阐明task - 2k2p通道在细胞内pH感应机制中的作用

W. González, Daniel Bustos, F. Sepúlveda, Guierdy Concha, Leandro Zúñiga
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引用次数: 0

摘要

双孔结构域钾离子(K2P)通道负责维持静息膜电位所必需的背景电导。K2P通道组装成二聚体,每个亚基包含两个成孔结构域和四个跨膜片段。两个开孔连接脂膜和中央传导腔,根据螺旋TM4的运动可以打开或关闭。K2P通道的TALK亚家族被碱性细胞外pH激活,由3个成员组成:TALK-1、TALK-2和TASK-2。TASK-2也受细胞内pH (pHi)的控制,通过细胞内酸化关闭,并通过pHi的增加激活。位于TM4螺旋末端的赖氨酸中和,可能在开孔内,通过K245A突变消除了ph -门控制。ph传感K245发挥其门控作用的分子机制尚不清楚。一种可能的机制表明,质子化的K245能够打开窗口,从而关闭通道。通过计算研究,我们模拟了两种开窗状态下TASK-2通道的三维结构,并以此模型为起点进行分子动力学模拟。轨迹分析表明,实验得到的K245的pK1/2与pKa预测的吻合良好,MOL2NET, 2018,4, http://sciforum.net/conference/mol2net-04 2。此外,我们证明了去氟西汀化合物是TASK-2通道的有效阻滞剂,其假定的结合位点在开孔内(数据未显示)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Elucidating the role of the intracellular pH sensing mechanism of TASK-2 K2P channel
Two-pore domain potassium (K2P) channels are responsible for maintaining the background conductance essential to the resting membrane potential. K2P channels assemble as dimers containing two pore-forming domains and four transmembrane segments per subunits. Two fenestrations connect the lipid membrane with the central conduction cavity, which can be open or closed depending of the movements of helix TM4. TALK subfamily of K2P channels is activated by alkaline extracellular pH and is formed by 3 members: TALK-1, TALK-2 and TASK-2. TASK-2 is also gated by intracellular pH (pHi), being closed by intracellular acidification and activated by increasing pHi. The neutralization of lysine positioned at the end of TM4 helix, and probably within the fenestrations, by a mutation to K245A abolishes pHi-gating . The molecular mechanism by which pHi-sensing K245 exerts its gating role is unknown. A possible mechanism suggest that K245 protonated is able to open the fenestrations and therefore close the channel. Through computational studies, we modeled the 3D structure of TASK-2 channel in both fenestration states, these models were used as a starting point to perform molecular dynamics simulations. The trajectories analysis reveals a good agreement between the pK1/2 of K245 obtained experimentally and the pKa predicted MOL2NET, 2018, 4, http://sciforum.net/conference/mol2net-04 2 when the fenestrations are closed. Besides, we proved that Norfluoxetine compound is a potent blocker of TASK-2 channels and its putative binding site is within the fenestrations (data not shown).
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