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The Journal of Neuroscience, May 17, 2006, 26(20):5329-5339; doi:10.1523/JNEUROSCI.0938-06.2006

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Cellular/Molecular
ASIC1a-Specific Modulation of Acid-Sensing Ion Channels in Mouse Cortical Neurons by Redox Reagents

Xiang-Ping Chu, Natasha Close, Julie A. Saugstad, and Zhi-Gang Xiong

Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232

Correspondence should be addressed to Dr. Zhi-Gang Xiong, Robert S. Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Avenue, Portland, OR 97232. Email: zxiong{at}Downeurobiology.org

Acid-sensing ion channel (ASIC)-1a, the major ASIC subunit with Ca²⁺ permeability, is highly expressed in the neurons of CNS. Activation of these channels with resultant intracellular Ca²⁺ accumulation plays a critical role in normal synaptic plasticity, learning/memory, and in acidosis-mediated glutamate receptor-independent neuronal injury. Here we demonstrate that the activities of ASICs in CNS neurons are tightly regulated by the redox state of the channels and that the modulation is ASIC1a subunit dependent. In cultured mouse cortical neurons, application of the reducing agents dramatically potentiated, whereas the oxidizing agents inhibited the ASIC currents. However, in neurons from the ASIC1 knock-out mice, neither oxidizing agents nor reducing reagents had any effect on the acid-activated current. In Chinese Hamster Ovary cells, redox-modifying agents only affected the current mediated by homomeric ASIC1a, but not homomeric ASIC1b, ASIC2a, or ASIC3. In current-clamp recordings and Ca²⁺-imaging experiments, the reducing agents increased but the oxidizing agents decreased acid-induced membrane depolarization and the intracellular Ca²⁺ accumulation. Site-directed mutagenesis studies identified involvement of cysteine 61 and lysine 133, located in the extracellular domain of the ASIC1a subunit, in the modulation of ASICs by oxidizing and reducing agents, respectively. Our results suggest that redox state of the ASIC1a subunit is an important factor in determining the overall physiological function and the pathological role of ASICs in the CNS.

Key words: ASIC1a; oxidizing/reducing agent; patch-clamp; ischemia; neuronal injury; redox reagents

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Received Nov. 3, 2005; revised April 9, 2006; accepted April 10, 2006.

Correspondence should be addressed to Dr. Zhi-Gang Xiong, Robert S. Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Avenue, Portland, OR 97232. Email: zxiong{at}Downeurobiology.org

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