Ca2+ -permeable acid-sensing ion channels and ischemic brain injury.

Abstract

Acidosis is a common feature of brain in acute neurological injury, particularly in ischemia where low pH has been assumed to play an important role in the pathological process. However, the cellular and molecular mechanisms underlying acidosis-induced injury remain unclear. Recent studies have demonstrated that activation of Ca(2+)-permeable acid-sensing ion channels (ASIC1a) is largely responsible for acidosis-mediated, glutamate receptor-independent, neuronal injury. In cultured mouse cortical neurons, lowering extracellular pH to the level commonly seen in ischemic brain activates amiloride-sensitive ASIC currents. In the majority of these neurons, ASICs are permeable to Ca(2+), and an activation of these channels induces increases in the concentration of intracellular Ca(2+) ([Ca(2+)](i)). Activation of ASICs with resultant [Ca(2+)](i) loading induces time-dependent neuronal injury occurring in the presence of the blockers for voltage-gated Ca(2+) channels and the glutamate receptors. This acid-induced injury is, however, inhibited by the blockers of ASICs, and by reducing [Ca(2+)](o). In focal ischemia, intracerebroventricular administration of ASIC1a blockers, or knockout of the ASIC1a gene protects brain from injury and does so more potently than glutamate antagonism. Furthermore, pharmacological blockade of ASICs has up to a 5 h therapeutic time window, far beyond that of glutamate antagonists. Thus, targeting the Ca(2+)-permeable acid-sensing ion channels may prove to be a novel neuroprotective strategy for stroke patients.

• Authors: Z-G Xiong, X-P Chu, R P Simon
• Journal: The Journal of membrane biology (J Membr Biol) Vol. 209 Issue 1 Pg. 59-68 (Jan 2006) ISSN: 0022-2631 [Print] United States
• PMID: 16685601 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• ASIC1 protein, human
• ASIC1 protein, mouse
• Acid Sensing Ion Channels
• Membrane Proteins
• Nerve Tissue Proteins
• Sodium Channels
• Calcium

Topics

• Acid Sensing Ion Channels
• Animals
• Brain Ischemia (metabolism, physiopathology)
• Calcium (metabolism)
• Humans
• Membrane Proteins (metabolism, physiology)
• Models, Biological
• Nerve Tissue Proteins (metabolism, physiology)
• Neurons (metabolism)
• Sodium Channels (metabolism, physiology)