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.
Highlights
Acidosis occurs commonly in a variety of neurological disorders and is a main contributing factor to neural injury (Xiong et al, 2004; Wemmie et al, 2013; Friese et al, 2007; Vergo et al, 2011)
We describe a novel form of neuronal necroptosis induced by extracellular acidosis and mediated by acid-sensing ion channel 1a (ASIC1a)
Compared to conventional death receptors (DRs)-dependent necroptosis, ASIC1adependent necroptosis did not require de novo synthesized ligands and extracellular protons may serve as the fast ‘extrinsic death signal’
Summary
Acidosis occurs commonly in a variety of neurological disorders and is a main contributing factor to neural injury (Xiong et al, 2004; Wemmie et al, 2013; Friese et al, 2007; Vergo et al, 2011). Besides ischemic stroke, accumulating evidence from cell/animal models shows that ASIC1a is an effective molecular target for mitigating acid-induced neural damage in many other diseases including multiple sclerosis, Huntington’s disease, and Parkinson’s disease (Wemmie et al, 2013). These previous findings strongly suggest that ASIC1a is the key extracellular proton receptor in neurons and the main mediator of acid-induced neuronal death. ASIC1a may be a potential broad-spectrum therapeutic target in many neurological disorders (Xiong et al, 2004; Wemmie et al, 2006, 2013)
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