Abstract
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.
Highlights
Administration of KA produces epilepsy in rats and mice accompanied by neuronal damage mainly in limbic structures
Of the glutamate receptor 6 (GluR6)-PSD95-MLK3 Signaling Module during Seizure Induced by Kainate in Hippocampal CA1 and CA3/dentate gyrus (DG) Regions—To investigate the alternation of the assembly of the GluR6-PSD95-MLK3 signaling module during seizure, rats were injected with KA at different times and decapitated immediately at several time points, and the hippocampi were removed for homogenization
The Tat-GluR6-9c Peptide Suppresses the Increased Assembly of the GluR6-PSD95-MLK3 Signaling Module Induced by Kainate in Hippocampal CA1 and CA3/DG Regions—Our results showed that the association of GluR6-PSD95-MLK3 reached its peak level at 6 h after KA injection
Summary
Administration of KA produces epilepsy in rats and mice accompanied by neuronal damage mainly in limbic structures. Tat-GluR6-9c decreases neuronal death induced by kainate in hippocampal CA1 and CA3 subregions via the nuclear and non-nuclear pathways of JNK.
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