Biophysics, pathophysiology, and pharmacology of ion channel gating pores.
Biophysics, pathophysiology, and pharmacology of ion channel gating pores.
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DOI：
10.3389/fphar.2014.00053
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发表时间：
2014
影响因子：
5.6
通讯作者：
Chahine M
中科院分区：
文献类型：
--
作者：
Moreau A;Gosselin-Badaroudine P;Chahine M
电压传感器结构域（VSD）是电压门控离子通道（VGIC）和电压敏感蛋白的特征。它们由四个跨膜（TM）区段（S1-S4）组成。通过VSD泄漏的电流称为Ω或门控孔电流。门控孔是由S4片段中高度保守的带正电荷的氨基酸突变引起的，其破坏了S4片段与门控电荷转移中心（GCTC）之间的相互作用。GCTC将细胞内和细胞外的水裂隙分开。S4-GCTC相互作用的破坏允许这些裂缝连通并产生快速活化和非失活的低电导的替代阳离子选择性渗透途径或门控孔。门控孔电流最近已被证明会导致周期性麻痹表型。越来越多的证据表明，门控毛孔与其他几种家族性疾病有关。例如，Nav1.5和Kv7.2通道中的门控孔可能是分别与扩张型心肌病（DCM）表型和外周神经过度兴奋（PNH）相关的混合性心律失常的基础。几乎没有证据表明存在门控孔阻滞剂。此外，已知许多毒素与Na+通道的特定结构域的VSD结合。因此，这些毒素可能会调节门控孔电流。这种对VSD基序的关注开辟了一个新的研究领域，该领域的研究重点是开发分子来治疗一些细胞兴奋性疾病，如癫痫，心律失常和疼痛。本综述的目的是总结现有的门控孔电流的病理生理学，生物物理学和药理学的知识，并作为未来研究的指导，旨在提高我们的理解门控孔及其病理生理作用。
Voltage sensor domains (VSDs) are a feature of voltage gated ion channels (VGICs) and voltage sensitive proteins. They are composed of four transmembrane (TM) segments (S1–S4). Currents leaking through VSDs are called omega or gating pore currents. Gating pores are caused by mutations of the highly conserved positively charged amino acids in the S4 segment that disrupt interactions between the S4 segment and the gating charge transfer center (GCTC). The GCTC separates the intracellular and extracellular water crevices. The disruption of S4–GCTC interactions allows these crevices to communicate and create a fast activating and non-inactivating alternative cation-selective permeation pathway of low conductance, or a gating pore. Gating pore currents have recently been shown to cause periodic paralysis phenotypes. There is also increasing evidence that gating pores are linked to several other familial diseases. For example, gating pores in Nav1.5 and Kv7.2 channels may underlie mixed arrhythmias associated with dilated cardiomyopathy (DCM) phenotypes and peripheral nerve hyperexcitability (PNH), respectively. There is little evidence for the existence of gating pore blockers. Moreover, it is known that a number of toxins bind to the VSD of a specific domain of Na+ channels. These toxins may thus modulate gating pore currents. This focus on the VSD motif opens up a new area of research centered on developing molecules to treat a number of cell excitability disorders such as epilepsy, cardiac arrhythmias, and pain. The purpose of the present review is to summarize existing knowledge of the pathophysiology, biophysics, and pharmacology of gating pore currents and to serve as a guide for future studies aimed at improving our understanding of gating pores and their pathophysiological roles.
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影响因子：
33.6
作者：
DeCoursey TE
通讯作者：
DeCoursey TE
影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
16.2
作者：
CHAHINE, M;GEORGE, AL;HORN, R
通讯作者：
HORN, R
影响因子：
4.5
作者：
CHAHINE, M;BENNETT, PB;HORN, R
通讯作者：
HORN, R
DOI：
10.1016/j.bbrc.2005.12.038
发表时间：
2006-02-10
影响因子：
3.1
作者：
El Chemaly, A;Guinamard, R;Bois, P
通讯作者：
Bois, P