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首页> 外文期刊>Cellular Physiology and Biochemistry >Alterations in the cytoplasmic domain of CLCN2 result in altered Gating kinetics
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Alterations in the cytoplasmic domain of CLCN2 result in altered Gating kinetics

机译：CLCN2胞质结构域的改变导致门控动力学改变

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摘要

Mutations in the human ClC-2 Cl- channel have been described to influence its function dramatically. To test for naturally occurring gene variants in a human population and their functionality, all 24 CLCN2 exons from a Central African population were sequenced. Six single amino acid exchanges in the intracellular N-terminus (P48R, R68H), in the pore domain (G199A), or in the intracellular C-terminus (R646Q, R725W, R747H) were identified at low frequency. Heterologous expression of these polymorphisms in Xenopus laevis oocytes demonstrated their functional significance as determined by two-electrode voltage-clamp. The polymorphisms R68H, R725W, and R747H exhibited faster voltage-stimulated gating as compared to the wild type channel, resulting in higher steady state currents of R725W. Probably due to decreased surface expression P48R, R68H, and R646Q mutants generated lower currents than the wild type channels. The inward currents of the mutated channels R725W, R747H, and G199A failed to increase during hypotonic swelling, a defect paralleled by impaired swelling-accelerated voltage-gating in one mutant (G199A). In conclusion, the Africans' gene pool comprises CLCN2 gene variants in the N-terminus, the C-terminus or the pore domain that affect surface expression and voltage- or cell-swelling-stimulated channel gating. Copyright (c) 2007 S. Karger AG, Basel.
机译：已经描述了人类ClC-2 Cl-通道中的突变会极大地影响其功能。为了测试人群中天然存在的基因变异及其功能，对来自中部非洲人群的所有24个CLCN2外显子进行了测序。低频鉴定了细胞内N末端（P48R，R68H），孔结构域（G199A）或细胞内C末端（R646Q，R725W，R747H）的六个单氨基酸交换。这些异型在非洲爪蟾卵母细胞中的异源表达证明了其功能意义，如通过两电极电压钳所确定的。与野生型通道相比，多态性R68H，R725W和R747H表现出更快的电压激励门控，从而导致R725W的稳态电流更高。可能是由于表面表达降低导致P48R，R68H和R646Q突变体产生的电流低于野生型通道。在低渗性肿胀过程中，突变的通道R725W，R747H和G199A的内向电流未能增加，这一缺陷与一个突变体（G199A）的肿胀加速电压门控受损并存。总之，非洲人的基因库在N端，C端或孔结构域中包含CLCN2基因变体，这些变体会影响表面表达以及电压或细胞膨胀刺激的通道门控。版权所有（c）2007 S.Karger AG，巴塞尔。

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