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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of (+/-)-cis-2,3-piperidine dicarboxylic acid [+/-)-cis-2,3-PDA) on formation of cyclic GMP by immature (7-8 day) rat cerebellar slices has been studied. Using magnesium free medium containing the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), (+/-)-cis-2,3-PDA behaves as an NMDA partial agonist. Thus in this medium, (+/-)-cis-2,3-PDA stimulates cyclic GMP formation, an effect completely blocked by the potent, specific NMDA antagonist (+/-)-2-amino-7-phosphonoheptanoic acid [+/-)-APH) with a Ki = 17.1 microM. The production of cyclic GMP by the full agonist (+/-)-trans-2,3-PDA, was also blocked by (+/-)-APH, suggesting that in this preparation it activates NMDA receptors. (+/-)-trans-2,3-PDA was approximately half as potent as NMDA. By constructing dose response curves to NMDA in the presence of increasing concentrations of (+/-)-APH or (+/-)-APV, these compounds were shown to be competitive NMDA antagonists using Schild analysis.
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PMID:(+/-)-cis-2,3-Piperidine dicarboxylic acid is a partial N-methyl-D-aspartate agonist in the in vitro rat cerebellar cGMP model. 287 Sep 27

The nitric oxide (NO) synthase/cGMP pathway has been studied in vivo in the adult rat hippocampus by monitoring the levels of extracellular cGMP during microdialysis in conscious unrestrained animals. The basal cGMP efflux was concentration-dependently reduced upon local infusion of the NO synthase inhibitor NG-nitro-L-arginine (NARG; 10 microM to 1 mM). The NO donors hydroxylamine and S-nitroso-N-penicillamine, perfused through the dialysis probe at 1 mM, increased by about 200% the extracellular levels of cGMP. The glutamate receptor agonist NMDA (125-500 microM) produced concentration-dependent cGMP responses that were abolished by the selective receptor antagonist D-2-amino-5-phosphonovaleric acid or by NARG. Local perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX; 1 mM) produced a steady eightfold increase of extracellular cGMP levels. The effect of IBMX was highly sensitive to NARG. The inhibition by NARG of the IBMX-induced cGMP response was reversed when the NO synthase substrate L-arginine was administered. It is concluded that cGMP collected during in vivo microdialysis reflects NO synthase activity in the rat hippocampus. The technique may be utilized to investigate the pathophysiology and the pharmacology of the NO/cGMP pathway in the hippocampus of living animals.
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PMID:Extracellular cGMP in the hippocampus of freely moving rats as an index of nitric oxide (NO) synthase activity. 750 60

The stimulation of excitatory amino acid receptors in the cerebellar cortex results in the Ca2+/calmodulin-dependent activation of nitric oxide synthase. This leads to an increase in tissue levels of cGMP following the interaction of nitric oxide with soluble guanylyl cyclase. The cerebellar cortex has the highest levels of nitric oxide synthase and cGMP in the brain; however, the levels of guanylyl cyclase and cGMP-phosphodiesterase are remarkably low. Thus, the mechanisms regulating cGMP levels in cerebellar cells are unclear. One report has noted that cGMP can be released from cerebellar slices. We have therefore used intracerebellar microdialysis in awake, freely moving rats to test the hypothesis that activation of nitric oxide synthase in the cerebellar cortex results in the release of cGMP. Climbing fibers, which release excitatory amino acids in the cerebellum, were activated with systemic harmaline. This resulted in an immediate increase in extracellular cGMP, which was blocked by TTX or the removal of extracellular Ca2+, and attenuated by prior lesion of the climbing fibers. Blockade of N-type calcium channels with omega-conotoxin also antagonized the harmaline-induced increase. In contrast, blockade of L-type calcium channels, or inhibition of anion transport with probenecid or bromosulfophthalein, potentiated the increase in cGMP seen in response to harmaline. Inhibitors of nitric oxide synthase or guanylyl cyclase prevented the harmaline-induced increase in extracellular cGMP, while phosphodiesterase inhibitors potentiated the increase. Local application of the NMDA antagonist 2-amino-5-phosphonopentanoic acid or the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione attenuated the effect of harmaline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide-dependent efflux of cGMP in rat cerebellar cortex: an in vivo microdialysis study. 750 65

General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
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PMID:Inhibitory effects of anesthetics on cyclic guanosine monophosphate (cGMP) accumulation in rat cerebellar slices. 752 47

The stimulation of NMDA receptor increased [3H]GABA release from preloaded cultured retina cells. This effect appears to be mediated by NO production, since addition of L-NA reduces NMDA-evoked [3H]GABA release. Spermine/NO complex, an NO donor, mimics the effect produced by NMDA. The addition of zaprinast, a phosphodiesterase inhibitor, as well as 8-Br-cGMP enhances the NMDA-evoked [3H]GABA release. These results agree with the existence in chick retina cells of NO/cGMP pathways and support a role for NO in NMDA-evoked events. The activation of this receptor complex through maturative stages of the retina together with the NO-mediated increase in GABA release may account for NMDA differentiative effect in culturing retina cells.
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PMID:Nitric oxide mediates NMDA-evoked [3H]GABA release from chick retina cells. 940 48

Previously, we have demonstrated that cells of the oligodendroglial lineage express non-NMDA glutamate receptor genes and are damaged by kainate-induced Ca2+ influx via non-NMDA glutamate receptor channels, representing oligodendroglial excitotoxicity. We find in the present study that agents that elevate intracellular cyclic AMP prevent oligodendroglial excitotoxicity. After oligodendrocyte-like cells, differentiated from the CG-4 cell line established from rat oligodendrocyte type-2 astrocyte progenitor cells, were exposed to 2 mM kainate for 24 h, cell death was evaluated by measuring activity of lactate dehydrogenase released into the culture medium. Released lactate dehydrogenase increased about threefold when exposed to 2 mM kainate. Kainate-induced cell death was prevented by one of the following agents: adenylate cyclase activator (forskolin), cyclic AMP analogues (dibutyryl cyclic AMP and 8-bromo-cyclic AMP), and cyclic AMP phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine, pentoxifylline, propentofylline, and ibudilast). Simultaneous addition of both forskolin and phosphodiesterase inhibitors prevented the kainate-induced cell death in an additive manner. A remarkable increase in Ca2+ influx (approximately 5.5-fold) also was induced by kainate. The cyclic AMP-elevating agents caused a partial suppression of the kainate-induced increase in Ca2+ influx, leading to a less prominent response of intracellular Ca2+ concentration to kainate. The suppressing effect of forskolin on the kainate-induced Ca2+ influx was partially reversed by H-89, an inhibitor of cyclic AMP-dependent protein kinase. In contrast to this, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, brought about a decrease in the kainate-induced Ca2+ influx. We therefore concluded that cyclic AMP-elevating agents prevented oligodendroglial excitotoxicity by cyclic AMP-dependent protein kinase-dependent protein phosphorylation, resulting in decreased kainate-induced Ca2+ influx.
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PMID:Cyclic AMP-elevating agents prevent oligodendroglial excitotoxicity. 960 6

The AMPA receptor, ubiquitous in brain, is termed "ionotropic" because it gates an ion channel directly. We found that an AMPA receptor can also modulate a G-protein to gate an ion channel indirectly. Glutamate applied to a retinal ganglion cell briefly suppresses the inward current through a cGMP-gated channel. AMPA and kainate also suppress the current, an effect that is blocked both by their general antagonist CNQX and also by the relatively specific AMPA receptor antagonist GYKI-52466. Neither NMDA nor agonists of metabotropic glutamate receptors are effective. The AMPA-induced suppression of the cGMP-gated current is blocked when the patch pipette includes GDP-beta-S, whereas the suppression is irreversible when the pipette contains GTP-gamma-S. This suggests a G-protein mediator, and, consistent with this, pertussis toxin blocks the current suppression. Nitric oxide (NO) donors induce the current suppressed by AMPA, and phosphodiesterase inhibitors prevent the suppression. Apparently, the AMPA receptor can exhibit a "metabotropic" activity that allows it to antagonize excitation evoked by NO.
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PMID:AMPA receptor activates a G-protein that suppresses a cGMP-gated current. 1019 13

Overwhelming evidence indicates that the glutamate/nitric oxide (NO) synthase/soluble guanylyl cyclase system is of primary importance in a variety of physiological and pathological processes of the brain. Most of our knowledge on this neurochemical pathway derives from in vitro and ex vivo studies but the recent improvement of microdialysis techniques combined with extremely sensitive measurements of the amplified end-product cyclic GMP (cGMP) has given new impulses to the investigation of this cascade of events, its modulation by neurotransmitters and its functional relevance, in a living brain. The first reports, appeared in the early 90's, have demonstrated that microdialysis monitoring of cGMP in the extracellular environment of the cerebellum and hippocampus exactly reflects what is expected to occur at the intracellular level; thus, in vivo extracellular cGMP is sensitive to NO-synthase and soluble guanylyl cyclase inhibitors, can be increased by NO-donors or phosphodiesterase blockers and is modulated by glutamate receptor stimulation in a NO-dependent fashion. Since then, other microdialysis studies have been reported showing that the brain NO synthase/guanylyl cyclase pathway is mainly controlled by NMDA, AMPA and metabotropic glutamate receptors but can be also influenced by other transmitters (GABA, acetylcholine, neuropeptides) through polysynaptic circuits interacting with the glutamatergic system. The available data indicate that this technique, applied to freely-moving animals and combined with behavioural tests, could be useful to get a better insight into the functional roles played by NO and cGMP in physiological and pathological situations such as learning, memory formation, epilepsy, cerebral ischemia and neurodegenerative diseases.
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PMID:In vivo studies of the cerebral glutamate receptor/NO/cGMP pathway. 1032 98

Chronic activity blockade increases synaptic levels of NMDA receptor immunoreactivity in hippocampal neurons. We show here that blockade-induced synaptic NMDA receptors are functional and mediate enhanced excitotoxicity in response to synaptically released glutamate. Activity blockade increased the cell surface association of NMDA receptors. Blockade-induced synaptic targeting of NMDA receptors did not require protein synthesis but required phosphorylation and specifically cAMP-dependent protein kinase (PKA). Furthermore, activation of PKA was sufficient to induce synaptic targeting of NMDA receptors regardless of receptor activity status. These results implicate PKA activity downstream of receptor blockade as a mediator of enhanced synaptic transport or stabilization of NMDA receptors. Synaptic clustering of NR1-green fluorescent protein was observed in living neurons in response to NMDA receptor and cAMP phosphodiesterase antagonists and occurred gradually over the course of a day. This pathway represents a cellular mechanism for synaptic homeostasis and is likely to function in metaplasticity, long-term regulation of the ability of a synapse to undergo potentiation or depression.
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PMID:cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. 1143 83

Nerve signals from the hippocampus to the nucleus accumbens (NAc) are transmitted through a glutamatergic pathway via the fornix/fimbria fibres. The aim of the present study was to investigate whether cholinergic neurons are activated by this projection and whether the nitric oxide (NO) system is also involved in the signal transduction within this nucleus. For this purpose, the NAc of urethane-anaesthetized rats was superfused, by the push-pull technique, with compounds that influence the NO system while the fornix/fimbria was electrically stimulated for short periods. The amount of acetylcholine (ACh) released in the superfusate was then determined. Electrical stimulation of the fornix/fimbria increased the ACh output in the NAc. This effect was abolished by superfusion with tetrodotoxin and decreased by superfusion with the glutamate receptor antagonists AP-5 and DNQX indicating the involvement of action potentials and glutamate. Superfusion with the inhibitor of neuronal NO synthase, NS 2028 also diminished stimulation-evoked ACh release. The NO donor PAPA/NO increased basal release. Simultaneous application of PAPA/NO and electrical stimulation led to an over-additive increase of ACh release. The effect of PAPA/NO on stimulation-evoked release was also abolished by NS 2028. The selective inhibitor of phosphodiesterase type 5 (PDE 5), 5-[2-ethoxy-5-(morpholinylacetyl)phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-one methanesulphanate monohydrate also enhanced stimulation-induced release of ACh. Our findings indicate, that action potentials propagated by the fornix/fimbria to the NAc release glutamate which increases ACh release predominantly via NMDA receptors. In addition, nitrergic neurons are activated to enhance NO synthesis. The released NO seems to exert, via cGMP, a potent facilitatory role in the transduction and processing of signals from the hippocampus within the NAc, while the PDE 5 decreases the effects of NO.
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PMID:The nitric oxide system modulates the in vivo release of acetylcholine in the nucleus accumbens induced by stimulation of the hippocampal fornix/fimbria-projection. 1168 2


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