4.8 Article

Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction

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ELIFE
卷 4, 期 -, 页码 -

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ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.05682

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  1. National Basic Research Program of China 973 Program
  2. National Basic Research Program of China [2014CB910300]
  3. National Natural Science Foundation of China [313111222, 91413122, 91213306, 91132303, 31230028]
  4. National Institutes of Health [U54NS083932]
  5. China Postdoctoral Science Foundation [2012M511106]
  6. American Heart Association [15GRNT23040032]

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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.

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