Neuroprotection of Tat-GluR6-9c against neuronal death induced by kainate in rat hippocampus via nuclear and non-nuclear pathways.
Previous studies have suggested that glutamate receptor 6 (GluR6) subunit- and JNK-deficient mice can resist kainate-induced epileptic seizure and neuronal toxicity (Yang, D. D., Kuan, C.-Y., Whitmarsh, A. J., Rinoćn, M., Zheng, T. S., Davis, R. J., Rakic, P., and Flavell, R. A. (1997) Nature 389, 865-870; Mulle, C., Seiler, A., Perez-Otano, I., Dickinson-Anson, H., Castillo, P. E., Bureau, I., Maron, C., Gage, F. H., Mann, J. R., Bettler, B., and Heinemmann, S. F. (1998) Nature 392, 601-605). In this study, we show that kainate can enhance the assembly of the GluR6-PSD95-MLK3 module and facilitate the phosphorylation of JNK in rat hippocampal CA1 and CA3/dentate gyrus (DG) subfields. More important, a peptide containing the Tat protein transduction sequence (Tat-GluR6-9c) perturbed the assembly of the GluR6-PSD95-MLK3 signaling module and suppressed the activation of MLK3, MKK7, and JNK. As a result, the inhibition of JNK activation by Tat-GluR6-9c diminished the phosphorylation of the transcription factor c-Jun and down-regulated Fas ligand expression in hippocampal CA1 and CA3/DG regions. The inhibition of JNK activation by Tat-Glur6-9c attenuated Bax translocation, the release of cytochrome c, and the activation of caspase-3 in CA1 and CA3/DG subfields. Furthermore, kainate-induced neuronal loss in hippocampal CA1 and CA3 subregions was prevented by intracerebroventricular injection of Tat-Glur6 - 9c. Taken together, our findings strongly suggest that the GluR6-PSD95-MLK3 signaling module mediates activation of the nuclear and non-nuclear pathways of JNK, which is involved in brain injury induced by kainate. Tat-GluR6-9c, the peptide we constructed, gives new insight into seizure therapy.
Liu
Xiao-Mei
XM
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Pei
Dong-Sheng
DS
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Guan
Qiu-Hua
QH
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Sun
Ya-Feng
YF
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Wang
Xiao-Tian
XT
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Zhang
Qing-Xiu
QX
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
Zhang
Guang-Yi
GY
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China. Electronic address: gyzhang@xzmc.edu.cn.
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D015195:Drug Design; D053222:Fas Ligand Protein; D015696:Gene Products, tat / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007608:Kainic Acid / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy; D048069:Tumor Necrosis Factors / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
D053222:Fas Ligand Protein; D015696:Gene Products, tat; D007608:Kainic Acid; D048670:MAP Kinase Kinase 4; D008562:Membrane Glycoproteins; D016755:Proto-Oncogene Proteins c-jun; D018092:Kainic Acid Receptors; D048069:Tumor Necrosis Factors; D000097806:GluK2 Kainate Receptor; C505662:Faslg protein, rat