Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade

Acid-sensing ion channels (ASICs) open when extracellular pH drops and they are enhanced by lactate, making them specialized for detecting lactic acidosis. Highly expressed on cardiac nociceptors and some other sensory neurons, ASICs may help trigger pain caused by tissue ischemia. We report that H+ opens ASIC3 by speeding release of Ca2+ from a high-affinity binding site (K-Ca = 150 nM) on the extracellular side of the pore. The bound Ca2+ blocks permeation and the channel conducts when multiple H+ ions relieve this block. Activation through Ca2+ explains sensitivity to lactate, which decreases extracellular [Ca2+], and it may prove relevant in CNS pathologies (stroke, seizure) that simultaneously drop pH and Ca2+.