title: Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yi-Zhi
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Wei-Zheng
authors.initials: WZ
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.affiliation: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United States.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000138:Acidosis / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000378:metabolism; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse
keywords: ASIC1a; acidotoxicity; cell biology; ion channel; ischemic stroke; mouse; necroptosis; neuroprotection; neuroscience