MULTIMERIC STRUCTURE OF CLC-1 CHLORIDE CHANNEL REVEALED BY MUTATIONS IN DOMINANT MYOTONIA-CONGENITA (THOMSEN)
MULTIMERIC STRUCTURE OF CLC-1 CHLORIDE CHANNEL REVEALED BY MUTATIONS IN DOMINANT MYOTONIA-CONGENITA (THOMSEN)
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DOI：
10.1002/j.1460-2075.1994.tb06315.x
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发表时间：
1994-02-15
期刊：
影响因子：
11.4
通讯作者：
JENTSCH, TJ
中科院分区：
文献类型：
--
作者：
STEINMEYER, K;LORENZ, C;JENTSCH, TJ
电压门控 ClC 氯离子通道在细胞体积调节、肌肉兴奋性控制以及可能的跨上皮转运中发挥重要作用。 ClC 通道可以在没有其他亚基的情况下进行功能表达，但尚不清楚它们是否作为单体发挥作用。我们现在利用人类肌肉氯离子通道 ClC-1 突变的特性来探索其多聚体结构。这是基于对导致先天性肌强直（MC，汤姆森氏病）的 ClC-1 突变的显性负面影响的分析，其中包括汤姆森家族中新发现的突变 (P480L)。在共表达测定中，Thomsen 的突变显着抑制正常的 ClC-1 功能。在加拿大 MC 家族 (G230E) 中发现的突变具有不太明显的显性负效应，这可以通过具有改变的动力学和选择性的功能性 WT/G230E 异寡聚通道来解释。对两种突变体的分析独立地表明，ClC-1 作为同源寡聚体发挥作用，很可能具有四个亚基。
Voltage-gated ClC chloride channels play important roles in cell volume regulation, control of muscle excitability, and probably transepithelial transport. ClC channels can be functionally expressed without other subunits, but it is unknown whether they function as monomers. We now exploit the properties of human mutations in the muscle chloride channel, ClC-1, to explore its multimeric structure. This is based on analysis of the dominant negative effects of ClC-1 mutations causing myotonia congenita (MC, Thomsen's disease), including a newly identified mutation (P480L) in Thomsen's own family. In a co-expression assay, Thomsen's mutation dramatically inhibits normal ClC-1 function. A mutation found in Canadian MC families (G230E) has a less pronounced dominant negative effect, which can be explained by functional WT/G230E heterooligomeric channels with altered kinetics and selectivity. Analysis of both mutants shows independently that ClC-1 functions as a homeoligomer with most likely four subunits.