Distinct modulation of inactivation by a residue in the pore domain of voltage-gated Na(+) channels: mechanistic insights from recent crystal structures.
Distinct modulation of inactivation by a residue in the pore domain of voltage-gated Na(+) channels: mechanistic insights from recent crystal structures.
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DOI：
10.1038/s41598-017-18919-1
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发表时间：
2018-01-12
影响因子：
4.6
通讯作者：
Todt H
中科院分区：
文献类型：
--
作者：
Cervenka R;Lukacs P;Gawali VS;Ke S;Koenig X;Rubi L;Zarrabi T;Hilber K;Sandtner W;Stary-Weinzinger A;Todt H
电压门控Na+通道（VGSC）的失活对于调节细胞兴奋性是必不可少的。作为失活基础的分子重排被认为涉及作为失活lid的结构域III和IV之间的细胞内接头、lid的受体（结构域III S4-S5接头）和孔衬S6片段。为了更好地理解结构域IV S6片段在失活中的作用，我们在rNav 1.4通道中对该区域进行了半胱氨酸扫描诱变，并筛选了稳态失活的电压依赖性扰动的构建体。该筛选是在野生型通道和携带突变K1237 E的通道的背景下进行的，突变K1237 E深刻地改变了渗透和门控特性。在所有测试的构建体中，突变I1581 C是独特的，因为突变诱导的门控变化受到突变背景的强烈影响。这表明I1581在失活过程中参与特定的短程相互作用。在最近公布的晶体结构VGSC中，与I1581同源的相应氨基酸似乎控制S6片段的弯曲，这对于门控过程是关键的。此外，I1581可能参与将DIII电压传感器的运动传输到域IV S6段。
Inactivation of voltage-gated Na+ channels (VGSC) is essential for the regulation of cellular excitability. The molecular rearrangement underlying inactivation is thought to involve the intracellular linker between domains III and IV serving as inactivation lid, the receptor for the lid (domain III S4-S5 linker) and the pore-lining S6 segements. To better understand the role of the domain IV S6 segment in inactivation we performed a cysteine scanning mutagenesis of this region in rNav 1.4 channels and screened the constructs for perturbations in the voltage-dependence of steady state inactivation. This screen was performed in the background of wild-type channels and in channels carrying the mutation K1237E, which profoundly alters both permeation and gating-properties. Of all tested constructs the mutation I1581C was unique in that the mutation-induced gating changes were strongly influenced by the mutational background. This suggests that I1581 is involved in specific short-range interactions during inactivation. In recently published crystal structures VGSCs the respective amino acids homologous to I1581 appear to control a bend of the S6 segment which is critical to the gating process. Furthermore, I1581 may be involved in the transmission of the movement of the DIII voltage-sensor to the domain IV S6 segment.
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影响因子：
5.5
作者：
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