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The Journal of Neuroscience, October 6, 2004, 24(40):8678-8689; doi:10.1523/JNEUROSCI.2844-04.2004
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Cellular/Molecular
Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels
Xiang-Ping Chu,1
John A. Wemmie,2,3,4
Wei-Zhen Wang,1
Xiao-Man Zhu,1
Julie A. Saugstad,1
Margaret P. Price,4
Roger P. Simon,1,5 and
Zhi-Gang Xiong1
1Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, 2Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, 3Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242, 4Department of Internal Medicine and Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa 52242, and 5Department of Neurology, Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239
Acid-sensing ion channels (ASICs), a novel class of ligand-gated cation channels activated by protons, are highly expressed in peripheral sensory and central neurons. Activation of ASICs may play an important role in physiological processes such as nociception, mechanosensation, and learning-memory, and in the pathology of neurological conditions such as brain ischemia. Modulation of the activities of ASICs is expected to have a significant influence on the roles that these channels can play in both physiological and/or pathological processes. Here we show that the divalent cation Zn2+, an endogenous trace element, dose-dependently inhibits ASIC currents in cultured mouse cortical neurons at nanomolar concentrations. With ASICs expressed in Chinese hamster ovary cells, Zn2+ inhibits currents mediated by homomeric ASIC1a and heteromeric ASIC1a-ASIC2a channels, without affecting currents mediated by homomeric ASIC1 , ASIC2a, or ASIC3. Consistent with ASIC1a-specific modulation, high-affinity Zn2+ inhibition is absent in neurons from ASIC1a knock-out mice. Current-clamp recordings and Ca2+-imaging experiments demonstrated that Zn2+ inhibits acid-induced membrane depolarization and the increase of intracellular Ca2+. Mutation of lysine-133 in the extracellular domain of the ASIC1a subunit abolishes the high-affinity Zn2+ inhibition. Our studies suggest that Zn2+ may play an important role in a negative feedback system for preventing overexcitation of neurons during normal synaptic transmission and ASIC1a-mediated excitotoxicity in pathological conditions.
Key words: acid-sensing ion channels; ASICs; zinc inhibition; excitability; patch clamp; neuron
Received July 14, 2004;
revised August 23, 2004;
accepted August 24, 2004.
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