Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels
Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels
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DOI：
10.1523/jneurosci.2844-04.2004
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发表时间：
2004-10-06
影响因子：
5.3
通讯作者：
Xiong, ZG
中科院分区：
文献类型：
--
作者：
Chu, XP;Wemmie, JA;Xiong, ZG
酸敏感离子通道（Acid-sensing ion channels，ASIC）是一类新型的质子激活配体门控阳离子通道，在外周感觉和中枢神经元中高度表达。ASIC的激活可能在生理过程如伤害感受、机械感觉和学习记忆中以及在神经病症如脑缺血的病理学中起重要作用。ASICs活性的调节预期对这些通道在生理和/或病理过程中可发挥的作用具有显著影响。在这里，我们表明，二价阳离子Zn 2+，内源性微量元素，剂量依赖性抑制ASIC电流在培养的小鼠皮层神经元在纳摩尔浓度。在中国仓鼠卵巢细胞中表达ASICs的情况下，Zn 2+抑制由同源ASIC 1a和异源ASIC 1a-ASIC 2a通道介导的电流，而不影响由同源ASIC 1 β、ASIC 2a或ASIC 3介导的电流。与ASIC 1a特异性调节一致，在ASIC 1a敲除小鼠的神经元中不存在高亲和力Zn 2+抑制。电流钳记录和Ca ~（2+）成像实验表明，Zn ~（2+）抑制酸诱导的细胞膜去极化和细胞内Ca ~（2+）的增加。ASIC 1a亚基胞外结构域中赖氨酸-133的突变消除了高亲和力Zn 2+抑制。我们的研究表明，Zn 2+可能在负反馈系统中发挥重要作用，以防止神经元在正常突触传递和ASIC 1a介导的兴奋性毒性在病理条件下的过度兴奋。
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.