Metabolic and thermal stimuli control K2P2.1 (TREK-1) through modular sensory and gating domains

被引:76
作者
Bagriantsev, Sviatoslav N. [2 ]
Clark, Kimberly A. [2 ]
Minor, Daniel L., Jr. [1 ,2 ,3 ,4 ]
机构
[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA
[3] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, San Francisco, CA 94158 USA
[4] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA 94720 USA
关键词
C-type gate; K-2P channel; leak current; potassium channel; temperature gating; RECTIFYING K+ CHANNELS; C-TYPE INACTIVATION; POTASSIUM-CHANNEL; CRYSTAL-STRUCTURE; ION-CHANNEL; SELECTIVITY FILTER; STRUCTURAL BASIS; INDUCED INHIBITION; HEAT ACTIVATION; CA2+ CHANNELS;
D O I
10.1038/emboj.2012.171
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
K(2P)2.1 (TREK-1) is a polymodal two-pore domain leak potassium channel that responds to external pH, GPCR-mediated phosphorylation signals, and temperature through the action of distinct sensors within the channel. How the various intracellular and extracellular sensory elements control channel function remains unresolved. Here, we show that the K(2P)2.1 (TREK-1) intracellular C-terminal tail (Ct), a major sensory element of the channel, perceives metabolic and thermal commands and relays them to the extracellular C-type gate through transmembrane helix M4 and pore helix 1. By decoupling Ct from the pore-forming core, we further demonstrate that Ct is the primary heat-sensing element of the channel, whereas, in contrast, the pore domain lacks robust temperature sensitivity. Together, our findings outline a mechanism for signal transduction within K(2P)2.1 (TREK-1) in which there is a clear crosstalk between the C-type gate and intracellular Ct domain. In addition, our findings support the general notion of the existence of modular temperature-sensing domains in temperature-sensitive ion channels. This marked distinction between gating and sensory elements suggests a general design principle that may underlie the function of a variety of temperature-sensitive channels. The EMBO Journal (2012) 31, 3297-3308. doi:10.1038/emboj.2012.171; Published online 22 June 2012
引用
收藏
页码:3297 / 3308
页数:12
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