title: GluR6-containing KA receptor mediates the activation of p38 MAP kinase in rat hippocampal CA1 region during brain ischemia injury.
abstract: 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.
authors.affiliation: Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Pei
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Liu
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Jiang
authors.forename: Xiao-Tian
authors.initials: XT
authors.lastname: Wang
authors.forename: Qiu-Hua
authors.initials: QH
authors.lastname: Guan
authors.forename: Xiang-Ru
authors.initials: XR
authors.lastname: Wen
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Hou
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D047908:Intracellular Signaling Peptides and Proteins; D048371:MAP Kinase Kinase 3; D020930:MAP Kinase Kinase Kinases; D020319:Oligodeoxyribonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D018092:Kainic Acid Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor; D000099190:MAP-Kinase-Activated Kinase 2