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

作者：Mari Yelenis; Katnik Christopher; Cuevas Javier^*

来源：Cell Calcium, 2010, 48(1): 70-82.

DOI：10.1016/j.ceca.2010.07.002

• Sigma receptors
• Ischemia
• Acidosis
• Neurotransmission
• Calcium
• Neurons
• Stroke

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.

• 出版日期2010-7