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)

Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as "scavengers" of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity. The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.
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PMID:Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death. 1471 72

We measured changes in nitric oxide (NO) concentration in the cerebral cortex during experimental carbon monoxide (CO) poisoning and assessed the role for N-methyl-d-aspartate receptors (NMDARs), a glutamate receptor subtype, with progression of CO-mediated oxidative stress. Using microelectrodes, NO concentration was found to nearly double to 280 nM due to CO exposure, and elevations in cerebral blood flow, monitored as laser Doppler flow (LDF), were found to loosely correlate with NO concentration. Neuronal nitric oxide synthase (nNOS) activity was the cause of the NO elevation based on the effects of specific NOS inhibitors and observations in nNOS knockout mice. Activation of nNOS was inhibited by the NMDARs inhibitor, MK 801, and by the calcium channel blocker, nimodipine, thus demonstrating a link to excitatory amino acids. Cortical cyclic GMP concentration was increased due to CO poisoning and shown to be related to NO, versus CO, mediated guanylate cyclase activation. Elevations of NO were inhibited when rats were infused with superoxide dismutase and in rats depleted of platelets or neutrophils. When injected with MK 801 or 7-nitroindazole, a selective nNOS inhibitor, rats did not exhibit CO-mediated nitrotyrosine formation, myeloperoxidase (MPO) elevation (indicative of neutrophil sequestration), or impaired learning. Similarly, whereas CO-poisoned wild-type mice exhibited elevations in nitrotyrosine and myeloperoxidase, these changes did not occur in nNOS knockout mice. We conclude that CO exposure initiates perivascular processes including oxidative stress that triggers activation of NMDA neuronal nNOS, and these events are necessary for the progression of CO-mediated neuropathology.
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PMID:Neuronal nitric oxide synthase and N-methyl-D-aspartate neurons in experimental carbon monoxide poisoning. 1476 84

In the present study, the actions of nitric oxide (NO) on NMDA mediated excitatory neurotransmission in substantia gelatinosa (SG) neurons of the adult rat spinal cord were investigated. Bath application of the NO donor sodium-nitroso-N-acetylpenicillamine (SNAP) reversibly inhibited NMDA receptor mediated excitatory postsynaptic currents evoked by electrical stimulation of the dorsal root. These effects of SNAP were prevented by pre-incubation with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy PTIO) or the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, and were mimicked by the membrane permeable cGMP analogue dibutyryl cGMP. Finally, these effects were shown to be mediated at a postsynaptic level using acutely applied exogenous NMDA. In conclusion, we demonstrate for the first time the inhibition of NMDA mediated excitatory neurotransmission by NO in spinal cord SG neurons, an action mediated at least in part via the activation of guanylate cyclase.
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PMID:Nitric oxide inhibits NMDA currents in a subpopulation of substantia gelatinosa neurons of the adult rat spinal cord. 1505 Jun 93

Nitric oxide (NO(*)) is a diffusible regulatory molecule involved in a wide range of physiological and pathological events. At the tissue level, a local and temporary increase in NO(*) concentration is translated into a cellular signal. From our current knowledge of biological synthesis and decay, the kinetics and mechanisms that determine NO(*) concentration dynamics in tissues are poorly understood. Generally, NO(*) mediates its effects by stimulating (e.g., guanylate cyclase) or inhibiting (e.g., cytochrome oxidase) transition metal-containing proteins and by post-translational modification of proteins (e.g., formation of nitrosothiol adducts). The borderline between the physiological and pathological activities of NO(*) is a matter of controversy, but tissue redox environment, supramolecular organization and compartmentalisation of NO(*) targets are important features in determining NO(*) actions. In brain, NO(*) synthesis in the dependency of glutamate NMDA receptor is a paradigmatic example; the NMDA-subtype glutamate receptor triggers intracellular signalling pathways that govern neuronal plasticity, development, senescence and disease, suggesting a role for NO(*) in these processes. Measurements of NO(*) in the different subregions of hippocampus, in a glutamate NMDA receptor-dependent fashion, by means of electrochemical selective microsensors illustrate the concentration dynamics of NO(*) in the sub-regions of this brain area. The analysis of NO(*) concentration-time profiles in the hippocampus requires consideration of at least two interrelated issues, also addressed in this review. NO(*) diffusion in a biological medium and regulation of NO(*) activity.
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PMID:Nitric oxide in brain: diffusion, targets and concentration dynamics in hippocampal subregions. 1505 18

In this study we have investigated the relationship between glutamate and arginine release from cultured cerebellar astrocytes. We found that the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) promoted the release of both amino acids in a concentration-dependent manner, and that these responses were partially reversed by a guanylate cyclase inhibitor. Application of the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) resulted in a 60% reduction in basal arginine release but no change in that of glutamate. This effect was not overcome by the subsequent addition of SNAP despite a two-fold increase in glutamate release. Incubation with the nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) elicited 40 and 60% reductions in the basal release of glutamate and arginine, respectively. Basal release of both amino acids was restored by the addition of SNAP. We conclude that glutamate released from cerebellar astrocytes in response to increased levels of extracellular NO acts in an autocrine manner to promote arginine release via the activation of non-NMDA receptors. In addition, our data suggest that basal glutamate release is regulated to some extent by tonic NO synthesis in these cells.
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PMID:Arginine release from rat cerebellar astrocytes: autocrine roles for glutamate and nitric oxide? 1554 52

Pancreastatin (PST), a chromogranin A-derived peptide, has an anti-insulin metabolic effect and inhibits growth and proliferation by producing nitric oxide (NO) in HTC rat hepatoma cells. When NO production is blocked, a proliferative effect prevails due to the activation a Galphaq/11-phospholipase C-beta (PLC-beta) pathway, which leads to an increase in [Ca2+]i, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activation. The aim of the present study was to investigate the NO synthase (NOS) isoform that mediates these effects of PST on HTC hepatoma cells and the possible roles of cyclic GMP (cGMP) and cGMP-dependent protein kinase. DNA and protein synthesis in response to PST were measured as [3H]-thymidine and [3H]-leucine incorporation in the presence of various pharmacological inhibitors: N-monomethyl-L-arginine (NMLA, nonspecific NOS inhibitor), L-NIO (endothelial nitric oxide synthase (eNOS) inhibitor), espermidine (neuronal nitric oxide synthase (nNOS) inhibitor), LY83583 (guanylyl cyclase inhibitor), and KT5823 (protein kinase G inhibitor, (PKG)). L-NIO, similarly to NMLA, reverted the inhibitory effect of PST on hepatoma cell into a stimulatory effect on growth and proliferation. Nevertheless, espermidine also prevented the inhibitory effect of PST, but there was no stimulation of growth and proliferation. When guanylyl cyclase activity was blocked, there was again a reversion of the inhibitory effect into a stimulatory action, suggesting that the effect of NO was mediated by the production of cGMP. PKG inhibition prevented the inhibitory effect of PST, but there was no stimulatory effect. Therefore, the inhibitory effect of PST on growth and proliferation of hepatoma cells may be mainly mediated by eNOS activation. In turn, the effect of NO may be mediated by cGMP, whereas other pathways in addition to PKG activation seem to mediate the inhibition of DNA and protein synthesis by PST in HTC hepatoma cells.
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PMID:eNOS, nNOS, cGMP and protein kinase G mediate the inhibitory effect of pancreastatin, a chromogranin A-derived peptide, on growth and proliferation of hepatoma cells. 1558 12

Nitric oxide synthase (NOS) positive neurons are located in most brain areas related to defensive reactions, including the dorsolateral periaqueductal grey (dlPAG). NOS inhibitors injected into this structure induce anxiolytic-like responses whereas NO donors promote flight reactions. Intra-dlPAG administration of carboxy-PTIO, a NO scavenger, or ODQ, a soluble guanylate cyclase inhibitor, produced anxiolytic-like effects on rats exposed to the elevated plus-maze (EPM). A double-staining experiment using NADPHd histochemistry and c-Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG, paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus. Cat exposure also increased activation of NOS neurons in the medial amygdala, dorsal pre-mammillary nucleus and bed nucleus of stria terminalis. Local infusion into the dlPAG of a glutamate NMDA-receptor antagonist (AP7) or a benzodiazepine agonist (midazolam) completely prevented the flight reactions induced by intra-dlPAG administration of SIN-1, a NO donor. The responses were also inhibited by the 5-HT2A/C agonist DOI but not by a 5-HT1A agonist. These results suggest a modulatory role for NO on brain areas related to defensive reactions, probably by interacting with glutamate, serotonin and/or GABA-mediated neurotransmission.
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PMID:Role of nitric oxide in brain regions related to defensive reactions. 1609 96

We previously reported that pre- and postsynaptic 5-hydroxytryptamine (5-HT) receptors effectively control glutamatergic transmission in adult rat cerebellum. To investigate where 5-HT acts in the glutamate ionotropic receptors/nitric oxide/guanosine 3',5'-cyclic monophosphate (cGMP) pathway, in the present study 5-HT modulation of the cGMP response to the nitric oxide donor S-nitroso-penicillamine (SNAP) was studied in adult rat cerebellar slices. While cGMP elevation produced by high-micromolar SNAP was insensitive to 5-HT, 1 microM SNAP, expected to release nitric oxide in the low-nanomolar concentration range, elicited cGMP production and endogenous glutamate release both of which could be prevented by activating presynaptic 5-HT1D receptors. Released nitric oxide appeared responsible for cGMP production and glutamate release evoked by 1 microM SNAP, as both the effects were mimicked by the structurally unrelated nitric oxide donor 2-(N,N-diethylamino)-diazenolate-2-oxide (0.1 microM). Dependency of the 1 microM SNAP-evoked release of glutamate on external Ca2+, sensitivity to presynaptic release-regulating receptors and dependency on ionotropic glutamate receptor functioning, suggest that nitric oxide stimulates exocytotic-like, activity-dependent glutamate release. Activation of ionotropic glutamate receptors/nitric oxide synthase/guanylyl cyclase pathway by endogenously released glutamate was involved in the cGMP response to 1 microM SNAP, as blockade of NMDA/non-NMDA receptors, nitric oxide synthase or guanylyl cyclase, abolished the cGMP response. To conclude, in adult rat cerebellar slices low-nanomolar exogenous nitric oxide could facilitate glutamate exocytotic-like release possibly from parallel fibers that subsequently activated the glutamate ionotropic receptors/nitric oxide/cGMP pathway. Presynaptic 5-HT1D receptors could regulate the nitric oxide-evoked release of glutamate and subsequent cGMP production.
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PMID:Nitric oxide-evoked glutamate release and cGMP production in cerebellar slices: control by presynaptic 5-HT1D receptors. 1646 16

Nitric oxide (NO) participates in long-term potentiation (LTP) and other forms of synaptic plasticity in many different brain areas but where it comes from and how it acts remain controversial. Using rat and mouse hippocampal slices, we tested the hypothesis that tonic and phasic NO signals are needed and that they derive from different NO synthase isoforms. NMDA increased NO production in a manner that was potently inhibited by three different neuronal NO synthase (nNOS) inhibitors. Tonic NO could be monitored after sensitizing guanylyl cyclase-coupled NO receptors, allowing the very low ambient NO concentrations to be detected by cGMP measurement. The levels were unaffected by inhibition of NMDA receptors, nNOS, or the inducible NO synthase (iNOS). iNOS was also undetectable in protein or activity assays. Tonic NO was susceptible to agents inhibiting endothelial NO synthase (eNOS) and was missing in eNOS knock-out mice. The eNOS knock-outs exhibited a deficiency in LTP resembling that seen in wild-types treated with a NO synthase inhibitor. LTP in the knock-outs could be fully restored by supplying a low level of NO exogenously. Inhibition of nNOS also caused a major loss of LTP, particularly of late-LTP. Again, exogenous NO could compensate, but higher concentrations were needed compared with those restoring LTP in the eNOS knock-outs. It is concluded that tonic and phasic NO signals are both required for hippocampal LTP and the two are generated, respectively, by eNOS and nNOS, the former in blood vessels and the latter in neurons.
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PMID:Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. 1709 72

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.
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PMID:Opioids block long-term potentiation of inhibitory synapses. 1746 Jun 74


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