Neuroprotection of Tat-GluR6-9c against Neuronal Death Induced by Kainate in Rat Hippocampus via Nuclear and Non-nuclear Pathways

• Published in: The Journal of biological chemistry Vol. 281; no. 25; pp. 17432 - 17445
• Main Authors: Liu, Xiao-Mei, Pei, Dong-Sheng, Guan, Qiu-Hua, Sun, Ya-Feng, Wang, Xiao-Tian, Zhang, Qing-Xiu, Zhang, Guang-Yi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.06.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Nucleus - metabolism; Drug Design; Fas Ligand Protein; Gene Products, tat - metabolism; GluK2 Kainate Receptor; Hippocampus - metabolism; Kainic Acid - metabolism; Male; MAP Kinase Kinase 4 - metabolism; Membrane Glycoproteins - metabolism; Neurons - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid - metabolism; Seizures - drug therapy; Tumor Necrosis Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M513490200

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.