On the mechanism of GIRK2 channel gating by phosphatidylinositol bisphosphate, sodium, and the G?? dimer
On the mechanism of GIRK2 channel gating by phosphatidylinositol bisphosphate, sodium, and the G?? dimer
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DOI：
10.1074/jbc.ra119.010047
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发表时间：
2019-12-06
影响因子：
4.8
通讯作者：
Logothetis, Diomedes E.
中科院分区：
文献类型：
--
作者：
Li, Dailin;Jin, Taihao;Logothetis, Diomedes E.
G蛋白？门控内向整流K+（GIRK）通道属于内向整流K+（Kir）家族，在心脏和大脑中大量表达，并且需要磷脂酰肌醇二磷酸存在，以便细胞内通道门控调节剂如GIRK？Na+离子可维持通道开放状态。然而，尽管高分辨率的结构（GIRK2）和大量的功能研究，我们没有一个连贯的图片如何G？和Na+离子控制GIRK2通道的门控。在这里，我们利用计算建模和全原子微秒尺度的分子动力学模拟，以确定哪些门控制Na+和G？以及每个调节器如何使用沟道域移动来控制栅极转换。我们发现，Na+离子控制细胞溶质门的通道通过逆时针旋转，而G？？通过胞质结构域的摇摆运动将跨膜门稳定在打开状态。这两种效应都改变了通道与磷脂酰肌醇二磷酸相互作用的方式，从而稳定了各自闸门的打开状态。GIRK通道动力学的这些研究第一次提出了一个全面的结构模型，与GIRK通道功能的大量文献相一致。
G protein?gated inwardly rectifying K+ (GIRK) channels belong to the inward-rectifier K+ (Kir) family, are abundantly expressed in the heart and the brain, and require that phosphatidylinositol bisphosphate is present so that intracellular channel-gating regulators such as G?? and Na+ ions can maintain the channel-open state. However, despite high-resolution structures (GIRK2) and a large number of functional studies, we do not have a coherent picture of how G?? and Na+ ions control gating of GIRK2 channels. Here, we utilized computational modeling and all-atom microsecond-scale molecular dynamics simulations to determine which gates are controlled by Na+ and G?? and how each regulator uses the channel domain movements to control gate transitions. We found that Na+ ions control the cytosolic gate of the channel through an anti-clockwise rotation, whereas G?? stabilizes the transmembrane gate in the open state through a rocking movement of the cytosolic domain. Both effects alter the way in which the channel interacts with phosphatidylinositol bisphosphate and thereby stabilizes the open states of the respective gates. These studies of GIRK channel dynamics present for the first time a comprehensive structural model that is consistent with the great body of literature on GIRK channel function.