Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus

Quan Guang Zhang, Hui Tian, Hong Chun Li, Guang Yi Zhang

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Cerebral ischemia induces kainate receptor glutamate receptor 6 (GluR6) binding to the postsynaptic density protein 95 (PSD95), which in turn anchors mixed lineage kinase 3 (MLK3) via SH3 domain in rat brain. MLK3 subsequently activates c-Jun NH2-terminal kinase (JNK) via MAP kinase kinases (MKKs). In this study, we investigated the association of PSD95 with GluR6 and MLK3, the autophosphorylation of MLK3, the combination of MLK3 with JNK3, and the phosphorylation of JNK3 during cerebral ischemia in rat hippocampus CA1. Our results indicate that the GluR6-PSD95-MLK3 complex quickly enhanced at 5 min of ischemia and peaked at 10 min of ischemia, and then gradually reduced with the prolonged time of ischemia. Interestingly, the combination of MLK3 and JNK3 gradually increased from 5 min to 30 min of ischemia. JNK3 phosphorylation first increased and then attenuated in cytosol, suggesting the translocation of activated JNK3 to nucleus during ischemia. To further investigate the possible mechanism of JNK3 activation, antioxidant N-acetylcysteine (NAC) was given to the rats 20 min prior to ischemia. Results indicate that NAC distinctly inhibited the association of PSD95 with GluR6 and MLK3, the autophosphorylation of MLK3, the combination of MLK3 with JNK3 and JNK3 activation. Taken together, these finding indicate that ischemic stimulation results in JNK3 activation through the GluR6-PSD95-MLK3 signaling module, and that the activation of JNK3 is closely related to oxidative stress.

Original languageEnglish (US)
Pages (from-to)159-164
Number of pages6
JournalNeuroscience Letters
Volume408
Issue number3
DOIs
StatePublished - Nov 20 2006
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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