title: ASIC1a channels are activated by endogenous protons during ischemia and contribute to synergistic potentiation of intracellular Ca(2+) overload during ischemia and acidosis.
abstract: Acidosis accompanying cerebral ischemia activates acid-sensing ion channels (ASIC) causing increases in intracellular calcium concentration ([Ca(2+)]i) and enhanced neuronal death. Experiments were undertaken in rat cortical neurons to explore the effects of ASIC1a activation on ischemia-induced [Ca(2+)]i elevations and whole-cell currents. There was a significant contribution of ASIC1a channels to ischemia-evoked [Ca(2+)]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 [Ca(2+)]i and plasma membrane currents relative to acidosis or ischemia alone. ASIC1a inhibitors significantly blunted [Ca(2+)]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 [Ca(2+)]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 [Ca(2+)]i overload in the absence of neurotransmission, independent of NMDA receptor or L-type voltage-gated Ca(2+) channel activation. Postsynaptic ASIC1a channels play a critical role in ischemia-induced [Ca(2+)]i dysregulation and membrane dysfunction.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL 33612-4799, USA.
authors.forename: Yelenis
authors.initials: Y
authors.lastname: Mari
authors.forename: Christopher
authors.initials: C
authors.lastname: Katnik
authors.forename: Javier
authors.initials: J
authors.lastname: Cuevas
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D011522:Protons; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D015222:Sodium Channels / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062565:Acid Sensing Ion Channels; D020746:Calcium Channels, L-Type; D009419:Nerve Tissue Proteins; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D013779:Tetrodotoxin; D015763:2-Amino-5-phosphonovalerate; D009543:Nifedipine; D002118:Calcium