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

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Summary

Introduction

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.

Results
Conclusion
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