Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6·PSD-95·MLK3 signaling module following cerebral ischemia in rat hippocampus
Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6·PSD-95·MLK3 signaling module following cerebral ischemia in rat hippocampus
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DOI：
10.1016/j.brainres.2005.09.001
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发表时间：
2005-11
期刊：
影响因子：
2.9
通讯作者：
Hui Tian;Quan-guang Zhang;G. Zhu;D. Pei;Qiu-hua Guan;Guang-yi Zhang
中科院分区：
文献类型：
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作者：
Hui Tian;Quan-guang Zhang;G. Zhu;D. Pei;Qiu-hua Guan;Guang-yi Zhang
红藻氨酸受体谷氨酸受体6（GluR 6）与突触后密度蛋白95（PSD-95）结合，PSD-95进而通过大鼠脑组织中的SH 3结构域锚定混合谱系激酶3（MLK 3）。MLK 3随后通过MAP激酶激酶（MKK）激活c-Jun NH 2-末端激酶（JNK）。我们研究了PSD-95与GluR 6和MLK 3的关系，MLK 3自磷酸化，MLK 3与JNK 3的相互作用，以及脑缺血后大鼠海马中JNK 3磷酸化。我们的结果表明，GluR 6·PSD-95·MLK 3复合物在再灌注6 h达到峰值。此外，MLK 3自身磷酸化以及MLK 3与JNK 3的相互作用还伴随着GluR 6·PSD-95·MLK 3信号模块的改变。为了进一步证实JNK 3在缺血海马中的激活是否是由GluR 6·PSD-95·MLK 3信号通路介导的，AMPA/KA受体拮抗剂6，7-二硝基喹喔啉-2，（1H，4 H）-二酮（DNQX）、GluR 6拮抗剂6，7，8，9-四氢-5-硝基-1H-苯并[g]吲哚-2，3-二酮-3-肟（NS 102）、AMPA受体拮抗剂1-缺血前20 min给予（4-氨基苯基）-4-甲基-7，8-亚甲二氧基-5H-2，3-苯并二氮杂卓（GYKI 52466）和NMDA受体拮抗剂氯胺酮。我们的研究结果表明，DNQX和NS 102都显着减弱PSD-95与GluR 6和MLK 3的关联，MLK 3自磷酸化，MLK 3与JNK 3的相互作用，以及JNK 3磷酸化，而GYKI 52466和氯胺酮没有影响。此外，在脑缺血前给予NS 102显著增加了再灌注5天时存活的海马CA 1锥体细胞的数量。因此，GluR 6，红藻氨酸受体的一个亚基，在诱导缺血损伤后JNK 3激活中起关键作用。
Kainate receptor glutamate receptor 6 (GluR6) binds to the postsynaptic density protein 95 (PSD-95), which in turn anchors mixed lineage kinase 3 (MLK3) via SH3 domain in rat brain tissue. MLK3 subsequently activates c-Jun NH2-terminal kinase (JNK) via MAP kinase kinases (MKKs). We investigated the association of PSD-95 with GluR6 and MLK3, MLK3 autophosphorylation, the interaction of MLK3 with JNK3, and JNK3 phosphorylation following cerebral ischemia in rat hippocampus. Our results indicate that the GluR6·PSD-95·MLK3 complex peaked at 6 h of reperfusion. Furthermore, MLK3 autophosphorylation and the interaction of MLK3 with JNK3 occurred with the alteration of GluR6·PSD-95·MLK3 signaling module. To further prove whether JNK3 activation in ischemic hippocampus is mediated by GluR6·PSD-95·MLK3 signaling pathway, the AMPA/KA receptor antagonist 6,7-dinitroquinoxaline-2, (1H, 4H)-dione (DNQX), the GluR6 antagonist 6,7,8,9-Tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS102), the AMPA receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo diazepine (GYKI52466), and the NMDA receptor antagonist ketamine were given to the rats 20 min prior to ischemia. Our findings indicate that both DNQX and NS102 significantly attenuated the association of PSD-95 with GluR6 and MLK3, MLK3 autophosphorylation, interaction of MLK3 with JNK3, and JNK3 phosphorylation, while GYKI52466 and ketamine had no effect. Moreover, administration of NS102 before cerebral ischemia significantly increased the number of the surviving hippocampal CA1 pyramidal cells at 5 days of reperfusion. Consequently, GluR6, one subunit of kainate receptor, plays a critical role in inducing JNK3 activation after ischemic injury.