Steinmeyer K, Lorenz C, Pusch M, Koch M C, Jentsch T J
Centre for Molecular Neurobiology (ZMNH), Hamburg University, Germany.
EMBO J. 1994 Feb 15;13(4):737-43. doi: 10.1002/j.1460-2075.1994.tb06315.x.
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 homooligomer with most likely four subunits.
电压门控性 ClC 氯离子通道在细胞容积调节、肌肉兴奋性控制以及可能的跨上皮转运过程中发挥着重要作用。ClC 通道无需其他亚基即可实现功能表达，但它们是否以单体形式发挥作用尚不清楚。我们现在利用人类肌肉氯离子通道 ClC-1 中的突变特性来探究其多聚体结构。这是基于对导致先天性肌强直（MC，汤姆森病）的 ClC-1 突变的显性负效应的分析，包括在汤姆森家族中新发现的一个突变（P480L）。在共表达实验中，汤姆森突变显著抑制正常 ClC-1 功能。在加拿大 MC 家族中发现的一个突变（G230E）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野生型/WT230E 异源寡聚体通道来解释。对这两种突变体的分析独立表明，ClC-1 作为一种最有可能由四个亚基组成的同型寡聚体发挥作用。
