Zn2+ and H+ are coactivators of acid-sensing ion channels
Zn2+ and H+ are coactivators of acid-sensing ion channels
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DOI：
10.1074/jbc.m105208200
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发表时间：
2001-09-21
影响因子：
4.8
通讯作者：
Lazdunski, M
中科院分区：
文献类型：
--
作者：
Baron, A;Schaefer, L;Lazdunski, M
酸敏感离子通道（ASIC）是由细胞外质子激活的阳离子通道。它们在感觉神经元中表达，在那里它们被认为参与与组织酸中毒相关的疼痛感知。它们也在大脑中表达。许多大脑区域，如海马，含有大量的可螯合的囊泡状Zn 2+。本文表明，Zn 2+增强了含同源和异源ASIC 2a通道（即ASIC 2a，ASIC 1a +2a，ASIC 2a +3）的酸激活，但不增强同源ASIC 1a和ASIC 3的酸激活。对于ASIC 2a，Zn 2+增强的EC 50为120和111 μ M。和ASIC 1a +2a电流。Zn 2+使ASICIa +2a电流的活化的pH依赖性从5.5的pH（0.5）移动到6.0。ASIC 2a的10个细胞外组氨酸的系统诱变导致两个残基（His-162和His-339）的鉴定，这两个残基对于Zn 2+增强效应是必需的。另一个组氨酸残基His-72的突变消除了ASIC 2a的pH敏感性。该残基位于第一个跨膜结构域之后，似乎是ASIC 2a细胞外pH传感器的重要组成部分。
Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. They are expressed in sensory neurons, where they are thought to be involved in pain perception associated with tissue acidosis. They are also expressed in brain. A number of brain regions, like the hippocampus, contain large amounts of chelatable vesicular Zn2+. This paper shows that Zn2+ potentiates the acid activation of homomeric and heteromeric ASIC2a-containing channels (i.e. ASIC2a, ASIC1a+2a, ASIC2a+3), but not of homomeric ASIC1a and ASIC3. The EC50 for Zn2+ potentiation is 120 and 111 muM for the ASIC2a. and ASIC1a+2a current, respectively. Zn2+ shifts the pH dependence of activation of the ASlCIa+2a current from a pH(0.5) of 5.5 to 6.0. Systematic mutagenesis of the 10 extracellular histidines of ASIC2a leads to the identification of two residues (His-162 and His-339) that are essential for the Zn2+ potentiating effect. Mutation of another histidine residue, His-72, abolishes the pH sensitivity of ASIC2a. This residue, which is located just after the first transmembrane domain, seems to be an essential component of the extracellular pH sensor of ASIC2a.