Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction
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 necr...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/05682 |
| _version_ | 1811180414941790208 |
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| author | Yi-Zhi Wang Jing-Jing Wang Yu Huang Fan Liu Wei-Zheng Zeng Ying Li Zhi-Gang Xiong Michael X Zhu Tian-Le Xu |
| author_facet | Yi-Zhi Wang Jing-Jing Wang Yu Huang Fan Liu Wei-Zheng Zeng Ying Li Zhi-Gang Xiong Michael X Zhu Tian-Le Xu |
| author_sort | Yi-Zhi Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:02:46Z |
| format | Article |
| id | doaj.art-642c42ffb9fb4c1ea170f06a356d0002 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:02:46Z |
| publishDate | 2015-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-642c42ffb9fb4c1ea170f06a356d00022022-12-22T04:32:43ZengeLife Sciences Publications LtdeLife2050-084X2015-11-01410.7554/eLife.05682Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conductionYi-Zhi Wang0Jing-Jing Wang1Yu Huang2Fan Liu3Wei-Zheng Zeng4Ying Li5Zhi-Gang Xiong6Michael X Zhu7Tian-Le Xu8Discipline 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, ChinaDiscipline 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, ChinaDiscipline 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, ChinaDiscipline 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, ChinaDiscipline 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, ChinaDiscipline 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, ChinaNeuroscience Institute, Morehouse School of Medicine, Atlanta, United StatesDepartment of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, United StatesDiscipline 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, ChinaAcidotoxicity 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.https://elifesciences.org/articles/05682ion channelischemic strokenecroptosisacidotoxicityASIC1aneuroprotection |
| spellingShingle | Yi-Zhi Wang Jing-Jing Wang Yu Huang Fan Liu Wei-Zheng Zeng Ying Li Zhi-Gang Xiong Michael X Zhu Tian-Le Xu Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction eLife ion channel ischemic stroke necroptosis acidotoxicity ASIC1a neuroprotection |
| title | Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction |
| title_full | Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction |
| title_fullStr | Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction |
| title_full_unstemmed | Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction |
| title_short | Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction |
| title_sort | tissue acidosis induces neuronal necroptosis via asic1a channel independent of its ionic conduction |
| topic | ion channel ischemic stroke necroptosis acidotoxicity ASIC1a neuroprotection |
| url | https://elifesciences.org/articles/05682 |
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