Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6·PSD-95·MLK3 signaling module following cerebral ischemia in rat hippocampus

Hui Tian, Quan Guang Zhang, Guang Xuan Zhu, Dong Sheng Pei, Qiu Hua Guan, Guang Yi Zhang

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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 NH 2-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.

Original languageEnglish (US)
Pages (from-to)57-66
Number of pages10
JournalBrain Research
Volume1061
Issue number1
DOIs
StatePublished - Nov 2 2005
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Glutamate receptor 6
  • Kainate receptor
  • Mixed lineage kinase 3
  • Postsynaptic density protein 95
  • c-Jun NH2-terminal kinase 3

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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