Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction
Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction
复制标题
组织酸中毒通过 ASIC1a 通道诱导神经元坏死性凋亡，与其离子传导无关
DOI：
10.7554/elife.05682
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发表时间：
2015-11-02
期刊：
影响因子：
7.7
通讯作者：
Xu, Tian-Le
中科院分区：
文献类型：
--
作者：
Wang, Yi-Zhi;Wang, Jing-Jing;Xu, Tian-Le
酸中毒在缺血性中风等神经系统疾病中很常见。传统上，Ca2+内流通过同质酸感离子通道1a （ASIC1a）被认为是缺血性酸中毒的主要原因。在这里，我们发现细胞外质子通过ASIC1a触发一种新型的神经元坏死，但独立于其离子传导功能。我们发现丝氨酸/苏氨酸激酶受体相互作用蛋白1 （RIP1）是这种形式的神经元坏死的关键组成部分。酸刺激将RIP1招募到ASIC1a c端，导致RIP1磷酸化和随后的神经元死亡。在小鼠局灶性缺血模型中，大脑中动脉闭塞导致ASIC1a-RIP1关联和RIP1磷酸化。Asic1a基因缺失可显著阻止RIP1磷酸化和脑损伤，提示Asic1a介导的RIP1激活在缺血性神经元损伤中具有重要作用。我们的研究结果表明，细胞外质子作为一种新的内源性配体，在缺血期间通过独立于其通道功能的ASIC1a触发神经元坏死。
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.