Opposite Effects of the S4-S5 Linker and PIP(2) on Voltage-Gated Channel Function: KCNQ1/KCNE1 and Other Channels.
Opposite Effects of the S4-S5 Linker and PIP(2) on Voltage-Gated Channel Function: KCNQ1/KCNE1 and Other Channels.
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DOI：
10.3389/fphar.2012.00125
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发表时间：
2012
影响因子：
5.6
通讯作者：
Loussouarn G
中科院分区：
文献类型：
--
作者：
Choveau FS;Abderemane-Ali F;Coyan FC;Es-Salah-Lamoureux Z;Baró I;Loussouarn G
电压门控钾（Kv）通道是四聚体，每个亚基有6个跨膜片段（S1-S6），每个S1-S4片段形成一个电压感应域（VSD），四个S5-S6形成传导途径及其门。S4片段控制细胞内激活门的打开，以响应膜电位的变化。几种电压门控离子通道的晶体结构结合生物物理和诱变研究强调了S4-S5连接子（S4S5L）和S6 c端部分（S6T）在VSD和激活门之间耦合中的关键作用。已经提出了几种机制来描述分子尺度上的耦合。这篇综述总结了各种电压门控离子通道的机制，包括我们描述的KCNQ1的机制，其中S4S5L像配体一样与S6T结合，使通道稳定在关闭状态。正如本文所讨论的，这一机制可能解释了hcn样通道对去极化的反向反应。与S4S5L相反，磷脂酰肌醇4,5-二磷酸（PIP2）使KCNQ1通道稳定在开放状态。许多其他离子通道（不仅仅是电压门控）需要PIP2才能正常工作，这证实了它作为离子通道辅助因子的重要性。这在PIP2改变离子通道调控导致通道病变的情况下得到了强调，正如在KCNQ1中观察到的那样。本文综述了对KCNQ1和其他电压门控通道（PIP2和S4S5L）功能至关重要的两种调控机制的最新研究进展，并评估了它们潜在的生理和病理生理作用。
Voltage-gated potassium (Kv) channels are tetramers, each subunit presenting six transmembrane segments (S1–S6), with each S1–S4 segments forming a voltage-sensing domain (VSD) and the four S5–S6 forming both the conduction pathway and its gate. S4 segments control the opening of the intracellular activation gate in response to changes in membrane potential. Crystal structures of several voltage-gated ion channels in combination with biophysical and mutagenesis studies highlighted the critical role of the S4–S5 linker (S4S5L) and of the S6 C-terminal part (S6T) in the coupling between the VSD and the activation gate. Several mechanisms have been proposed to describe the coupling at a molecular scale. This review summarizes the mechanisms suggested for various voltage-gated ion channels, including a mechanism that we described for KCNQ1, in which S4S5L is acting like a ligand binding to S6T to stabilize the channel in a closed state. As discussed in this review, this mechanism may explain the reverse response to depolarization in HCN-like channels. As opposed to S4S5L, the phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2), stabilizes KCNQ1 channel in an open state. Many other ion channels (not only voltage-gated) require PIP2 to function properly, confirming its crucial importance as an ion channel cofactor. This is highlighted in cases in which an altered regulation of ion channels by PIP2 leads to channelopathies, as observed for KCNQ1. This review summarizes the state of the art on the two regulatory mechanisms that are critical for KCNQ1 and other voltage-gated channels function (PIP2 and S4S5L), and assesses their potential physiological and pathophysiological roles.
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DOI：
10.1085/jgp.200308927
发表时间：
2003-12
期刊：
The Journal of general physiology
影响因子：
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DOI：
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发表时间：
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影响因子：
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