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

被引:130
作者
Chu, XP
Wemmie, JA
Wang, WZ
Zhu, XM
Saugstad, JA
Price, MP
Simon, RP
Xiong, ZG
机构
[1] Legacy Res, Robert S Dow Neurobiol Labs, Portland, OR 97232 USA
[2] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA
[3] Dept Vet Affairs Med Ctr, Iowa City, IA 52242 USA
[4] Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA
[5] Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA
[6] Oregon Hlth & Sci Univ, Dept Neurol Physiol & Pharmacol, Portland, OR 97239 USA
关键词
acid-sensing ion channels; ASICs; zinc inhibition; excitability; patch clamp; neuron;
D O I
10.1523/JNEUROSCI.2844-04.2004
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:8678 / 8689
页数:12
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