INSIGHTS INTO THE STIMULATORY MECHANISM OF 2-AMINOETHOXYDIPHENYL BORATE ON TREK-2 POTASSIUM CHANNEL
INSIGHTS INTO THE STIMULATORY MECHANISM OF 2-AMINOETHOXYDIPHENYL BORATE ON TREK-2 POTASSIUM CHANNEL
复制标题
2-氨基乙氧基二苯硼酸盐对 TREK-2 钾通道刺激机制的见解
DOI：
10.1016/j.neuroscience.2015.05.012
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发表时间：
2015-08-06
期刊：
影响因子：
3.3
通讯作者：
Ma, X. -Y.
中科院分区：
文献类型：
--
作者：
Zhuo, R. -G.;Liu, X. -Y.;Ma, X. -Y.
2-氨基乙氧基二苯基硼酸酯（2-APB）是一种常见的双孔结构域钾通道（K2 P）亚家族--TWIK-related K+ channel（TREK）/TRAAK channels的激动剂。与TREK-1相比，TREK-2对2-APB显示出更高的敏感性，尽管这两个通道在K2 P成员中具有最高的同源性。然而，它们对2-APB反应差异的结构基础仍然未知。我们发现胞浆C端结构域在调控2-APB对TREK-2通道的刺激作用中起主导作用。远端Ct区域负调节2-APB的作用，而近端Ct足以引起通道的完全2-APB激活。在近端Ct内的进一步定位揭示了His 368是2-APB激活所必需的，并且其他非保守残基的合作也是必要的。我们还确定了2-APB的次级活性位点，其位于跨膜段M2的底部。最后，我们证明了2-APB激活所需的关键残基或结构域不参与选择性过滤器的门控机制。总之，我们揭示了TREK-2-Ct的独特调节模型，该模型在对2-APB的高敏感性方面将其与TREK-1区分开来。TREK-2的近端Ct内的非保守残基的合作在2-APB诱导的通道开放中起主导作用，而远端Ct负调控该过程。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
2-Aminoethoxydiphenyl borate (2-APB) has been recently identified as a common agonist of TWIK-related K+ channel (TREK)/TRAAK channels, a subfamily of two-pore domain K+ (K2P) channels. TREK-2 displays much higher sensitivity to 2-APB compared with TREK-1, despite that these two channels share the highest homology among K2P members. However, the structural basis for their difference in response to 2-APB still remains unknown. Here we identified that the cytosolic C-terminus (Ct) domain plays a dominant role in controlling the stimulatory effects of 2-APB on TREK-2 channel. The distal Ct region negatively regulates the effect of 2-APB, while the proximal Ct is sufficient to evoke the full 2-APB activation of the channel. Further mapping within the proximal Ct revealed that His368 is required for 2-APB activation, and the cooperation of the other non-conserved residues is also necessary. We also identified a secondary active site for 2-APB, which is located at the bottom of the transmembrane segment M2. Finally, we demonstrated that key residues or domains required for 2-APB activation are not involved in the gating mechanism of the selectivity filter. In summary, we reveal a unique modulatory model of TREK-2-Ct that distinguishes it from TREK-1 in high sensitivity to 2-APB. The cooperation of the nonconserved residues within the proximal Ct of TREK-2 plays a dominant role in the 2-APB-induced channel opening, whereas the distal Ct negatively regulates the process. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.