Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction

被引:107
|
作者
Wang, Yi-Zhi [1 ]
Wang, Jing-Jing [1 ]
Huang, Yu [1 ]
Liu, Fan [1 ]
Zeng, Wei-Zheng [1 ]
Li, Ying [1 ]
Xiong, Zhi-Gang [2 ]
Zhu, Michael X. [3 ]
Xu, Tian-Le [1 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Key Lab Tumor Microenvironm & Inflammat, Collaborat Innovat Ctr Brain Sci,Sch Med, Discipline Neurosci,Dept Anat Histol & Embryol, Shanghai 200030, Peoples R China
[2] Morehouse Sch Med, Inst Neurosci, Atlanta, GA 30310 USA
[3] Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA
来源
ELIFE | 2015年 / 4卷
基金
中国博士后科学基金; 中国国家自然科学基金; 美国国家卫生研究院;
关键词
TARANTULA TOXIN PSALMOTOXIN-1; CELL-DEATH; PROTEIN; KINASE; CONTRIBUTES; NECROSIS; CALCIUM; INJURY; NEUROPROTECTION; TRANSMISSION;
D O I
10.7554/eLife.05682
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Acidotoxicity is common among neurological disorders, such as ischemic stroke. Traditionally, Ca2+ influx via homomeric acid-sensing ion channel 1a (ASIC1a) was considered to be the leading cause of ischemic acidotoxicity. Here we show that extracellular protons trigger a novel form of neuronal necroptosis via ASIC1a, but independent of its ion-conducting function. We identified serine/threonine kinase receptor interaction protein 1 (RIP1) as a critical component of this form of neuronal necroptosis. Acid stimulation recruits RIP1 to the ASIC1a C-terminus, causing RIP1 phosphorylation and subsequent neuronal death. In a mouse model of focal ischemia, middle cerebral artery occlusion causes ASIC1a-RIP1 association and RIP1 phosphorylation in affected brain areas. Deletion of the Asic1a gene significantly prevents RIP1 phosphorylation and brain damage, suggesting ASIC1a-mediated RIP1 activation has an important role in ischemic neuronal injury. Our findings indicate that extracellular protons function as a novel endogenous ligand that triggers neuronal necroptosis during ischemia via ASIC1a independent of its channel function.
引用
收藏
页数:21
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