ASIC1a channels are activated by endogenous protons during ischemia and contribute to synergistic potentiation of intracellular Ca2+ overload during ischemia and acidosis

Acidosis accompanying cerebral ischemia activates acid-sensing ion channels (ASIC) causing increases in intracellular calcium concentration ([Ca2+]i) and enhanced neuronal death. Experiments were undertaken in rat cortical neurons to explore the effects of ASIC1a activation on ischemia-induced [Ca2+]i elevations and whole-cell currents. There was a significant contribution of ASIC1a channels to ischemia-evoked [Ca2+]i increases at pH 7.4, suggesting that ASIC1a channels are activated by endogenous protons during ischemia. The combination of ischemia and acidosis resulted in synergistic increases in [Ca2+]i and plasma membrane currents relative to acidosis or ischemia alone. ASIC1a inhibitors significantly blunted [Ca2+]i increases and a transient current activated by ischemia + acidosis, demonstrating that homomeric ASIC1a channels are involved. However, ASIC1a inhibitors failed to diminish a sustained current activated in response to combined ischemia and acidosis, indicating that acidosis can potentiate ischemia effects through mechanisms other than ASIC1a. The [Ca2+]i overload produced by acidosis and ischemia was not blocked by tetrodotoxin, 2-amino-5-phosphonopentanoic acid or nifedipine. Thus, acidosis and activation of ASIC1a channels during ischemia can promote [Ca2+]i overload in the absence of neurotransmission, independent of NMDA receptor or L-type voltage-gated Ca2+ channel activation. Postsynaptic ASIC1a channels play a critical role in ischemia-induced [Ca2+]i dysregulation and membrane dysfunction.