A novel mechanism for human K2P2.1 channel Gating -: Facilitation of C-type gating by protonation of extracellular histidine residues
A novel mechanism for human K2P2.1 channel Gating -: Facilitation of C-type gating by protonation of extracellular histidine residues
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DOI：
10.1074/jbc.m801273200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Zilberberg, Noam
中科院分区：
文献类型：
--
作者：
Cohen, Asi;Ben-Abu, Yuval;Zilberberg, Noam
哺乳动物K(2P)2.1钾通道（TREK-1, KCNK2）在兴奋性组织中高度表达，在神经保护、麻醉、疼痛感知和抑郁的细胞机制中起关键作用。在这里，我们报道了外部酸化，在生理范围内，通过诱导“c型”关闭强烈抑制人类K(2P)2.1通道。我们已经确定了位于通道第一个外部环的两个组氨酸残基（即His-87和His-141），它们控制通道对外部ph的响应。我们证明这些残基与谷氨酸84在物理上接近，与Shaker Glu-418， KcsA Glu-51和KCNK0 Glu-28残基同源，所有这些残基都被认为通过与孔邻近残基形成氢键来稳定开放构象的外孔门。因此，我们提出了一种新的pH感应机制，其中His-141和His-87的质子化产生了一个局部正电荷，该正电荷有助于将Glu-84从其自然相互作用中吸引出来，从而促进选择性过滤区域的崩溃。根据这一机制，低pH修饰K(2P)2.1对钾的选择性。此外，质子介导的效应被外部钾离子抑制，并被已知加速c型门控的突变（S164Y）增强。此外，质子诱导的电流抑制在负电位下更为明显。因此，电压依赖的质子c型门控加速代表了K(2P)2.1向外整流的新机制。
The mammalian K(2P)2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report that external acidification, within the physiological range, strongly inhibits the human K(2P)2.1 channel by inducing "C-type" closure. We have identified two histidine residues (i.e. His-87 and His-141), located in the first external loop of the channel, that govern the response of the channel to external pH. We demonstrate that these residues are within physical proximity to glutamate 84, homologous to Shaker Glu-418, KcsA Glu-51, and KCNK0 Glu-28 residues, all previously argued to stabilize the outer pore gate in the open conformation by forming hydrogen bonds with pore-adjacent residues. We thus propose a novel mechanism for pH sensing in which protonation of His-141 and His-87 generates a local positive charge that serves to draw Glu-84 away from its natural interactions, facilitating the collapse of the selectivity filter region. In accordance with this proposed mechanism, low pH modified K(2P)2.1 selectivity toward potassium. Moreover, the proton-mediated effect was inhibited by external potassium ions and was enhanced by a mutation (S164Y) known to accelerate C-type gating. Furthermore, proton-induced current inhibition was more pronounced at negative potentials. Thus, voltage-dependent C-type gating acceleration by protons represents a novel mechanism for K(2P)2.1 outward rectification.