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)

Postsynaptic processes induced by glutamate, GABA, and dopamine in dendritic spines of inhibitory striatal neurones, were studied. Some functional features were revealed in striatal neurones activation of two protein kinases, cAMP-dependent PKA and cGMP-dependent PKG; presence of calcium/calmodulin-independent adenylate cyclase; bidirectional changes of the cAMP concentration with dopamine. Rise of the cGMP concentration in striatum seems to be a result of activation of the membrane-bound guanylate cyclase via the GABAb receptors. The findings suggest that the active protein kinases/phosphatases ratio is affected by calcium influx through the NMDA-channels.
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PMID:[Interconnected biochemical processes in striatal neurons induced by activation of excitatory, inhibitory, and dopamine inputs]. 1088 13

The NMDA receptor/nitric oxide (NO)/cyclic GMP pathway and its modulation by 5-hydroxytryptamine (5-HT) was studied in slices of neocortical samples obtained from patients undergoing neurosurgery. The cyclic GMP elevation produced by 100 microM NMDA was blocked by 100 microM of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG) or by 10 microM of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha] quinoxaline-1-one (ODQ). The NMDA effect was prevented by 5-HT or by the 5-HT(2) agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI; EC(50)=22 nM). The (+/-)-DOI inhibition was insensitive to the 5-HT(2A) receptor antagonist MDL 100907 or the 5-HT(2B) antagonist rauwolscine; it was largely prevented by 1 microM of the non-selective 5-HT(2C) antagonists mesulergine (5-HT(2A,B,C)), ketanserin (5-HT(2A,C)) or SB 200646A (5-HT(2B,C)); it was completely abolished by 0.1 microM of the selective 5-HT(2C) receptor antagonist SB 242084. The NMDA-induced cyclic GMP elevation also was potently inhibited by the selective 5-HT(2C) agonist RO 60-0175 and by the antidepressant trazodone, both added at 1 microM, in an SB 242084-sensitive manner. Finally, the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 1 microM) inhibited the NMDA-evoked cyclic GMP response, an effect blocked by the selective 5-HT(1A) receptor antagonist WAY 100635. In conclusion, the NMDA receptor/NO/cyclic GMP pathway in human neocortex slices can be potently inhibited by activation of 5-HT(2C) or 5-HT(1A) receptors.
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PMID:Serotonin inhibition of the NMDA receptor/nitric oxide/cyclic GMP pathway in human neocortex slices: involvement of 5-HT(2C) and 5-HT(1A) receptors. 1095 74

S-nitroso-cysteinyl-glycine, a novel nitric oxide-adduct thiol compound, can be detected in the brain (2.3+/-0.6 pmol/mg protein), and released following stimulation of sensory afferents to the rat ventrobasal thalamus in vivo (resting conditions 17 nM; stimulation: 186 nM). Iontophoretic application of CysNOGly (20-80 nA) onto thalamic neurons in vivo resulted in enhancements of excitatory responses to either NMDA or AMPA (182+/-13.6% and 244+/-27.8% of control values, n = 15). CysNOGly enhanced responses to stimulation of vibrissal afferents to 132+/-2.2% (n = 7) of control values. In contrast, the dipeptide CysGly reduced responses of ventrobasal neurons to NMDA and AMPA (54+/-8.4% and 55+/-10.8% of control, n = 5). CysNOGly was also a potent activator of soluble guanylate cyclase in vitro. Moreover, we found that NMDA elevated CysNOGly levels in vitro and this stimulatory effect was reduced by inhibitors of the neuronal NO synthase and of the gamma-glutamyl transpeptidase, suggesting that production of NO and CysGly is a prelude to CysNOGly synthesis. These findings suggest that the nitrosothiol CysNOGly plays a role in synaptic transmission in the ventrobasal thalamus. We propose a novel synaptic buffering mechanism where S-nitroso-cysteinyl-glycine serves to restrict the locus of action of nitric oxide and so increase its local availability for target delivery. This could lead to a change in neuronal responses favouring sensory transmission similar to that seen in wakefulness or arousal in order to locally enhance transmission of persistent sensory stimuli.
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PMID:Novel mode of nitric oxide neurotransmission mediated via S-nitroso-cysteinyl-glycine. 1106 87

Whole brain spheroids provide a suitable model to study neurodevelopment. In the literature a role for the nitric oxide (NO)-cyclic guanosine 3',5'-monophosphate (cGMP) signalling pathway during development has frequently been suggested. In this study we investigated whether functional cGMP pathways were present in differentiated spheroids. In 3-week-old spheroids soluble guanylate cyclase was stimulated with N-methyl D-aspartic acid or sodium nitroprusside (NO donor). The results showed that the NO synthase-cGMP pathway is present in the culture system. Soluble guanylate cyclase-dependent cGMP formation was found in NO synthase containing neurons, in neurons of the GABAergic, glutamatergic and cholinergic system, and in astroglia and oligodendroglia. Activation of particulate guanylate cyclase by atrial natriuretic peptide also triggered an increase in cGMP production. Particulate guanylate cyclase was found in astroglia and in microglia as well as in glutamic acid decarboxylase and calbindin containing structures and neuronal NO synthase containing neurons. Chronic inhibition of NO synthase during culture development had no effect on soluble or particulate guanylate cyclase functioning. Similarly, inhibition of soluble guanylate cyclase during culture development did not have any effect on NO synthase and particulate guanylate cyclase functioning. It is concluded that NO synthase and both soluble and particulate guanylate cyclase are present in whole brain spheroid cultures and that their activity can be influenced by several stimuli. The spheroid culture system constitutes a suitable model to study the NO-cGMP pathway during brain development in mammals.
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PMID:Whole brain spheroid cultures as a model to study the development of nitric oxide synthase-guanylate cyclase signal transduction. 1115 66

It is shown that the glutamate-NO-cGMP pathway is impaired in cerebellum of rats with portacaval anastomosis in vivo as assessed by in vivo brain microdialysis in freely moving rats. NMDA-induced increase in extracellular cGMP in the cerebellum was significantly reduced (by 27%) in rats with portacaval anastomosis. Activation of soluble guanylate cyclase by the NO-generating agent S-nitroso-N-acetyl-penicillamine and by the NO-independent activator YC-1 was also significantly reduced (by 35-40%), indicating that portacaval anastomosis leads to remarkable alterations in the modulation of guanylate cyclase in cerebellum. Moreover, the content of soluble guanylate cyclase was increased ca. two-fold in the cerebellum of rats with portacaval anastomosis. Activation of soluble guanylate cyclase by NO was higher in lymphocytes isolated from rats with portacaval anastomosis (3.3-fold) than in lymphocytes from control rats (2.1-fold). The results reported show that the content and modulation of soluble guanylate cyclase are altered in brain of rats with hepatic failure, resulting in altered function of the glutamate-NO-cGMP pathway in the rat in vivo. This may lead to alterations in cerebral processes such as intercellular communication, circadian rhythms, including the sleep-waking cycle, long-term potentiation, and some forms of learning and memory.
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PMID:Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis. 1145 95

Microinjection of excitatory amino acids (EAA) into the dorsolateral periaqueductal gray (dlPAG) induces flight reactions while EAA antagonists show anxiolytic effects. Part of the effects mediated by NMDA receptors may involve an increase in nitric oxide (NO) production. We showed that nitric oxide synthase (NOS) inhibitors injected into the dlPAG induced anxiolytic effects. Conversely, SIN-1, a NO donor, produced orientated flight reactions that resemble stimulation of the medial hypothalamus. This compound also produced extensive Fos-like immunoreactivity in this region and in other areas related to defensive reactions such as the medial amygdala and cingulate cortex. Since part of the effects of NO involves increases in guanylate cyclase levels, we found that intra-dlPAG injection of 8-Br-cGMP induced a brief flight reaction followed by increased locomotion. In another experiment, we showed that single or repeated restraint stress produced an increased expression of neuronal NOS in the dlPAG and other areas related to defense, as measured by in situ hybridization, diaphorase histochemistry and immunocytochemistry. Together, these data suggest that NO may participate in the modulation of defensive responses in the dlPAG.
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PMID:Effects of excitatory amino acids and nitric oxide on flight behavior elicited from the dorsolateral periaqueductal gray. 1180 Dec 93

Nitric oxide (NO) may act as a toxin in several neuropathologies, including the brain damage resulting from cerebral ischaemia. Rat striatal slices were used to determine the mechanism of enhanced NO release following simulated ischaemia and, for estimating the NO concentrations, the activity of guanylyl cyclase served as a biosensor. Exposure of the slices for 10 min to an oxygen- and glucose-free medium caused a 70% fall in cGMP levels. On recovery, cGMP increased 2-fold above basal, where it remained for 40 min before declining. The pattern of changes matched those of cGMP or NO oxidation products measured during and after brain ischaemia in vivo. The increase observed during the recovery period was blocked by inhibition of NO synthase or NMDA receptors and was curtailed by tetrodotoxin, implying that it was caused by glutamate release leading to activation of the NMDA receptor-NO synthase pathway. Calibration of the cGMP levels against NO-stimulated guanylyl cyclase yielded a basal NO concentration of 0.6 nm. The peak NO concentration achieved on recovery from simulated ischaemia was estimated as 0.8 nm. These values are compatible with the low micromolar concentrations of NO oxidation products (chiefly nitrate) found by microdialysis in vivo, providing the NO inactivation rate (forming nitrate) is accounted for. NO at a concentration around 1 nm is unlikely to be toxic to cells. However, if the NO inactivation mechanism were to fail (as it can) the NO production rate normally providing only subnanomolar NO could readily generate toxic (microM) NO concentrations.
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PMID:Dynamics of nitric oxide during simulated ischaemia-reperfusion in rat striatal slices measured using an intrinsic biosensor, soluble guanylyl cyclase. 1191 55

2,5-Hexanedione is a neurotoxic metabolite of hexane. The mechanisms of its neurotoxicity remain unclear. We assessed whether chronic exposure to 2,5-hexanedione affects the glutamate-nitric oxide-cGMP pathway in primary cultures of cerebellar neurons and/or in the cerebellum of rats. Chronic exposure of cultured cerebellar neurons to 2,5-hexanedione (200 microM) reduced by approximately 50% NMDA-induced formation of cGMP. Activation of soluble guanylate cyclase by nitric oxide was reduced by 46%. This treatment reduced the content of neuronal nitric oxide synthase and soluble guanylate cyclase in neurons by 23 and 20%, respectively. In the cerebellum of rats chronically exposed to 2,5-hexanedione (in the drinking water) NMDA-induced formation of cGMP was reduced by 55% as determined by in vivo brain microdialysis. Activation of soluble guanylate cyclase by nitric oxide was reduced by 65%. The content of neuronal nitric oxide synthase and of soluble guanylate cyclase was reduced by 25 and 21%, respectively, in the cerebellum of these rats. The effects are the same in both systems, indicating that cultured neurons are a good model to study the mechanisms of neurotoxicity of 2,5-hexanedione. These results indicate that chronic exposure to 2,5-hexanedione affects the glutamate-nitric oxide-cGMP pathway at different steps both in cultured neurons and in cerebellum of the animal in vivo. The alteration of this pathway may contribute to the neurotoxic effects of 2,5-hexanedione.
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PMID:Chronic exposure to 2,5-hexanedione impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in rat brain in vivo. 1259 Sep 34

The dorsolateral periaqueductal grey (dlPAG) is proposed to play a role in the elaboration of defensive behaviors. Nitric oxide (NO) donors, injected into this region, induce flight reactions. The reactions have also been observed after electrical or chemical stimulation of the inferior colliculus (IC). The enzyme responsible for NO formation, neuronal nitric oxide synthase (nNOS), is expressed in the IC. The aims of this study were to investigate if NO donors injected into the IC would also cause aversive reactions and if these reactions would involve activation of NMDA receptors. The results showed that 3-morpholinosylnomine hydrochloride (SIN-1; 300 nmol), an NO donor, injected into the central nucleus but not into the dorsal cortex of the IC (CIC and DCIC, respectively) of male Wistar rats induced flight reactions characterized by galloping and jumps. Pretreatment (10 min) with methylene blue (MB; 100 or 200 nmol), a guanylate cyclase (GC) inhibitor, partially inhibited this flight reaction, decreasing the number of jumps. 8-Bromo-cGMP (8-Br-GMP), a membrane-permeable cGMP analogue, increased the number of contralateral turnings. Pretreatment (10 min) with the NMDA receptor antagonist amino-7-phosphonoheptanoic acid (AP7; 2 nmol) completely prevented the effects of SIN-1. It is concluded that NO may induce aversive reactions in the CIC and that these reactions depend on NMDA receptor activation. They may also partially involve facilitation of GC activity.
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PMID:Flight reactions to nitric oxide in the inferior colliculus of rats depend on NMDA receptor activation. 1367 15

The biosynthesis, localization and fate of catecholamines in the ink gland of the cuttlefish Sepia officinalis were investigated by combined biochemical and immunohistocytochemical methodologies. HPLC analysis of crude ink gland extracts indicated the presence of dopa (2.18+/-0.82 nmol/mg of protein) and DA (dopamine, 0.06+/-0.02 nmol/mg of protein), but no detectable noradrenaline or adrenaline. DA was shown to derive from L-tyrosine, according to experiments performed by incubating intact ink glands with [L-14C]tyrosine. The biosynthetic process involves a tyrosine hydroxylase and a dopa decarboxylase pathway and is independent of tyrosinase. The tyrosine hydroxylase activity was detected under conditions of tyrosinase suppression in the cytosolic fraction, but not in the melanosomal fraction, of ink gland extracts, and the presence of the enzyme was confirmed by Western-blot analysis. Dopa and DA were found to be released from the ink glands by processes controlled through the NMDA-nitric oxide-cGMP (where NMDA stands for N -methyl-D-aspartate) signalling pathway, as apparent from incubation experiments performed with [L-14C]tyrosine in the presence of NMDA, diethylamine NONOate (diethylamine diazeniumdiolate), a nitric oxide donor, 8-bromo-cGMP or a guanylyl cyclase inhibitor. Immunohistochemical results coupled with electron microscopy indicated that DA was concentrated in vesicles specifically localized in the mature melanin-producing cells of the ink gland proximal to the lumen and separated from the melanin-containing melanosomes. NMDA receptor stimulation or exposure to an NO donor caused a marked loss of DA immunoreactivity in mature cells, consistent with a release process. In the lumen of the ink gland, where mature exhausted cells pour their contents, DA immunoreactivity was found to be associated with the melanin granules, due apparently to physical adsorption. Overall, these results point to DA as a marker of cell maturation in Sepia ink gland subject to release by the NO/cGMP signalling pathway, and disclose apparently overlooked DA-melanin interactions in secreted ink of possible relevance to the defence mechanism.
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PMID:Dopamine in the ink defence system of Sepia officinalis: biosynthesis, vesicular compartmentation in mature ink gland cells, nitric oxide (NO)/cGMP-induced depletion and fate in secreted ink. 1467 74


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