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Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels
Journal article   Open access   Peer reviewed

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 and Zhi-Gang Xiong
The Journal of neuroscience, Vol.24(40), pp.8678-8689
10/06/2004
DOI: 10.1523/jneurosci.2844-04.2004
PMCID: PMC3799792
PMID: 15470133
url
https://doi.org/10.1523/jneurosci.2844-04.2004View
Published (Version of record) Open Access

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 ASIC1beta, 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.
 Mutation Cricetulus Calcium - metabolism Molecular Sequence Data Electric Conductivity Cerebral Cortex - cytology Protein Subunits - metabolism Nerve Tissue Proteins - chemistry Neurons - physiology Neurons - drug effects CHO Cells Protein Subunits - genetics Amino Acid Sequence Nerve Tissue Proteins - antagonists & inhibitors Cricetinae Acid Sensing Ion Channels Membrane Proteins - genetics Cells, Cultured Chelating Agents - pharmacology Nerve Tissue Proteins - genetics Mice, Knockout Lysine - genetics Patch-Clamp Techniques Animals Membrane Potentials Membrane Proteins - antagonists & inhibitors Membrane Proteins - chemistry Sodium Channels - chemistry Mice Protein Subunits - antagonists & inhibitors Sodium Channels - genetics Zinc - pharmacology Hydrogen-Ion Concentration

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