Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions
Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions
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DOI：
10.1038/11103
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发表时间：
1999-07-01
影响因子：
21.3
通讯作者：
Logothetis, DE
中科院分区：
文献类型：
--
作者：
Zhang, HL;He, C;Logothetis, DE
磷脂酰肌醇-4，5-二磷酸(PtdIns(4，5)P-2)与内向整流钾通道的直接相互作用更强，与PtdIns(4，5)P-2(如IRK1)结合使通道呈结构性激活，而不是G蛋白门控通道(GIRKs)，因此，单独PtdIns(4，5)P-2可激活IRK1，但不能激活GIRKs，后者需要额外的门控分子，如G蛋白或钠离子的Py亚基。在这里，我们确定了在这些通道的内膜界面附近的两个保守残基，它们在与PtdIns(4，5)P-2的相互作用中是关键的。在这两个精氨酸之间，GIRK4中的异亮氨酸残基229保守地改变为IRK1中发现的相应的亮氨酸，加强了GIRK4-PtdIns(4，5)P-2的相互作用，消除了额外的门控分子的需要。一个带负电荷的GIRK4残基，距离最强相互作用的精氨酸两个位置，通过加强通道-PtdIns(4，5)P-2相互作用来介导钠对通道活动的刺激。我们的结果为理解不同的内向整流钾通道的门控机制如何使这些通道发挥其生理作用提供了一个机制框架。
Direct interactions of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P-2) with inwardly rectifying potassium channels are stronger with channels rendered constitutively active by binding to PtdIns(4,5)P-2, such as IRK1, than with G-protein-gated channels (GIRKs), As a result, PtdIns(4,5)P-2 alone can activate IRK1 but not GIRKs, which require extra gating molecules such as the py subunits of G proteins or sodium ions. Here we identify two conserved residues near the inner-membrane interface of these channels that are critical in interactions with PtdIns(4,5)P-2. Between these two arginines, a conservative change of isoleucine residue 229 in GIRK4 to the corresponding leucine found in IRK1 strengthens GIRK4-PtdIns(4,5)P-2 interactions, eliminating the need for extra gating molecules. A negatively charged GIRK4 residue, two positions away from the most strongly interacting arginine, mediates stimulation of channel activity by sodium by strengthening channel-PtdIns(4,5)P-2 interactions. Our results provide a mechanistic framework for understanding how distinct gating mechanisms of inwardly rectifying potassium channels allow these channels to subserve their physiological roles.