may play an important role in the pathophysiology of certain disease states associated with cardiac dysfunction.
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PMID:Role of nitric oxide in the regulation of myocardial function. 756 4

1. The mechanism of human sunburn is poorly understood but its characteristic features include the development of erythema. In this study we attempted to determine whether human keratinocytes possess a nitric oxide (NO) synthase (NOS), if this enzyme could be activated to release NO following exposure to ultraviolet B (u.v.B) and to define whether this photo-induced response could be involved in the pathogenesis of sunburn erythema. 2. Treatment of human keratinocytes with various doses of u.v.B (290-320 nm) radiation (up to 100 mJ cm-2) resulted in a dose-dependent release of NO and cyclic GMP production that was reduced by NG-monomethyl-L-arginine (L-NMMA). 3. u.v.B irradiation of keratinocyte cytosol at varying doses (up to 50 mJ cm-2), resulted in a gradual rise in NO production, with a concomitant increase in soluble guanylate cyclase activity (sGC). 4. NOS isolated from the keratinocyte cytosol was constitutively expressed and was dependent on NADPH, Ca2+/calmodulin, tetrahydrobiopterin and flavins. 5. In reconstitution experiments, when purified NOS was added to purified sGC, both isolated from keratinocyte cytosol, a four fold increase in cyclic GMP was observed. The GMP was increased by NO synthesized following u.v.B radiation (up to 20 mJ cm-2) of NOS. 6. In in vivo experiments, guinea-pigs were subjected to u.v.B light. A Protection Factor (PF) of 8.71 +/- 2.85 was calculated when an emulsified cream formulation containing L-NMMA (2%) was applied to their skin. 7. The present results indicate that u.v.B radiation acts as a potent stimulator of NOS in keratinocytes. NO is lipophilic and may diffuse out of the keratinocytes, activating sGC in endothelial cells and neighbouring smooth muscle cells. This may be a major part of the integrated response of the skin leading to vasodilatation and erythema.
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PMID:Release by ultraviolet B (u.v.B) radiation of nitric oxide (NO) from human keratinocytes: a potential role for nitric oxide in erythema production. 762 Jul 17

Nitric oxide (NO) is a free radical that has been recently recognized as a neuronal messenger molecule. In order to understand the way in which NO functions in the central nervous system (CNS), it is important to identify the NO-generator and NO-target cells in the brain. I measured firstly the distribution of NO synthase in the brain, which catalyzes L-arginine to form NO, by the measurement of citrulline formation that is also synthesized from L-arginine together with NO in equal molar bass. In the brain of adult rat, the most potent activity of NOS was apparent in the cerebellum, next in the olfactory bulb and medium in the cerebrum. Further, in the presence of NADPH and Ca2+, NOS activity was detected in the neuron cultures derived from the cerebrum of fetal rat. Astrocytes, one type of glia, prepared also from the cerebrum of fetal rat, appeared to have a small but significant NOS activity. As astrocytes possess a high amount of cytosolic guanylate cyclase that is known to be activated by NO, the changes in the intracellular cGMP levels in the astrocytes were measured as another index of NO formation. The treatment of astrocytes with NOS inhibitor caused the suppression of the intracellular cGMP levels. These results indicate that NO is definitely produced by astrocytes. In addition, in the blood vessel system of the brain, although NOS has been thought to be localized in the endothelial cells of only larger vessels, NOS activity was also observed in the microvessel endothelial cells of the cerebrum of both adult and fetal pig. These data suggest that neuronal cells may be the major site of NO generation in the brain, and that the NOS is a constitutive type. The data also suggest that astrocytes can also express constitutive NOS, although the potency is not so large. Microvessel endothelial cells of the brain are also one of the sources of NO. The NO produced by these cells increases the cGMP levels in the astrocytes and may affect some physiological and/or pathophysiological events in the brain.
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PMID:Evidence for nitric oxide-generator cells in the brain. 769 25

Bradykinin-induced activation of peripheral sensory fibres was studied using an in vitro preparation of the neonatal rat spinal cord with attached tail. Noxious heat stimulation, as well as the applications of bradykinin and capsaicin, to the tail evoked reproducible responses recorded as a depolarization of a lumbar ventral root. Prolonged administration of a supramaximal concentration of bradykinin invariably induced a complete but selective desensitization to a subsequent bradykinin challenge. Bradykinin-induced desensitization was significantly attenuated by concanavalin-A and the effect of concanavalin-A was prevented by alpha-methyl mannoside. Both cyclic GMP and sodium nitroprusside induced a long lasting reduction of bradykinin responsiveness in peripheral fibres. The effect of nitroprusside was prevented by concanavalin-A, and by methylene blue, an inhibitor of guanylyl cyclase. Methylene blue also reduced bradykinin-induced desensitization. L-arginine, but not D-arginine, induced a desensitization to bradykinin. On the other hand, 7-nitroindazole (7-NI, 200-500 nM), an inhibitor of NOS, reduced the desensitization of bradykinin responses but higher concentrations of 7-NI (IC50 = 6.7 +/- 0.9 microM) selectively attenuated responses to bradykinin. The effects of 7-NI were attenuated by L-arginine pretreatment. These data suggest that bradykinin-induced desensitization of peripheral sensory fibres is mediated in part via NO and cyclic GMP dependent mechanisms: possibly NO production is required for guanylate cyclase activation.
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PMID:Regulation of bradykinin sensitivity in peripheral sensory fibres of the neonatal rat by nitric oxide and cyclic GMP. 786 49

The evidence is very strong that NO serves as a neurotransmitter in some autonomic neurons. In the canine proximal colon, NOS is localized in fibers and varicosities of inhibitory motor neurons that course through the muscle layers. Excitation of inhibitory neurons enhances Ca2+ entry into varicosities and activates NOS. In the GI tract enteric inhibitory neurons not only possess the ability to synthesize NO, they may also recycle the by-product, citrulline, back to arginine, thus sustaining inhibitory neurotransmission. NO appears to diffuse freely from nerve terminals and into nearby postjunctional cells. Interstitial cells appear to be innervated by nerves that release NO, and postjunctional effects in these cells include production of cGMP and synthesis of additional NO. In smooth muscle cells NO signals are transduced by guanylate cyclase, the production of cGMP, and activation of protein kinase G, but direct stimulation by NO of some cellular effectors, such as K+ channels also appears to play a role. Responses of smooth muscle cells include activation of K+ channels, inhibition of Ca2+ channels, and a reduction in the sensitivity of the contractile apparatus to Ca2+. All of these factors may contribute to the reduction in mechanical activity produced by stimulation of enteric inhibitory neurons. NO-dependent neurotransmission is critical for many of the physiological processes of the GI tract, such as relaxation of sphincters, gastric accommodation, and receptive relaxation during feeding, and the descending inhibition arc of the peristaltic reflex.
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PMID:Involvement of nitric oxide in neuromuscular transmission in canine proximal colon. 859 14


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