Neuroprotection in Ischemia: Blocking Calcium-Permeable Acid-Sensing Ion Channels

• Published in: Cell 2004-09, Vol.118 (6), p.687-698
• Main Authors: Xiong, Zhi-Gang, Zhu, Xiao-Man, Chu, Xiang-Ping, Minami, Manabu, Hey, Jessica, Wei, Wen-Li, MacDonald, John F., Wemmie, John A., Price, Margaret P., Welsh, Michael J., Simon, Roger P.
• Format: Article
• Language: English
• Subjects: Acid Sensing Ion Channels; Acidosis - complications; Acidosis - drug therapy; Acidosis - metabolism; Animals; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Calcium - metabolism; Calcium - toxicity; Calcium Channel Blockers - pharmacology; Calcium Signaling - drug effects; Calcium Signaling - genetics; Cells, Cultured; COS Cells; Disease Models, Animal; Drug Design; Excitatory Amino Acid Antagonists - pharmacology; Glutamic Acid - metabolism; Glutamic Acid - toxicity; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration - drug therapy; Nerve Degeneration - etiology; Nerve Degeneration - metabolism; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neuroprotective Agents - pharmacology; Rats; Receptors, Glutamate - drug effects; Receptors, Glutamate - metabolism; Sodium Channel Blockers - pharmacology; Sodium Channels - genetics; Sodium Channels - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2004.08.026

Ca 2+ toxicity remains the central focus of ischemic brain injury. The mechanism by which toxic Ca 2+ loading of cells occurs in the ischemic brain has become less clear as multiple human trials of glutamate antagonists have failed to show effective neuroprotection in stroke. Acidosis is a common feature of ischemia and is assumed to play a critical role in brain injury; however, the mechanism(s) remain ill defined. Here, we show that acidosis activates Ca 2+-permeable acid-sensing ion channels (ASICs), inducing glutamate receptor-independent, Ca 2+-dependent, neuronal injury inhibited by ASIC blockers. Cells lacking endogenous ASICs are resistant to acid injury, while transfection of Ca 2+-permeable ASIC1a establishes sensitivity. In focal ischemia, intracerebroventricular injection of ASIC1a blockers or knockout of the ASIC1a gene protects the brain from ischemic injury and does so more potently than glutamate antagonism. Thus, acidosis injures the brain via membrane receptor-based mechanisms with resultant toxicity of [Ca 2+] i, disclosing new potential therapeutic targets for stroke.