title: Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia.
abstract: 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.
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Qiu-Ju
authors.initials: QJ
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Fan-Shu
authors.initials: FS
authors.lastname: Kong
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Cai-Ping
authors.initials: CP
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Chang-Cheng
authors.initials: CC
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu 221004, China xyhou@xzmc.edu.cn.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Hou
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000097806:GluK2 Kainate Receptor
chemical_list: D048057:Mitogen-Activated Protein Kinase 10; D016755:Proto-Oncogene Proteins c-jun; D018092:Kainic Acid Receptors; D014443:Tyrosine; D019061:src-Family Kinases; D000097806:GluK2 Kainate Receptor