Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-nitrosylation, as a post-translational protein modification, recently has been paid more and more attention in stroke research. S-nitrosylation regulates protein function by the mechanisms of covalent attachment that control the addition or the removal of nitric oxide (NO) from a cysteine thiol. The derivation of NO is established by the demonstration that, in cerebral neurons, NO mainly generates from neuronal nitric oxide synthase (nNOS) during the early stages of reperfusion. In the past researches, we demonstrate that global ischemia-reperfusion facilitates the activation of glutamate receptor 6 (GluR6) -mediated c-Jun N-terminal kinase (JNK) signaling pathway. The objective of this study is primarily to determine, during the early stages of reperfusion in rat four-vessel occlusion (4-VO) ischemic model, whether nNOS-derived NO affects the GluR6-mediated JNK signaling route via S-nitrosylation which is performed mainly by the biotin switch assay. Here, we show that administration of 7-nitroindazole, an inhibitor of nNOS, or ketamine, an antagonist of N-methyl-d-aspartate receptor (NMDAR), diminishes the increased S-nitrosylation of GluR6 induced by cerebral ischemia-reperfusion. In contrast, 2-amion-5,6-dihydro-6-methyl-4H-1,3-thiazine, an inhibitor of inducible NO synthase does not affect S-nitrosylation of GluR6. Moreover, treatment with sodium nitroprusside (SNP), an exogenous NO donor, increases the S-nitrosylation and phosphorylation of nNOS, leading to the attenuation of the increased S-nitrosylation of GluR6 and the assembling of GluR6* postsynaptic density protein 95 (PSD95)* mixed lineage kinase 3 (MLK3) signaling module induced by cerebral ischemia-reperfusion. The results also show that GluR6 downstream MLK3* mitogen activated protein kinase kinase 4/7* JNK signaling module and nuclear or non-nuclear apoptosis pathways are involved in the above signaling route. However, dithiothreitol (DTT) antagonizes the neuroprotection of SNP. Treatment with DTT alone, as a negative control, prevents S-nitrosylation of proteins, which indicates the existence of endogenously produced S-nitrosylation. These data suggest that GluR6 is S-nitrosylated by endogenous NO in cerebral ischemia-reperfusion, which is possibly correlated with NMDAR* PSD95* nNOS signaling module, and further activates GluR6* PSD95* MLK3 signaling module and JNK signaling pathway. In contrast, exogenous NO donor antagonizes the above action of endogenous NO generated from nNOS. Thus, our results provide the coupling of nNOS with GluR6 by S-nitrosylation during the early stages of ischemia-reperfusion, which can be a new approach for stroke therapy.
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PMID:Coupling between neuronal nitric oxide synthase and glutamate receptor 6-mediated c-Jun N-terminal kinase signaling pathway via S-nitrosylation contributes to ischemia neuronal death. 1867 85

Our previous studies showed that the assembly of the GluR6-PSD95-mixed lineage kinase 3 (MLK3) signaling module played an important role in rat ischemic brain injury. In this study, we aimed to elucidate whether ischemic preconditioning could downregulate the assembly of the GluR6-PSD95-MLK3 signaling module and suppress the activation of MLK3, MKK4/7, and c-Jun N-terminal kinase (JNK). As a result, ischemic preconditioning could not only inhibit the assembly of the GluR6-PSD95-MLK3 signaling module, diminish the phosphorylation of the transcription factor c-Jun, downregulate Fas ligand expression, attenuate the phosphorylation of 14-3-3 and Bcl-2 and the translocation of Bax to mitochondria, but also increase the release of cytochrome c and the activation of caspase-3. In contrast, both GluR6 antisense ODNs (oligodeoxynucleotides) and 6,7,8,9-tetrahydro-5-nitro-1 H-benz[g]indole-2,3-dione-3-oxime (NS102), an antagonist of GluR6 receptor, prevented the above effects of preconditioning, which shows that suppressing the expression of GluR6 or inhibiting GluR6 activity contributes negatively to preconditioning-induced ischemia tolerance. Taken together, our results indicate that preconditioning can inhibit the over-assembly of the GluR6-PSD95-MLK3 signaling module and the JNK3 activation. GluR6 subunit-containing kainite receptors play an important role in the preconditioning-induced neuronal survival and provide new insight into stroke therapy.
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PMID:Neuroprotection of preconditioning against ischemic brain injury in rat hippocampus through inhibition of the assembly of GluR6-PSD95-mixed lineage kinase 3 signaling module via nuclear and non-nuclear pathways. 1932 23

GluR6 kainate receptor subunit is largely expressed in hippocampus of brain regions and plays an important role in brain ischemia/reperfusion-mediated neuronal cell death. Our previous researches have shown that cerebral ischemia/reperfusion could facilitate the assembly of GluR6 and postsynaptic density protein 95(PSD95) as well as mixed lineage kinase 3(MLK3) and further induce the activation of c-Jun NH2-terminal kinase 3(JNK3), leading to neuronal death of hippocampal CA1. Here, we show that over-expression of C-terminal amino acids of GluR6 can interrupt the combination of GluR6 with PSD95, inhibit the assembly of GluR6.PSD-95.MLK3 signaling module, suppress the activation of JNK3 and the downstream signaling pathway. Thus, our results imply that over-expression of C-terminal amino acids of GluR6 induce neuroprotection against ischaemic brain injury in rat hippocampal CA1 region via suppressing proapoptosis signaling pathways, which can be an experimental foundation for gene therapy of stroke.
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PMID:Inhibition of cerebral ischemia/reperfusion-induced injury by adenovirus expressed C-terminal amino acids of GluR6. 1974 68

Previous studies in our laboratory have shown that mixed lineage kinase 3 (MLK3) can be activated following global ischemia. In addition, other laboratories have reported that the activation of MLK3 may be linked to the accumulation of free radicals. However, the mechanism of MLK3 activation remains incompletely understood. We report here that MLK3, overexpressed in HEK293 cells, is S-nitrosylated (forming SNO-MLK3) via a reaction with S-nitrosoglutathione, an exogenous nitric oxide (NO) donor, at one critical cysteine residue (Cys-688). We further show that the S-nitrosylation of MLK3 contributes to its dimerization and activation. We also investigated whether the activation of MLK3 is associated with S-nitrosylation following rat brain ischemia/reperfusion. Our results show that the administration of 7-nitroindazole, an inhibitor of neuronal NO synthase (nNOS), or nNOS antisense oligodeoxynucleotides diminished the S-nitrosylation of MLK3 and inhibited its activation induced by cerebral ischemia/reperfusion. In contrast, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (an inhibitor of inducible NO synthase) or nNOS missense oligodeoxynucleotides did not affect the S-nitrosylation of MLK3. In addition, treatment with sodium nitroprusside (an exogenous NO donor) and S-nitrosoglutathione or MK801, an antagonist of the N-methyl-D-aspartate receptor, also diminished the S-nitrosylation and activation of MLK3 induced by cerebral ischemia/reperfusion. The activation of MLK3 facilitated its downstream protein kinase kinase 4/7 (MKK4/7)-JNK signaling module and both nuclear and non-nuclear apoptosis pathways. These data suggest that the activation of MLK3 during the early stages of ischemia/reperfusion is modulated by S-nitrosylation and provides a potential new approach for stroke therapy whereby the post-translational modification machinery is targeted.
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PMID:S-nitrosylation of mixed lineage kinase 3 contributes to its activation after cerebral ischemia. 2212 24