A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels.
A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels.
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DOI：
10.1016/j.cell.2016.02.002
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发表时间：
2016-02-25
期刊：
影响因子：
64.5
通讯作者：
Baukrowitz T
中科院分区：
文献类型：
--
作者：
Schewe M;Nematian-Ardestani E;Sun H;Musinszki M;Cordeiro S;Bucci G;de Groot BL;Tucker SJ;Rapedius M;Baukrowitz T
双孔结构域 (K2P) K+ 通道是兴奋性的主要调节因子，赋予细胞向外校正背景“泄漏”电导。在一些 K2P 通道中，已经观察到强烈的电压依赖性激活，但由于它们缺乏规范的电压传感域，因此该机制仍未解决。在这里，我们表明电压依赖性门控对于大多数 K2P 通道来说是常见的，并且这种电压敏感性源于三到四个离子移动到非活动选择性过滤器的高电场中。总体而言，这种离子通量门控机制在过滤器内产生了一个单向“止回阀”，因为 K+ 的向外运动导致过滤器打开，而向内运动则促进失活。此外，许多生理刺激会关闭这种通量门控模式，将 K2P 通道转换为漏电导。这些发现提供了对 K+ 选择性过滤器的功能可塑性的深入了解，并加深了我们对 K2P 通道和离子通道感知电压机制的理解。大多数 K2P 通道表现出强电压门控，而不是简单的泄漏通道 电压传感涉及 K+ 移动到非活动过滤器的电场中 渗透的 MD 模拟揭示了对过滤器门控机制的深入了解 许多生理刺激调节这种电压门控行为 K2P 通道不具有规范的电压传感域，可以通过离子止回阀机制进行电压门控。
Two-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K+-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage. Most K2P channels exhibit strong voltage gating and are not simple leak channels Voltage sensing involves movement of K+ into the electric field of an inactive filter MD simulation of permeation reveals insight into the filter gating mechanism Many physiological stimuli modulate this voltage-gating behavior K2P channels, which do not possess a canonical voltage-sensing domain, can be voltage gated by an ion check valve mechanism.