Poster Presentation 2014 International Biophysics Congress

Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction (#580)

Yi-Zhi Wang 1 , Tian-Le Xu 1
  1. Shanghai Jiao Tong University School of Medicine, Shanghai, China

Acidotoxicity is common among many neurological diseases, such as ischemic stroke. Traditionally, Ca2+ influx via homomeric acid-sensing ion channel 1a (ASIC1a) was considered as the leading cause of acid-induced neuronal death. We show here, however, that extracellular protons trigger a novel form of necroptosis in neurons via ASIC1a independent of its ion-conducting function. We identified the serine/threonine kinase receptor interaction protein 1 (RIP1) as a critical component in this form of neuronal necroptosis. Acid stimulation recruits RIP1 to ASIC1a C-terminus, leading to RIP1 phosphorylation and subsequent neuronal death. Importantly, we show that a peptide representing the proximal C-terminal region of ASIC1a mimicked acid-induced necroptosis at the neutral pH, suggesting the essential role of this region in mediating acidic neuronal death. Furthermore, ASIC1a-RIP1 interaction was also observed in mouse focal ischemic models, indicating the important pathological relevance of this finding, which may provide a novel drug invention target against ischemic stroke for clinical therapy.