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 receptor subtypes mediating excitatory synaptic neurotransmission in the cerebellar cortex are briefly reviewed from molecular biological, electrophysiological and pharmacological points of view. In particular, molecular biological findings of a novel family of AMPA-selective glutamate receptors are introduced, and the pharmacological and electrophysiological properties and the identity of cerebellar N-methyl-D-aspartate-sensitive receptors probably existing on Purkinje cells are discussed in comparison with well-established cerebral NMDA receptors. As possible intracellular mechanisms of the long-term depression of parallel fiber-Purkinje cell neurotransmission, the perspective of the roles of novel messengers, nitric oxide and arachidonic acid, is particularly commented based on recent information about cerebral long-term events. The specificity and possible independence of cerebellar excitatory amino acid receptors and linked intracellular second messengers are also suggested, taking the highly active guanylate cyclase system in Purkinje cells and other cerebellum-specific proteins into consideration.
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PMID:Synaptic receptors and intracellular signal transduction in the cerebellum. 185 Dec 70

The function of serotonin afferents to the cerebellum has been investigated by monitoring the effects of serotoninergic drugs on the production of cyclic GMP elicited in cerebellar slices by activation of ionotropic glutamate receptors. Exposure of adult rat cerebellar slices to N-methyl-D-aspartate (1 nM to 1 microM) or to (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA; 1 nM to 10 microM) elicited concentration-dependent and saturable rises in the levels of cyclic GMP. These responses were blocked by selective antagonists at the N-methyl-D-aspartate or AMPA receptors and by inhibiting nitric oxide synthase, but were insensitive to tetrodotoxin. When tested between 0.1 and 10 nM, serotonin, the serotonin1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin and the serotonin2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane inhibited, concentration-dependently, the cyclic GMP responses evoked by near-maximal (0.1 microM) concentrations of N-methyl-D-aspartate or AMPA. The EC50 values (concentrations causing half-maximal effect) ranged between 0.7 and 2.1 nM. The actions of serotonin were totally abolished by methiothepin, a mixed-type serotonin receptor antagonist. Thus, the serotonergic cerebellar afferents may exert a potent inhibitory control on the excitatory transmission mediated by N-methyl-D-aspartate and AMPA receptors; the inhibition occurs through both serotonin1A and serotonin2 receptors. As the glutamate receptor-dependent cyclic GMP responses involve production of nitric oxide, a diffusible activator of guanylate cyclase, the above inhibitory serotonin receptors may have multiple localization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Low nanomolar serotonin inhibits the glutamate receptor/nitric oxide/cyclic GMP pathway in slices from adult rat cerebellum. 747 56

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

In the present investigation we have tested the hypothesis that spinal glutamate release by inflammatory stimuli causes hyperalgesia through sensitization of the primary sensory neurons associated with nociception. In these experiments, the rat paw hyperalgesia pressure test in which inflammatory hyperalgesia is blocked by the intraplantar administration of morphine (MPH) or SNAP, a NO donor was used. Glutamate and glutamatergic ionotropic agonists such as NMDA or AMPA injected intrathecally (i.t.) caused a dose-dependent hyperalgesia. Quisqualate or ACPD, both of which are glutamate metabotropic receptor agonists, had no hyperalgesic effect. The hyperalgesic response to glutamate and NMDA injected i.t. was antagonized by the intraplantar (i.pl.) injection of either MPH or SNAP. This observation indicates that the hyperalgesia induced by glutamate acting through an NMDA pre-synaptic receptor causes sensitization of the primary sensory neurons. Confirming that the analgesia by i.pl. injection of SNAP or MPH was due to an action in primary peripheral sensory neurons, it was shown that pretreatment of the paws with methylene blue (MB, an inhibitor of guanylate cyclase) or with MB and L-NMMA (an inhibitor of NO synthase) abolished their respective analgesic effect. AMPA i.t. induced hyperalgesia was not inhibited by either i.pl. administration of MPH or SNAP, indicating that its hyperalgesic capacity results from an action at a site other than the primary sensory neuron.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate spinal retrograde sensitization of primary sensory neurons associated with nociception. 753 32

1. Nitric oxide (NO) is known to stimulate soluble guanylyl cyclase, thereby eliciting an elevation of guanosine 3':5'-cyclic monophosphate (cyclic GMP) in target cells. Recently, a selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), has been identified and characterized in vitro. We have investigated the in vivo effects of ODQ on the glutamate receptor/NO/ cyclic GMP pathway by monitoring extracellular cyclic GMP during microdialysis of the cerebellum or the hippocampus of freely-moving adult rats. 2. Intracerebellar administration of ODQ (1-100 microM) via the microdialysis probe inhibited, in a concentration-dependent manner, the basal extracellular level of cyclic GMP. The maximal inhibition, measured after a 20 min perfusion with 100 microM ODQ, amounted to 80% and persisted unchanged as long as ODQ was perfused. When ODQ was removed from the perfusion stream after 20 min, the levels of cyclic GMP started to recover, suggesting reversibility of guanylyl cyclase inhibition by ODQ. 3. The cyclic GMP response evoked in the cerebellum by NMDA (200 microM) or by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 100 microM) was largely attenuated by 100 microM ODQ. The pattern of the inhibition curves suggests competition for guanylyl cyclase between ODQ and the NO generated by NMDA or AMPA receptor activation. 4. ODQ (100 microM) prevented the elevation of extracellular cyclic GMP levels provoked by intracerebellar infusion of the NO generator S-nitroso-N-acetylpenicillamine (SNAP; 1 mM). The inhibition of the SNAP effect was rapidly relieved when ODQ was removed from the perfusion fluid. However, ODQ (100 microM) was unable to affect the cyclic GMP response elicited by 5 mM SNAP, in keeping with the proposed idea that ODQ binds to the "NO receptor' in a reversible and competitive manner. 5. Infusion of ODQ (10, 100 or 300 microM) into the hippocampus of freely-moving rats diminished the basal extracellular level of cyclic GMP. The maximal inhibition amounted to 50% and was produced by 100 microM ODQ. 6. The cyclic GMP response observed when 1 mM SNAP was perfused in the hippocampus, similar in percentage terms to that seen in cerebellum, was dramatically reduced during co-infusion of 100 microM ODQ. 7. ODQ appears to act in vivo as a selective, reversible and possibly competitive inhibitor of the soluble guanylyl cyclase targeted by NO. This enzyme may generate most (about 80%) of the cyclic GMP found under basal conditions in the extracellular space of the cerebellum. In the hippocampus, about 50% of the basal cyclic GMP does not seem to originate from the ODQ-sensitive soluble guanylyl cyclase.
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PMID:In vivo microdialysis study of a specific inhibitor of soluble guanylyl cyclase on the glutamate receptor/nitric oxide/cyclic GMP pathway. 889 83

A dose of N-methyl-D-aspartic acid (NMDA, 50 ng) that induces penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus, increased the concentration of NO2- from 1.10 +/- 0.28 microM to 7.32 +/- 1.12 microM and of NO3 from 4.96 +/- 0.69 microM to 10.5 +/- 1.61 microM in the paraventricular dialysate obtained from male rats by in vivo microdialysis. NO2- concentration was not increased by (+/-)-alpha-(amino)-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA, 100 ng) or by trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD) (100 ng), which were unable to induce these behavioral responses. N-Methyl-D-aspartic acid effect on NO2- concentration, penile erection and yawning was prevented by dizolcipine (MK-801) (10-100 ng) or by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (20 microg), but not by the oxytocin receptor antagonist [d(CH2)5,Tyr(Me)2,Orn8]vasotocin (100 ng), or by the guanylate cyclase inhibitor methylene blue (20 microg) given in the paraventricular nucleus 15 min before N-methyl-D-aspartic acid or by the dopamine receptor antagonist haloperidol (0.5 mg/kg) given intraperitoneally 30 min before N-methyl-D-aspartic acid. In contrast, the nitric oxide scavenger hemoglobin (20 microg) given in the paraventricular nucleus prevented N-methyl-D-aspartic acid-induced NO2- concentration increase, but was unable to prevent penile erection and yawning. The results suggest that N-methyl-D-aspartic acid induces penile erection and yawning by increasing nitric oxide synthase activity in the paraventricular nucleus of the hypothalamus, possibly in the cell bodies of oxytocinergic neurons projecting to extra-hypothalamic brain areas and mediating these behavioral responses.
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PMID:N-methyl-D-aspartic acid-induced penile erection and yawning: role of hypothalamic paraventricular nitric oxide. 921 92

Monitoring of extracellular cGMP during intracerebral microdialysis in freely moving rats permits the study of the functional changes occurring in the glutamate receptor/nitric oxide (NO) synthase/guanylyl cyclase pathway and the relationship of these changes to animal behaviour. When infused into the rat hippocampus in Mg2+-free medium, cyclothiazide, a blocker of desensitization of the AMPA-preferring receptor, increased cGMP levels. The effect of cyclothiazide (300 microM) was abolished by the NO synthase inhibitor L-NARG (100 microM) or the soluble guanylyl cyclase inhibitor ODQ (100 microM). During cyclothiazide infusion the animals displayed a pre-convulsive behaviour characterized by frequent "wet dog shakes" (WDS). Neither L-NARG nor ODQ decreased the WDS episodes. Both cGMP and WDS responses elicited by cyclothiazide were prevented by blocking NMDA receptor function with the glutamate site antagonist CGS 19755 (100 microM), the channel antagonist MK-801 (30 microM) or Mg2+ ions (1 mM). The AMPA/kainate receptor antagonists DNQX (100 microM) and NBQX (100 microM) abolished the WDS episodes but could not inhibit the cyclothiazide-evoked cGMP response. DNQX or NBQX (but not MK-801) elevated, on their own, extracellular cGMP levels. The cGMP response elicited by the antagonists appears to be due to prevention of a glutamate-dependent inhibitory GABAergic tone, since infusion of bicuculline (50 microM) caused a strong cGMP response. The results suggest that (a) AMPA/kainate receptors linked to the NO/cGMP pathway in the hippocampus (but not NMDA receptors) are tonically activated and kept in a desensitized state by endogenous glutamate; (b) blockade of AMPA/kainate receptor desensitization by cyclothiazide leads to endogenous activation of NMDA receptors; (c) the hippocampal NO/cGMP system is under a GABAergic inhibitory tone driven by non-NMDA ionotropic receptors; (d) the pre-convulsive episodes observed depend on hippocampal NMDA receptor activation but not on NO and cGMP production.
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PMID:The glutamate receptor/NO/cyclic GMP pathway in the hippocampus of freely moving rats: modulation by cyclothiazide, interaction with GABA and the behavioural consequences. 942 27

Intrahippocampal perfusion of bicuculline (50 microM) in Mg2+-free medium caused elevation of extracellular cGMP and epileptic-like behaviour. Both effects were partially prevented by blocking NMDA receptors with MK-801 or Mg2+ ions. Similarly, the GABA(B) receptor antagonists CGP52432 (0.1-30 microM) and CGP35348 (0.3-1 mM) evoked increases of extracellular cGMP. CGP52432 also elicited behavioural responses ranging from wet dog shakes to convulsions. MK-801 or Mg2+ ions reduced the effects of CGP52432. Local application of muscimol (100-300 microM) or (-)baclofen (300 microM) caused inhibition of extracellular cGMP. Administration of the AMPA/kainate receptor antagonist NBQX (100 microM) caused cGMP elevation which was almost abolished by co-perfusion of muscimol and (-)baclofen. In the presence of physiological Mg2+, perfusion of AMPA (30 microM) failed to affect cGMP levels, although rats displayed wet dog shakes episodes. When AMPA was co-perfused with low concentrations of bicuculline or CGP52432, cGMP elevations were observed in 60% of the rats. Addition of both antagonists to AMPA resulted in 85% of rats displaying a cGMP response. To conclude: (a) extracellular hippocampal cGMP is controlled by inhibitory GABA(A) and GABA(B) receptors tonically activated through GABAergic interneurons receiving AMPA/kainate-mediated glutamatergic inputs; (b) the GABAergic receptors are not endogenously saturated and can be further stimulated by exogenous agonists; (c) blockade of the GABA-mediated inhibition causes increase of cGMP and epileptic-like behaviour, due largely to endogenous activation of NMDA receptors; (d) reproducible cGMP responses to AMPA can be observed when the inhibitory GABAergic inputs to the NO/guanylyl cyclase system are blocked, confirming the previously proposed existence of AMPA/kainate receptors able to increase the nucleotide synthesis.
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PMID:In vivo microdialysis study of GABA(A) and GABA(B) receptors modulating the glutamate receptor/NO/cyclic GMP pathway in the rat hippocampus. 942 28

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

The diffusible intercellular messenger nitric oxide may have a modulatory role in the thalamus and this action may be mediated via activation of soluble guanylate cyclase. In order to investigate this possibility, we applied the cyclic-GMP analogue 8-Bromo-cyclic-GMP (8-Br-cGMP) onto neurones in the ventrobasal and lateral geniculate nuclei of the thalamus in anaesthetised rats, and compared its effects with those of a nitric oxide donor. 8-Br-cGMP enhanced the responses of neurones to iontophoretically applied NMDA and AMPA. Furthermore, somatosensory and visual responses of ventrobasal and lateral geniculate neurones were enhanced to 274+/-76% and 217+/-69% of control values, respectively. These effects were similar to those seen with nitric oxide donors in this study and previous work from this laboratory. When applied to thalamic neurones in an in vitro slice preparation, 8-Br-cGMP caused a membrane depolarisation associated with a decrease in input resistance. These findings indicate that activation of guanylate cyclase can cause a membrane depolarisation of thalamic neurones in vitro, and that this effect is sufficient to enhance action responses to ionotropic glutamate receptor stimulation via either exogenous agonists or sensory stimulation.
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PMID:Actions of 8-bromo-cyclic-GMP on neurones in the rat thalamus in vivo and in vitro. 1037 3


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