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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

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Received July 14, 2004; revised August 23, 2004; accepted August 24, 2004.

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