Mechanism of Mechanosensitive Gating of the TREK-2 Potassium Channel
Mechanism of Mechanosensitive Gating of the TREK-2 Potassium Channel
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DOI：
10.1016/j.bpj.2018.01.030
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发表时间：
2018-03-27
影响因子：
3.4
通讯作者：
de Groot, Bert L.
中科院分区：
文献类型：
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作者：
Brennecke, Julian T.;de Groot, Bert L.
离子通道的机械敏感门控机制是许多生理过程的基础，包括触觉、听觉和痛觉。TREK-2是双孔结构域钾通道家族中研究得最好的机械敏感成员。除了压力感应，它还能对各种各样的刺激做出反应。两种状态，称为“上”和“下”，是已知的x射线结构晶体学研究，并已提出不同的电导。然而，浇注行为的结构细节在很大程度上是未知的。在这项工作中，我们使用分子动力学模拟来研究电导状态以及机械膜拉伸对通道的影响。我们发现下电态的导电性比上电态小。在模拟中，膜拉伸的引入使通道的状态转向向上配置，与初始配置无关，并且还增加了其电导。选择性滤波状态与电导的相关性支持了选择性滤波通过羰基翻转而关闭的模型。这个门是由孔螺旋稳定的。我们建议通过跨膜螺旋的界面来调制这些螺旋。膜压力直接改变了跨膜螺旋的构象，从而也影响了通道的电导。
The mechanism of mechanosensitive gating of ion channels underlies many physiological processes, including the sensations of touch, hearing, and pain perception. TREK-2 is the best-studied mechanosensitive member of the two-pore domain potassium channel family. Apart from pressure sensing, it responds to a diverse range of stimuli. Two states, termed "up" and "down," are known from x-ray structural crystallographic studies and have been suggested to differ in conductance. However, the structural details of the gating behavior are largely unknown. In this work, we used molecular dynamics simulations to study the conductance of the states as well as the effect of mechanical membrane stretch on the channel. We find that the down state is less conductive than the up state. The introduction of membrane stretch in the simulations shifts the state of the channel toward an up configuration, independent of the starting configuration, and also increases its conductance. The correlation of the selectivity filter state and the conductance supports a model in which the selectivity filter gates by a carbonyl flip. This gate is stabilized by the pore helices. We suggest a modulation of these helices by an interface to the transmembrane helices. Membrane pressure changes the conformation of the transmembrane helices directly and consequently also influences the channel conductance.