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首页> 美国卫生研究院文献>The Journal of Biological Chemistry >Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop
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Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop

机译：体积调节阴离子通道（VRAC）的失活和阴离子选择性取决于第一个细胞外环的C末端残基

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Canonical volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have many other important roles, including tumor drug resistance and release of neurotransmitters. Although VRAC-mediated swelling-activated chloride currents (ICl,vol) have been studied for decades, exploration of the structure-function relationship of VRAC has become possible only after the recent discovery that VRACs are formed by differently composed heteromers of LRRC8 proteins. Inactivation of ICl,vol at positive potentials, a typical hallmark of VRACs, strongly varies between native cell types. Exploiting the large differences in inactivation between different LRRC8 heteromers, we now used chimeras assembled from isoforms LRRC8C and LRRC8E to uncover a highly conserved extracellular region preceding the second LRRC8 transmembrane domain as a major determinant of ICl,vol inactivation. Point mutations identified two amino acids (Lys-98 and Asp-100 in LRRC8A and equivalent residues in LRRC8C and -E), which upon charge reversal strongly altered the kinetics and voltage dependence of inactivation. Importantly, charge reversal at the first position also reduced the iodide > chloride permeability of ICl,vol. This change in selectivity was stronger when both the obligatory LRRC8A subunit and the other co-expressed isoform (LRR8C or -E) carried such mutations. Hence, the C-terminal part of the first extracellular loop not only determines VRAC inactivation but might also participate in forming its outer pore. Inactivation of VRACs may involve a closure of the extracellular mouth of the permeation pathway.
机译：规范的体积调节阴离子通道（VRAC）对于细胞体积调节至关重要，并具有许多其他重要作用，包括肿瘤耐药性和神经递质的释放。尽管对VRAC介导的溶胀激活的氯离子电流（ICl，vol）进行了数十年的研究，但只有在最近发现VRAC是由LRRC8蛋白的不同组成的异聚体形成后，才有可能探索VRAC的结构-功能关系。在自然电势类型之间，ICl，vol的失活在正电势（VRAC的典型标志）上存在很大差异。利用不同LRRC8异构体之间灭活的巨大差异，我们现在使用由同工型LRRC8C和LRRC8E组装而成的嵌合体来发现第二个LRRC8跨膜结构域之前高度保守的细胞外区域，这是ICl，vol失活的主要决定因素。点突变鉴定出两个氨基酸（LRRC8A中的Lys-98和Asp-100以及LRRC8C和-E中的等效残基），它们在电荷反转后强烈改变了失活的动力学和电压依赖性。重要的是，在第一位置的电荷反转也降低了ICl，vol的碘化物>氯化物渗透率。当必需的LRRC8A亚基和另一个共表达的同工型（LRR8C或-E）都带有这种突变时，选择性的变化会更强。因此，第一个细胞外环的C末端部分不仅决定了VRAC的失活，而且可能参与了其外孔的形成。 VRAC的失活可能涉及渗透途径的细胞外口的闭合。

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