Wang Yi-Zhi, Wang Jing-Jing, Huang Yu, Liu Fan, Zeng Wei-Zheng, Li Ying, Xiong Zhi-Gang, Zhu Michael X, Xu Tian-Le
Discipline of Neuroscience, Department of Anatomy, Histology and Embryology, Collaborative Innovation Center for Brain Science, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States.
Elife. 2015 Nov 2;4:e05682. doi: 10.7554/eLife.05682.
Acidotoxicity is common among neurological disorders, such as ischemic stroke. Traditionally, Ca(2+) 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.
酸毒性在诸如缺血性中风等神经疾病中很常见。传统上，通过同聚体酸敏感离子通道1a（ASIC1a）的Ca(2+)内流被认为是缺血性酸毒性的主要原因。在此我们表明，细胞外质子通过ASIC1a触发一种新型的神经元坏死性凋亡，但与其离子传导功能无关。我们确定丝氨酸/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性凋亡的关键成分。酸刺激将RIP1招募到ASIC1a的C末端，导致RIP1磷酸化并随后导致神经元死亡。在局灶性缺血的小鼠模型中，大脑中动脉闭塞会导致受影响脑区的ASIC1a-RIP1结合和RIP1磷酸化。Asic1a基因的缺失显著阻止了RIP1磷酸化和脑损伤，表明ASIC1a介导的RIP1激活在缺血性神经元损伤中起重要作用。我们的研究结果表明，细胞外质子作为一种新型内源性配体，在缺血期间通过ASIC1a触发神经元坏死性凋亡，与其通道功能无关。
