文章基本信息

标题：Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia
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作者：Qiu-Ju Zhu ; Fan-Shu Kong ; Hao Xu 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：38
页码：13990-13995
DOI：10.1073/pnas.1403493111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGlutamate is the principal excitatory neurotransmitter in the brain. Kainate receptors, a subfamily of the ionotropic glutamate receptors, mediate the pre- and postsynaptic actions of glutamate. Overactivation of postsynaptic kainate receptors plays an important role in neurodegeneration after ischemic stroke. Because Src kinases show increased activity after brain ischemia, we evaluated their roles in regulating kainate receptor function after brain ischemia. Our results demonstrate that Src kinases bind to and phosphorylate GluK2 at Y590 and facilitate kainate-evoked whole-cell currents and calcium influx. Furthermore, long-term kainate stimulation promotes apoptosis through the endocytosis of GluK2 subunits and activation of JNK3-c-Jun signaling. In summary, our results demonstrate that Src phosphorylation of GluK2 regulates kainate receptor activity and downstream excitatory signaling. Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.