TY - JOUR
T1 - Activation of c-Jun NH2-terminal kinase 3 is mediated by the GluR6·PSD-95·MLK3 signaling module following cerebral ischemia in rat hippocampus
AU - Tian, Hui
AU - Zhang, Quan Guang
AU - Zhu, Guang Xuan
AU - Pei, Dong Sheng
AU - Guan, Qiu Hua
AU - Zhang, Guang Yi
N1 - Funding Information:
This project is supported by the National Nature Science Foundation of China (No. 30330190).
PY - 2005/11/2
Y1 - 2005/11/2
N2 - 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.
AB - 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.
KW - Cerebral ischemia
KW - Glutamate receptor 6
KW - Kainate receptor
KW - Mixed lineage kinase 3
KW - Postsynaptic density protein 95
KW - c-Jun NH2-terminal kinase 3
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UR - http://www.scopus.com/inward/citedby.url?scp=27444434211&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2005.09.001
DO - 10.1016/j.brainres.2005.09.001
M3 - Article
C2 - 16256962
AN - SCOPUS:27444434211
SN - 0006-8993
VL - 1061
SP - 57
EP - 66
JO - Brain Research
JF - Brain Research
IS - 1
ER -