Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death

被引:303
作者
Gao, J
Duan, B
Wang, DG
Deng, XH
Zhang, GY
Xu, L
Xu, TL [1 ]
机构
[1] Chinese Acad Sci, Inst Neurosci, Shanghai 200031, Peoples R China
[2] Chinese Acad Sci, Key Lab Neurobiol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
[3] Univ Sci & Technol China, Hefei 230027, Peoples R China
[4] Xuzhou Med Coll, Res Ctr Biochem & Mol Biol, Xuzhou 221002, Peoples R China
[5] Chinese Acad Sci, Kunming Inst Zool, Lab Learning & Memory, Kunming 650223, Peoples R China
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
D O I
10.1016/j.neuron.2005.10.011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Acid-sensing ion channels (ASICs) composed of ASIC1a subunit exhibit a high Ca2+ permeability and play important roles in synaptic plasticity and acid-induced cell death. Here, we show that ischemia enhances ASIC currents through the phosphorylation at Ser478 and Ser479 of ASIC1a, leading to exacerbated ischemic cell death. The phosphorylation is catalyzed by Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, as a result of activation of NR2B-containing N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) during ischemia. Furthermore, NR2B-specific antagonist, CaMKII inhibitor, or overexpression of mutated form of ASIC1a with Ser478 or Ser479 replaced by alanine (ASICla-S478A, ASIC1a-S479A) in cultured hippocampal neurons prevented ischemia-induced enhancement of ASIC currents, cytoplasmic Ca2+ elevation, as well as neuronal death. Thus, NMDAR-CaMKII cascade is functionally coupled to ASICs and contributes to acidotoxicity during ischemia. Specific blockade of NMDAR/CaMKII-ASIC coupling may reduce neuronal death after ischemia and other pathological conditions involving excessive glutamate release and acidosis.
引用
收藏
页码:635 / 646
页数:12
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