A unique lower X-gate in TASK channels traps inhibitors within the vestibule
A unique lower X-gate in TASK channels traps inhibitors within the vestibule
复制标题
TASK 通道中独特的下部 X 门将抑制剂捕获在前庭内
DOI：
10.1101/706168
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Rödström K
中科院分区：
文献类型：
--
作者：
Rödström K
任务通道是两孔域钾(K2P)通道家族中不常见的成员，具有独特的、未知的生理和药理特性。任务存在于神经元、心肌细胞和血管平滑肌细胞中，它们参与心率、肺动脉张力、睡眠/醒来周期的调节以及对挥发性麻醉剂的反应。K2P通道调节静息膜电位，提供受多种生理刺激控制的背景K+电流。与其他K2P通道不同，任务通道具有与抑制剂结合的能力，具有高亲和力、特殊的选择性和非常慢的复合洗脱率。这些特性使TASK通道成为最容易下药的钾通道之一，事实上，TASK-1抑制剂目前正在进行阻塞性睡眠呼吸暂停(OSA)和房颤(AFib)的临床试验(DOCTOS和Sandman试验)。通常，钾通道有一个膜内前庭，上面有一个选择性过滤器，下面有一个门，有四个平行的螺旋。然而，到目前为止，研究的K2P通道都缺乏较低的门槛。在这里，我们介绍了TASK-1的结构，揭示了一个独特的下门，它是由前庭入口处两个交叉的C-末端M4跨膜螺旋相互作用产生的，我们称之为“X门”。这种结构由6个残基(V243LRFMT248)组成，它们是对挥发性麻醉剂、神经递质和G蛋白偶联受体的反应所必需的。有趣的是，X门及其周围区域的突变极大地影响了打开概率和麻醉剂的激活。具有两种新型高亲和力阻滞剂的TASK-1的结构显示，这两种抑制剂都结合在选择性过滤器下方，被X门捕获在前庭，从而解释了它们异常低的洗脱率。因此，X门在任务通道中的存在解释了它们不寻常的生理和药理学行为的许多方面，这对于未来开发和优化用于治疗心、肺和睡眠障碍的任务调节剂是非常宝贵的。
TASK channels are unusual members of the two-pore domain potassium (K2P) channel family, with unique and unexplained physiological and pharmacological characteristics. TASKs are found in neurons,, cardiomyocytes–and vascular smooth muscle cells where they are involved in regulation of heart rate, pulmonary artery tone,, sleep/wake cycles and responses to volatile anaesthetics–. K2Pchannels regulate the resting membrane potential, providing background K+currents controlled by numerous physiological stimuli,. Unlike other K2Pchannels, TASK channels have the capacity to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. These characteristics make the TASK channels some of the the most easily druggable potassium channels, and indeed TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnea (OSA) and atrial fibrillation (Afib) (The DOCTOS and SANDMAN Trials). Generally, potassium channels have an intramembrane vestibule with a selectivity filter above and a gate with four parallel helices below. However, K2Pchannels studied to date all lack a lower gate. Here we present the structure of TASK-1, revealing a unique lower gate created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance, which we designate as an ‟X-gate”. This structure is formed by six residues (V243LRFMT248) that are essential for responses to volatile anaesthetics, neuro-transmitters and G-protein coupled receptors. Interestingly, mutations within the X-gate and surrounding regions drastically affect both open probability and activation by anaesthetics. Structures of TASK-1 with two novel, high-affinity blockers, shows both inhibitors bound below the selectivity filter, trapped in the vestibule by the X-gate, thus explaining their exceptionally low wash-out rates. Thus, the presence of the X-gate in TASK channels explains many aspects of their unusual physiological and pharmacological behaviour, which is invaluable for future development and optimization of TASK modulators for treatment of heart, lung and sleep disorders.
登录
查看更多内容
K2P 通道 K 流门控变构抑制的分子基础
影响因子：
7.7
作者：
S. Rinné;Aytuğ K. Kiper;Kirsty S. Vowinkel;D. Ramírez;Marcus Schewe;M. Bedoya;Diana Aser;Isabella Gensler;Michael F. Netter;P. Stansfeld;T. Baukrowitz;W. González;N. Decher
通讯作者：
N. Decher
DOI：
10.1016/s0034-5687(01)00288-2
发表时间：
2001-12-01
期刊：
RESPIRATION PHYSIOLOGY
影响因子：
--
作者：
Bayliss, DA;Talley, EM;Lei, QB
通讯作者：
Lei, QB
影响因子：
9.8
作者：
Barel, Ortal;Shalev, Stavit A.;Birk, Ohad S.
通讯作者：
Birk, Ohad S.
影响因子：
--
作者：
Decher, Niels;Wemhoener, Konstantin;Maier, Sebastian K. G.
通讯作者：
Maier, Sebastian K. G.
K+ 通道 TASK-1 和 TASK-3 的细胞内交通：N 端和 C 端分选信号的作用以及与 14-3-3 蛋白的相互作用
DOI：
--
发表时间：
2009
期刊：
Journal of Physiology
影响因子：
--
作者：
Marylou Zuzarte;K. Heusser;Vijay Renigunta;G. Schlichthörl;S. Rinné;E. Wischmeyer;J. Daut;B. Schwappach;R. Preisig
通讯作者：
R. Preisig