Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels

Ca2+ toxicity remains the central focus of ischemic brain injury. The mechanism by which toxic Ca2+ loading of cells occurs in the ischemic brain has become less clear as multiple human trials of glutamate antagonists have failed to show effective neuroprotection in stroke. Acidosis is a common feature of ischemia and is assumed to play a critical role in brain injury; however, the mechanism(s) remain ill defined. Here, we show that acidosis activates Ca2+-permeable acid-sensing ion channels (ASICs), inducing glutamate receptor-independent, Ca2+-dependent, neuronal injury inhibited by ASIC blockers. Cells lacking endogenous ASICs are resistant to acid injury, while transfection of Ca2+-permeable ASIC1a establishes sensitivity. In focal ischemia, intracerebroventricular injection of ASIC1 a blockers or knockout of the ASIC1 a gene protects the brain from ischemic injury and does so more potently than glutamate antagonism. Thus, acidosis injures the brain via membrane receptor-based mechanisms with resultant toxicity of [Ca2+](i), disclosing new potential therapeutic targets for stroke.