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GluR6-containing KA receptor mediates the activation of p38 MAP kinase in rat hippocampal CA1 region during brain ischemia injury.

Author	Juan Chen, Chong Li, Dong-Sheng Pei, Dong Han, Xiao-Mei Liu, Hai-Xia Jiang, Xiao-Tian Wang, Qiu-Hua Guan, Xiang-Ru Wen, Xiao-Yu Hou, Guang-Yi Zhang
Citation Information	Hippocampus, 19:79-89 (2009)
Keywords	Animals, Brain Infarction, Cell Survival, Disease Models, Animal, Down-Regulation, Enzyme Activation, Enzyme Inhibitors, Glutamic Acid, Hippocampus, Hypoxia-Ischemia, Brain, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 3, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Male, Oligodeoxyribonucleotides, Antisense, Phosphorylation, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, Receptors, Kainic Acid, Reperfusion Injury, Synaptic Transmission, p38 Mitogen-Activated Protein Kinases
Related Products	S7100
Pub Med ID	18680160

Our previous study showed that kainate (KA) receptor subunit GluR6 played an important role in ischemia-induced MLK3 and JNK activation and neuronal degeneration through the GluR6-PSD95-MLK3 signaling module. However, whether the KA receptors subunit GluR6 is involved in the activation of p38 MAP kinase during the transient brain ischemia/reperfusion (I/R) in the rat hippocampal CA1 subfield is still unknown. In this present study, we first evaluated the time-course of phospho-p38 MAP kinase at various time-points after 15 min of ischemia and then observed the effects of antagonist of KA receptor subunit GluR6, GluR6 antisence oligodeoxynucleotides on the phosphorylation of p38 MAP kinase induced by I/R. Results showed that inhibiting KA receptor GluR6 or suppressing the expression of KA receptor GluR6 could down-regulate the elevation of phospho-p38 MAP kinase induced by I/R. These drugs also reduced the phosphorylation of MLK3, MKK3/MKK6, MKK4, and MAPKAPK2. Additionally, our results indicated administration of three drugs, including p38 MAP kinase inhibitor before brain ischemia significantly decreased the number of TUNEL-positive cells detected at 3 days of reperfusion and increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion after 15 min of ischemia. Taken together, we suggest that GluR6-contained KA receptors can mediate p38 MAP kinase activation through a kinase cascade, including MLK3, MKK3/MKK6, and MKK4 and then induce increased phosphorylation of MAPKAPK-2 during ischemia injury and ultimately result in neuronal cell death in the rat hippocampal CA1 region.