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首页> 外文期刊>The Journal of biological chemistry >LRRC8 N termini influence pore properties and gating of volume-regulated anion channels (VRACs)
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LRRC8 N termini influence pore properties and gating of volume-regulated anion channels (VRACs)

机译：LRRC8 N末端影响孔的性质和体积调节阴离子通道（VRAC）的门控

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Volume-regulated anion channels (VRACs) are crucial for cell volume regulation and have various roles in physiology and pathology. VRACs were recently discovered to be formed by heteromers of leucine-rich repeat–containing 8 (LRRC8) proteins. However, the structural determinants of VRAC permeation and gating remain largely unknown. We show here that the short stretch preceding the first LRRC8 transmembrane domain determines VRAC conductance, ion permeability, and inactivation gating. Substituted-cysteine accessibility studies revealed that several of the first 15 LRRC8 residues are functionally important and exposed to a hydrophilic environment. Substituting glutamate 6 with cysteine decreased the amplitudes of swelling-activated ICl,vol currents, strongly increased iodide-over-chloride permeability, and markedly shifted the voltage dependence of channel inactivation. Importantly, these effects were reversed by 2-sulfonatoethyl methanethiosulfonate, which restores the negative charge at this amino acid position. Cd2+-mediated blocking of ICl,vol in cysteine variants suggested that the LRRC8 N termini come close together in the multimeric channel complex and might form part of the pore. We propose a model in which the N termini of the LRRC8 subunits line the cytoplasmic portion of the VRAC pore, possibly by folding back into the ion permeation pathway.
机译：体积调节阴离子通道（VRAC）对于细胞体积调节至关重要，并且在生理学和病理学中具有多种作用。最近发现VRACs由富含亮氨酸重复序列的8（LRRC8）蛋白的异聚体形成。但是，VRAC渗透和门控的结构决定因素仍然未知。我们在这里显示，在第一个LRRC8跨膜结构域之前的短暂拉伸决定了VRAC电导，离子渗透性和失活门控。取代的半胱氨酸可及性研究表明，前15个LRRC8残基中有几个在功能上很重要，并且暴露于亲水环境中。用半胱氨酸代替谷氨酸6可以降低溶胀激活的ICl，vol电流的幅度，大大增加碘化物对氯化物的渗透性，并显着改变通道失活的电压依赖性。重要的是，这些反应被甲硫代磺酸2-磺基乙基乙酯逆转，它恢复了该氨基酸位置的负电荷。 Cd2 +介导的半胱氨酸变异体中ICl，vol的阻断表明，LRRC8 N末端在多聚体通道复合物中靠得很近，可能形成孔的一部分。我们提出了一个模型，其中LRRC8亚基的N末端排列在VRAC孔的细胞质部分，可能通过折回到离子渗透途径中来进行。

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