The role of ASICs in cerebral ischemia

Cerebral ischemia is a leading cause of death and long-term disabilities worldwide. Excessive intracellular Ca(2+) accumulation in neurons has been considered essential for neuronal injury associated with cerebral ischemia. Although the involvement of glutamate receptors in neuronal Ca(2+) accumulation and toxicity has been the subject of intensive investigation, inhibitors for these receptors showed little effect in clinical trials. Thus, additional Ca(2+) toxicity pathway(s) must be involved. Acidosis is a common feature in cerebral ischemia and was known to cause brain injury. The mechanisms were, however, unclear. The finding that ASIC1a channels are highly enriched in brain neurons, their activation by ischemic acidosis, and their demonstrated Ca(2+) permeability suggested a role for these channels in Ca(2+) accumulation and neuronal injury associated with cerebral ischemia. Indeed, a number of studies have now provided solid evidence supporting the involvement of ASIC1a channel activation in ischemic brain injury.