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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.
AuthorsQiu-Ju Zhu, Fan-Shu Kong, Hao Xu, Yi Wang, Cai-Ping Du, Chang-Cheng Sun, Yong Liu, Ting Li, Xiao-Yu Hou
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 38 Pg. 13990-5 (Sep 23 2014) ISSN: 1091-6490 [Electronic] United States
PMID25201974 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Gluk2 kainate receptor
  • Proto-Oncogene Proteins c-jun
  • Receptors, Kainic Acid
  • Tyrosine
  • Mitogen-Activated Protein Kinase 10
  • src-Family Kinases
Topics
  • Animals
  • Brain Ischemia (genetics, metabolism, pathology)
  • HEK293 Cells
  • Hippocampus (metabolism, pathology)
  • Humans
  • Male
  • Mitogen-Activated Protein Kinase 10 (genetics, metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-jun (genetics, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Kainic Acid (genetics, metabolism)
  • Signal Transduction (physiology)
  • Stroke (genetics, metabolism, pathology)
  • Tyrosine (genetics, metabolism)
  • Up-Regulation (physiology)
  • src-Family Kinases (genetics, metabolism)

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