Multiple domains contribute to the distinct inactivation properties of human heart and skeletal muscle Na+ channels.
Multiple domains contribute to the distinct inactivation properties of human heart and skeletal muscle Na+ channels.
复制标题
多个结构域导致人类心脏和骨骼肌 Na 通道的独特失活特性。
DOI：
10.1161/01.res.78.2.244
复制
发表时间：
1996
影响因子：
20.1
通讯作者：
GeorgeJr,AL
中科院分区：
文献类型：
--
作者：
Makita,N;BennettJr,PB;GeorgeJr,AL
电压门控Na+通道对于神经元和横纹肌膜的正常电兴奋性是必不可少的。Na+通道α亚基的不同亚型已通过分子克隆鉴定，其功能属性已通过异源表达结合电生理记录确定。两种密切相关的Na+通道α亚基亚型hH 1（人心脏）和hSkM 1（人骨骼肌）在失活特性和对共表达β1亚基的反应方面表现出差异。为了定位有助于失活和β1亚基反应的区域，我们通过研究由hH 1和hSkM 1片段组成的嵌合通道来利用这些功能差异。其中一个或多个胞质结构域间区域（ID 1 -2、ID 2 -3和ID 3 -4）在hH 1和hSkM 1之间交换的嵌合体表现出与背景通道同种型相同的失活特性，表明这些区域不足以引起门控差异。与此相反，失活特性的嵌合体组成的两个通道亚型的大约相等的一半之间的H1和hSkM 1的中间。此外，对共表达的β1亚基的反应依赖于位于α亚基的羧基端一半的结构，尽管结构域D3、D4和羧基端并不是这种效应的唯一原因。这些数据表明hH 1和hSkM 1之间的失活差异是由多个α亚基结构域决定的。
Voltage-gated Na+channels are essential for the normal electrical excitability of neuronal and striated muscle membranes. Distinct isoforms of the Na+channel α-subunit have been identified by molecular cloning, and their functional attributes have been defined by heterologous expression coupled with electrophysiological recording. Two closely related Na+channel α-subunit isoforms, hH1 (human heart) and hSkM1 (human skeletal muscle), exhibit differences in their inactivation properties and in their response to the coexpressed β1-subunit. To localize regions that contribute to inactivation and to β1-subunit response, we have exploited these functional differences by studying chimeric channels composed of segments from both hH1 and hSkM1. Chimeras in which one or more of the cytoplasmic interdomain regions (ID1-2, ID2-3, and ID3-4) were exchanged between hH1 and hSkM1 exhibit inactivation properties identical with the background channel isoform, suggesting that these regions are not sufficient to cause gating differences. In contrast, inactivation properties of chimeras composed of approximately equal halves of the two channel isoforms were intermediate between hH1 and hSkM1. Furthermore, the response to the coexpressed β1-subunit was dependent on structures located in the carboxy-terminal half of the α-subunit, although domains D3, D4, and the carboxy terminal are not singularly responsible for this effect. These data indicate that inactivation differences between hH1 and hSkM1 are determined by multiple α-subunit domains.