Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels

Xiang Ping Chu, John A. Wemmie, Wei Zhen Wang, Xiao Man Zhu, Julie A. Saugstad, Margaret P. Price, Roger P. Simon, Zhi Gang Xiong

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

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 ASIC1β, 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 Ca 2+-imaging experiments demonstrated that Zn2+ inhibits acid-induced membrane depolarization and the increase of intracellular Ca 2+. 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.

Original languageEnglish (US)
Pages (from-to)8678-8689
Number of pages12
JournalJournal of Neuroscience
Volume24
Issue number40
DOIs
StatePublished - Oct 6 2004

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Keywords

  • ASICs
  • Acid-sensing ion channels
  • Excitability
  • Neuron
  • Patch clamp
  • Zinc inhibition

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chu, X. P., Wemmie, J. A., Wang, W. Z., Zhu, X. M., Saugstad, J. A., Price, M. P., Simon, R. P., & Xiong, Z. G. (2004). Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels. Journal of Neuroscience, 24(40), 8678-8689. https://doi.org/10.1523/JNEUROSCI.2844-04.2004