First Author | Wang YZ | Year | 2015 |
Journal | Elife | Volume | 4 |
PubMed ID | 26523449 | Mgi Jnum | J:228084 |
Mgi Id | MGI:5705192 | Doi | 10.7554/eLife.05682 |
Citation | Wang YZ, et al. (2015) Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. Elife 4:e05682 |
abstractText | 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. |