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 effects of the metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] on ionic current responses produced by ionotropic glutamate and gamma-aminobutyric acid (GABA)A receptor activation in the nucleus of the tractus solitarius (NTS) were examined. Recordings were made in the dorsomedial subdivision of the NTS adjacent to the area postrema in transverse brainstem slices of the rat. (1S,3R)-ACPD produced a small inward current (IACPD) associated with a decrease in conductance in approximately 50% of recordings. Monosynaptic excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation in the region of the tractus solitarius in the presence of D-amino-5-phosphonopentanoic acid and bicuculline were reversibly reduced by (1S,3R)-ACPD in > 90% of cells. The inward current evoked by pressure application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (IAMPA) was potentiated in the presence of (1S,3R)-ACPD, whereas the outward current evoked by the GABAA receptor agonist muscimol (IMUSC) was inhibited. We have previously demonstrated that these effects may involve the activation of soluble guanylate cyclase. The diffusible second messengers nitric oxide and carbon monoxide are known to activate soluble guanylate cyclase. The nitric oxide synthase inhibitor L-omega-nitroarginine failed to inhibit responses to (1S,3R)-ACPD. The selective heme oxygenase inhibitor Zn-protoporphyrin-IX, which would be expected to block the production of carbon monoxide, antagonized the effects of (1S,3R)-ACPD on EPSCs, IAMPA, and IMUSC. However, IACPD was not blocked. A relatively inactive metalloprotoporphyrin, Cu-protoporphyrin-IX was ineffective. A cell-permeant form of cGMP, 8-Br-cGMP inhibited EPSCs, IAMPA, and IMUSC in the presence of Zn-protoporphyrin-IX but did not induce an inward current. These results further support the hypothesis that multiple metabotropic glutamate receptors exist in the NTS, and they suggest that one of these may be coupled to the activation of a soluble guanylate cyclase via the liberation of an easily diffusible second messenger such as carbon monoxide.
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PMID:Zinc protoporphyrin-IX blocks the effects of metabotropic glutamate receptor activation in the rat nucleus tractus solitarii. 839 Nov 21

Rat liver is known to contain both a nitric oxide-stimulated guanylate cyclase and a cGMP-stimulated cAMP-phosphodiesterase. To evaluate the possible function of this system, the effect of the nitric oxide generating compound S-nitroso-N-acetylpenicillamine on glycogenolysis was evaluated in isolated rat hepatocytes. S-nitroso-N-acetylpenicillamine (1.0 mM) inhibited glucagon-stimulated glycogenolysis by 15%, but had no effect on basal rates of glycogenolysis. Inhibition of hepatocyte glycogenolysis by S-nitroso-N-acetylpenicillamine was associated with accumulation of cGMP (1.5 pmol/2.0 x 10(6) cells/2 min.). Exogenous 8-Br-cGMP (1.0 mM) inhibited hepatocyte glucagon-stimulated glycogenolysis by a magnitude similar to that observed with S-nitroso-N-acetylpenicillamine. S-nitroso-N-acetylpenicillamine had no effect on phenylephrine-stimulated glycogenolysis, but inhibited 8-bromo-cAMP-stimulated glycogenolysis by 15%. These observations suggest that S-nitroso-N-acetylpenicillamine inhibits cAMP-mediated stimulation of glycogenolysis at a site distal to adenylate cyclase. In summary, hepatocyte glucagon-stimulated glycogenolysis was inhibited to a small, but significant, degree by S-nitroso-N-acetylpenicillamine. This inhibition is consistent with a nitric oxide mediated stimulation of guanylate cyclase and consequent stimulation of cAMP-phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiologic conditions.
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PMID:Inhibition of glucagon-stimulated glycogenolysis by S-nitroso-N-acetylpenicillamine. 839 88

Augmentation of nitric oxide (NO) production in vivo decreases lesions in a variety of models of arterial injury, and inhibition of NO synthase exacerbates experimental intimal lesions. Both vascular smooth muscle cell (VSMC) proliferation and migration contribute to lesion formation. Although NO inhibits VSMC proliferation, its effects on VSMC migration are unknown. To test the hypothesis that NO inhibits VSMC migration independent of inhibition of proliferation, we examined migration of rat aortic VSMCs after wounding of a confluent culture in the presence of chemical donors of NO. Hydroxyurea was used to eliminate any confounding effect of NO on proliferation. Three NO donors, diethylamine NONOate, spermine NONOate, and S-nitrosoglutathione, exhibited concentration-dependent inhibition of both number of migrating VSMCs and maximal distance migrated. Inhibition of migration was also seen with 8-Br-cGMP, suggesting that activation of guanylate cyclase may play a role in mediating the antimigratory effects of NO. Migration resumed after removal of NO donors, as evidenced by an increase in distance migrated. Measurement of VSMC protein synthesis and mitochondrial respiration indicated that inhibition of migration by NO donors was not due to metabolic cytostasis. These findings indicate that NO reversibly inhibits VSMC migration independent of proliferation or cytotoxicity, a novel mechanism by which both endogenous and pharmacological NO may alter vascular pathology.
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PMID:Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. 857 65

Interleukin 1 and nitric oxide (NO) from infiltrating macrophages and activated mesangial cells may act in concert to sustain and promote glomerular damage. To evaluate if such synergy occurs, we evaluated the effect if IL-1 beta and NO on the formation of prostaglandin (PG)E2 and cyclooxygenase (COX) expression. The NO donors, sodium nitroprusside and S-nitroso-N-acetylpenicillamine, alone did not increase basal PGE2 formation. However, these compounds amplified IL-1 beta-induced PGE2 production. Similarly, sodium nitroprusside and S-nitroso-N-acetylpenicillamine by themselves did not induce mRNA and protein for COX-2, the inducible isoform of COX; however, they both potentiated IL-1 beta-induced mRNA and protein expression of COX-2. The stimulatory effect of NO is likely to be mediated by cGMP since (a) an inhibitor of the soluble guanylate cyclase, methylene blue, reversed the stimulatory effect of NO donors on COX-2 mRNA expression; (b) the membrane-permeable cGMP analogue, 8-Br-cGMP, mimicked the stimulatory effect of NO donors on COX-2-mRNA expression; and (c) atrial natriuretic peptide, which increases cellular cGMP by activating the membrane-bound guanylate cyclase, also amplified IL-1 beta-induced COX-2 mRNA expression. These data indicate a novel interaction between NO and COX pathways.
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PMID:Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. 862 94

In the present study we demonstrate that gap junction coupling between developing layer II/III pyramidal cells in rat sensorimotor cortex is strongly modified by the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system. Dye coupling was revealed by intracellular injection of the gap junction-permeable tracer neurobiotin into single neurones. Following incubation of slices with sodium nitroprusside, a source of NO, the size of dye-coupled cell clusters was significantly reduced. In many cases, 2-3 cells remained strongly dye-coupled. These effects were blocked by intracellular injection of the guanylyl cyclase inhibitor cystamine and mimicked by both application of the membrane-permeant cGMP analogue 8-Br-cGMP and intracellular injection of cGMP. cGMP injection also induced a 60% increase in neuronal input resistance. These results indicate that NO modulates gap junction coupling in the developing neocortex via stimulation of guanylyl cyclase.
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PMID:Nitric oxide-stimulated increase in intracellular cGMP modulates gap junction coupling in rat neocortex. 873 Aug 31

1. Inhibitory junction potentials (IJPs) and relaxations evoked in response to field stimulation (supramaximal voltage, 0.1 ms, single stimulus and 5 stimuli at 5-40 Hz) of non-adrenergic non-cholinergic (NANC) nerves with atropine and phentolamine (each 1 microM) were measured in the guinea-pig internal anal sphincter (gpIAS). The mean resting membrane potential was -44.2 +/- 0.2 mV (n = 1119 cells from 260 preparations). 2. NANC nerve stimulation evoked frequency-dependent IJPs (19.7 +/- 1.1 mV, n = 165, 33 tissues to a single stimulus) and relaxations. IJPs consisted of two tetrodotoxin (1 microM)-sensitive components: one was abolished by apamin (0.3 microM) and the P2-purinoceptor antagonist suramin (100 microM); the other, smaller in amplitude, was sensitive to inhibitors of nitric oxide synthase (NOS, e.g. L-NAME, 100 microM) and the nitric oxide (NO) scavenger oxyhaemoglobin (HbO, 10 microM). 3. ATP (1 mM), vasoactive intestinal polypeptide (VIP, 0.01-0.25 microM) and pituitary adenylate cyclase-activating peptide (PACAP(1-27), 0.84 microM) each hyperpolarized and relaxed the gpIAS; only ATP responses resembled the evoked IJPs in time course. 4. The guanylyl cyclase inhibitor LY83583 (10 microM) abolished apamin-insensitive IJPs and relaxations. The cGMP phosphodiesterase inhibitor M&B 22948 (30 microM) and 8-Br-cGMP (100 microM) each hyperpolarized the gpIAS. 5. Two components comprise the IJP and relaxation evoked in response to NANC nerve stimulation in the gpIAS. One, sensitive to apamin, resembles the response to ATP and is modulated by purinoceptor antagonists; the other, apamin and suramin insensitive, is inhibited by NO antagonists.
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PMID:Neuronal mediators of inhibitory junction potentials and relaxation in the guinea-pig internal anal sphincter. 878 13

In order to provide further support for a role of central nitric oxide as a mediator of penile erection and yawning, the nitric oxide donors sodium nitroprusside, hydroxylamine, isoamyl nitrite and S-nitroso-N-acetyl-penicillamine were injected into the lateral ventricles (i.c.v.) or into the paraventricular nucleus of the hypothalamus of male rats. Of the above compounds injected i.c.v., only isoamyl nitrite (10-100 micrograms) induced penile erection and yawning, while the others induced dramatic behavioral changes, such as motor hyperactivity and convulsions, that masked the above responses. Nevertheless, nitric oxide donors in doses ranging from 10 to 50 micrograms, for except S-nitroso-N-acetyl-penicillamine that was injected only at the dose of 10 micrograms and isoamyl nitrite that was not injected at all because of poor solubility, induced penile erection and yawning when injected in the paraventricular nucleus. Nitric oxide donor-induced responses were prevented by methylene blue and LY 83583, inhibitors of guanylate cyclase, the best known target of nitric oxide, given i.c.v. but not in the paraventricular nucleus. However, 8-bromo-guanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a stable cGMP analog, and hemoglobin, a nitric oxide scavenger, were ineffective in inducing and preventing, respectively, penile erection and yawning when injected either i.c.v. or in the paraventricular nucleus. Nitric oxide donor-induced responses were also prevented by the nonapeptide oxytocin receptor antagonist d(CH2)5-Tyr(Me)-Orn8-vasotocin given i.c.v. but not in the paraventricular nucleus. The present results suggest that nitric oxide donors induce penile erection and yawning by activating central oxytocinergic transmission in the paraventricular nucleus of the hypothalamus via a cGMP-independent mechanism.
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PMID:Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. 878 10

Fura-2 fluorescence imaging was used to measure changes in intracellular Ca2+ concentration in individual N1E-115 neuroblastoma cells during repeated activation of M1 muscarinic receptors with carbachol. Ca2+ transients could be elicited repeatedly at 4 min intervals with little decrement as long as external Ca2+ was present. When the cells were bathed in Ca(2+)-free saline, however, the response amplitude decreased rapidly in a use-dependent fashion, indicating that external Ca2+, and presumably Ca2+ influx, is required for refilling Ca2+ stores during the interval between trials. The response amplitude also decreased during repeated stimulation in cells treated with the NO-synthase inhibitor L-NMMA or with the guanylyl cyclase inhibitor LY-83583 even when Ca2+ was present. Application of the membrane permeable cGMP analog 8-Br-cGMP reversed the effect of L-NMMA and promoted refilling in the continued presence of NO-synthase inhibitor. These results indicate that activation of the NO/cGMP pathway is necessary for refilling Ca2+ stores during muscarinic signaling. Evidence is also presented suggesting that the NO/cGMP pathway is involved in long term modulation of the content of Ca2+ stores.
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PMID:Activation of the nitric oxide/cGMP pathway is required for refilling intracellular Ca2+ stores in a sympathetic neuron cell line. 879 80

Chemoattractants transiently activate guanylyl cyclase in Dictyostelium discoideum cells. Mutant analysis demonstrates that the produced cGMP plays an essential role in chemotactic signal transduction, controlling the actomyosin-dependent motive force. Guanylyl cyclase activity is associated with the particulate fraction of a cell homogenate. The addition of the cytosol stimulates guanylyl cyclase activity, whereas the cytosol plus ATP/Mg2+ inhibits enzyme activity. We have analyzed the regulation of guanylyl cyclase in chemotactic mutants and present evidence that a cGMP-binding protein mediates both stimulation and ATP-dependent inhibition of guanylyl cyclase. Upon chromatography of cytosolic proteins, cGMP binding activity co-elutes with both guanylyl cyclase-stimulating and ATP-dependent-inhibiting activities. In addition, ATP-dependent inhibition of guanylyl cyclase activity is enhanced by the cGMP analogue 8-Br-cGMP, suggesting that a cGMP-binding protein regulates guanylyl cyclase activity. Mutant KI-4 has an aberrant cGMP binding activity with very low Kd and shows a very small chemoattractant-mediated cGMP response; the cytosol from this mutant does not stimulate guanylyl cyclase. In contrast to KI-4, the aberrant cGMP binding activity of mutant KI-7 has a very high Kd and chemoattractants induce a prolonged cGMP response. The cytosol of this mutant stimulates guanylyl cyclase activity, but ATP does not inhibit the enzyme. Thus, two previously isolated chemotactic mutants are defective in the activation and inhibition of guanylyl cyclase, respectively. The positive and negative regulation of guanylyl cyclase by its product cGMP may well explain how cells process the temporospatial information of chemotactic signals, which is necessary for sensing the direction of the chemoattractant.
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PMID:Regulation of guanylyl cyclase by a cGMP-binding protein during chemotaxis in Dictyostelium discoideum. 879 95

1. The exogenous nitric oxide (NO) donor, SIN-1, decreased the postsynaptic response evoked by a presynaptic spike at an identified cholinergic neuro-neuronal synapse in the buccal ganglion of Aplysia californica. 2. The statistical analysis of long duration postsynaptic responses evoked by square depolarizations of the voltage-clamped presynaptic neurone showed that the number of evoked acetylcholine (ACh) quanta released was decreased by SIN-1, pointing to a presynaptic action of the drug. 3. Vitamin E, a scavenger of free radicals, prevented the effects of SIN-1 on ACh release. SIN-1 still decreased ACh release in the presence of superoxide dismutase, whereas haemoglobin suppressed the effects of SIN-1. These results showed that NO is the active compound. 4. 8-Bromoguanosine 3', 5' cyclic monophosphate (8-Br-cGMP) mimicked the inhibitory effect of NO on ACh release suggesting the involvement of a NO-sensitive guanylate cyclase. This was reinforced by the reversibility of the effects of SIN-1 by inhibitors of guanylate cyclase, Methylene Blue, cystamine or LY83583. Methylene Blue partially reduced the inhibitory effect of NO. In addition, in the presence of superoxide dismutase, Methylene Blue blocked and cystamine significantly reduced the NO-induced inhibition of ACh release. 5. In the presence of KT5823 or R-p-8-pCPT-cGMPS, two inhibitors of protein kinase G, the reduction of ACh release by SIN-1 still took place indicating that the effects of NO most probably did not involve protein kinase G-dependent phosphorylation. 6. Presynaptic voltage-dependent Ca2+ (L-, N- and P-types) and K+ (IA and late outward rectifier) currents were unmodified by SIN-1. 7. The modulation of ACh release in opposite ways by L-arginine and N omega-nitro-L-arginine points to the involvement of an endogenous NO synthase-dependent regulation of transmitter release.
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PMID:NO decreases evoked quantal ACh release at a synapse of Aplysia by a mechanism independent of Ca2+ influx and protein kinase G. 879 98


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