Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the abilities of 7-nitroindazole and methylene blue, inhibitors of the neuronal isoform of nitric oxide synthase (NOS) and nitric oxide-stimulated guanylate cyclase activity respectively, to attenuate explosive episodic jumping behavior(s) ("popping") elicited by MK-801 in mice. MK-801, like phencyclidine (PCP), is a high-affinity, noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. We have postulated that MK-801-elicited popping behavior in mice represents an animal model of schizophrenia, because popping behavior is markedly inhibited/antagonized by both typical and atypical antipsychotic drugs. In the present study, popping behavior induced by MK-801 was measured using an automated detection system that quantifies vertical displacements on the testing platform. 7-Nitroindazole (100 mg/kg) and methylene blue (32 and 100 mg/kg) significantly reduced the number and force of MK-801-elicited popping behavior. Mouse rotorod performance did not differ between animals receiving 7-nitroindazole, methylene blue, or their respective vehicles, suggesting that attenuation of MK-801-elicited popping behavior was not due to either sedation or ataxia caused by 7-nitroindazole or methylene blue. Our findings suggest that nitric oxide may, in part, mediate behaviors induced by NMDA receptor antagonists, like MK-801, and that inhibitors of NOS may have antipsychotic actions.
 ...
PMID:7-Nitroindazole and methylene blue, inhibitors of neuronal nitric oxide synthase and NO-stimulated guanylate cyclase, block MK-801-elicited behaviors in mice. 879 90

We previously verified the effectiveness of tetrahydrobiopterin (BH4) on the ataxia in Machado-Joseph disease (MJD; SCA3 [spinocerebellar ataxia type 3]) as one of the most common types of dominantly inherited spinocerebellar ataxias. We hypothesized as to the pharmacological mechanism of BH4 that on the basis of 'cerebellar long-term depression' theory, BH4 may exert its actions at the levels of soluble guanylate cyclase in the Purkinje cells and of nitric oxide synthase in the granule cells. If cerebellar long-term depression is the case as the theoretical basis of BH4, it will open a new page of therapeutic strategy for spinocerebellar ataxias.
 ...
PMID:Effects of tetrahydrobiopterin on ataxia in Machado-Joseph disease may be based upon the theory of 'cerebellar long-term depression'. 1146 Nov 69

We have reported previously that intracerebellar nicotine attenuates ethanol ataxia via nicotinic-cholinergic receptors. We report now that attenuation of ethanol ataxia by intracerebellar nicotine is modulated by cerebellar nitric oxide-guanylyl cyclase (GC) messenger system. Intracerebellar microinfusion of SNP (sodium nitroprusside, a nitric oxide donor; 15, 30, and 60 pg) and SMT (S-methylisothiourea; 70, 140, and 280 fg; an inhibitor of inducible nitric oxide synthase), significantly enhanced and reduced, respectively, intracerebellar nicotine-induced attenuation of ethanol ataxia in a dose-related manner. Similarly, intracerebellar isoliquiritigenin (an activator of GC; 1, 2, and 4 pg) and ODQ (1H [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, an inhibitor of GC; 375, 750, and 1500 fg), significantly enhanced and reduced, respectively, intracerebellar nicotine-induced attenuation of ethanol ataxia in a dose-related fashion. These results suggest that the functional interaction between nicotine and ethanol may involve modulation by cerebellar nitric oxide and cGMP. Intracerebellar microinfusion of isoliquiritigenin (4, 8, and 16 pg) in the absence of nicotine significantly attenuated ethanol ataxia dose-dependently indicating a tonic involvement of cGMP in ethanol ataxia. Finally, intracerebellar nicotine (5 ng) significantly increased and ethanol 2 g/kg i.p. decreased levels of total cerebellar nitrite+nitrate (NOx) which were functionally correlated with ethanol ataxia and its attenuation by intracerebellar nicotine. The ethanol-induced decrease in NOx was significantly antagonized by intracerebellar nicotine. The NOx data further supported an involvement of nitric oxide in the behavioral interaction between nicotine and ethanol. Overall, the results of the present investigation demonstrate a functional correlation between cerebellar nitric oxide messenger system and the behavioral interaction between nicotine and ethanol.
 ...
PMID:Antagonism of ethanol ataxia by intracerebellar nicotine: possible modulation by mouse cerebellar nitric oxide and cGMP. 1653 69

We have recently reported that mediation of intracerebellar nicotine-induced attenuation of cerebellar delta9-THC ataxia was via the alpha4beta2 nAChR. The present study was meant to investigate the role of cerebellar nitric oxide (NO)-guanylyl cyclase (GC) signaling in the alpha4beta2-mediated attenuation in CD-1 male mice. Drugs were given via intracerebellar microinfusion using stereotaxically implanted guide cannulas, with ataxia evaluated by Rotorod. Intracerebellar microinfusion of SNP (sodium nitroprusside, NO donor; 15, 30, 60 pg) and SMT (S-methylisothiourea, inhibitor of inducible NO synthase; 70, 140, 280 fg) significantly enhanced and reduced, respectively, intracerebellar RJR-2403 (selective alpha4beta2 agonist)-induced attenuation of delta9-THC ataxia dose-dependently. Intracerebellar isoliquiritigenin (GC-activator; 1, 2, 4 pg) and ODQ (1H[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, GC inhibitor; 200, 400, 800 fg), significantly enhanced and reduced, respectively, intracerebellar RJR-2403-induced attenuation of delta9-THC ataxia dose-dependently. Further support for the role of NO was evidenced via increases in cerebellar NO(x) (nitrate+nitrite) levels following microinfusion of nicotine or RJR-2403 as compared to control, whereas delta9-THC significantly decreased NO(x) levels. "Nicotine/RJR-2403+delta9-THC" treated mice had cerebellar NO(x) levels significantly increased as compared to mice infused with delta9-THC alone. Results of the present investigation support the role of cerebellar NO-GC signaling in alpha4beta2 nAChR subtype-mediated attenuation of delta9-THC ataxia.
 ...
PMID:Involvement of the alpha4beta2 nicotinic receptor subtype in nicotine-induced attenuation of delta9-THC cerebellar ataxia: role of cerebellar nitric oxide. 1727 78

Purkinje cell (PC) dysfunction or death has been implicated in a number of disorders including ataxia, autism and multiple sclerosis. Plasma membrane calcium ATPase 2 (PMCA2), an important calcium (Ca(2+)) extrusion pump that interacts with synaptic signaling complexes, is most abundantly expressed in PCs compared to other neurons. Using the PMCA2 heterozygous mouse as a model, we investigated whether a reduction in PMCA2 levels affects PC function. We focused on Ca(2+) signaling and the expression of glutamate receptors which play a key role in PC function including synaptic plasticity. We found that the amplitude of depolarization and 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor (AMPAR)-mediated Ca(2+) transients are significantly higher in cultured PMCA2(+/-) PCs than in PMCA2(+/+) PCs. This is due to increased Ca(2+) influx, since P/Q type voltage-gated Ca(2+) channel (VGCC) expression was more pronounced in PCs and cerebella of PMCA2(+/-) mice and VGCC blockade prevented the elevation in amplitude. Neuronal nitric oxide synthase (nNOS) activity was higher in PMCA2(+/-) cerebella and inhibition of nNOS or the soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, which mediates nitric oxide (NO) signaling, reduced the amplitude of Ca(2+) transients in PMCA2(+/-) PCs, in vitro. In addition, there was an age-dependent decrease in metabotropic glutamate receptor 1 (mGluR1) and AMPA receptor subunit GluR2/3 transcript and protein levels at 8 weeks of age. These changes were followed by PC loss in the 20-week-old PMCA2(+/-) mice. Our studies highlight the importance of PMCA2 in Ca(2+) signaling, glutamate receptor expression and survival of Purkinje cells.
 ...
PMID:Purkinje cell dysfunction and delayed death in plasma membrane calcium ATPase 2-heterozygous mice. 2278 21