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: Yelenis Mari, Christopher Katnik, Javier Cuevas
• Journal: Cell calcium (Cell Calcium) Vol. 48 Issue 1 Pg. 70-82 (Jul 2010) ISSN: 1532-1991 [Electronic] Netherlands
• PMID: 20678793 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Acid Sensing Ion Channels
• Calcium Channels, L-Type
• Nerve Tissue Proteins
• Protons
• Receptors, N-Methyl-D-Aspartate
• Sodium Channels
• Tetrodotoxin
• 2-Amino-5-phosphonovalerate
• Nifedipine
• Calcium

Topics

• 2-Amino-5-phosphonovalerate (pharmacology)
• Acid Sensing Ion Channels
• Acidosis (physiopathology)
• Animals
• Brain Ischemia (physiopathology)
• Calcium (metabolism)
• Calcium Channels, L-Type (physiology)
• Cerebral Cortex (metabolism)
• Nerve Tissue Proteins (antagonists & inhibitors, metabolism)
• Neurons (drug effects)
• Nifedipine (pharmacology)
• Protons
• Rats
• Receptors, N-Methyl-D-Aspartate (physiology)
• Sodium Channels (metabolism)
• Synaptic Transmission (drug effects)
• Tetrodotoxin (pharmacology)