A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues

doi:10.1124/mol.118.115303

	A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues
	Tian, Fuyun 1,2; Qiu, Yunguang 1,2; Lan, Xi 1,2; Li, Min 3,4; Yang, Huaiyu 5; Gao, Zhaobing 1,2
刊名	MOLECULAR PHARMACOLOGY
	2019-07-01
卷号	96 期号:1 页码:26-35
ISSN号	0026-895X
DOI	10.1124/mol.118.115303
通讯作者	Gao, Zhaobing(zbgao@simm.ac.cn)
英文摘要	The TASK-3 channel is a member of the K2P family that is important for the maintenance of the resting membrane potential. Previous studies have demonstrated that the TASK-3 channel is involved in several physiologic and pathologic processes, including sleep/wake control, cognition, and epilepsy. However, there is still a lack of selective pharmacological tools for TASK-3, which limits further research on channel function. In this work, using a high-throughput screen, we discovered that N-(2-((4-nitro-2-(trifluoromethyl)phenyl)-amino)ethyl) benzamide (NPBA) showed excellent potency and selectivity as a novel TASK-3 activator. The molecular determinants of NPBA activation were then investigated by combining chimera and mutagenesis analysis. Two distant clusters of residues located at the extracellular end of the second transmembrane domain (A105 and A108) and the intracellular end of the third transmembrane domain (E157) were found to be critical for NPBA activation. We then compared the essentials of the actions of NPBA with inhalation anesthetics that nonselectively activate TASK-3 and found that they may activate TASK-3 channels through different mechanisms. Finally, we transplanted the three residues A105, A108, and E157 into the TASK-1 channel, which resists NPBA activation, and the constructed mutant TASK-1(G105A, V108A, A157E) showed dramatically increased activation by NPBA, confirming the importance of these two distant clusters of residues. SIGNIFICANCE STATEMENT TASK-3 channels conduct potassium and are involved in various physiological and pathological processes. However, the lack of selective modulators has hindered efforts to increase our understanding of the physiological roles of TASK-3 channels. By using a high-throughput screen, we identified NPBA as a potent and selective TASK-3 activator, and we show that NPBA is a more potent activator than terbinafine, the only reported TASK-3 selective activator to date. We also show here that NPBA has outstanding selectivity for TAS-3 channels. These characteristics make NPBA a promising pharmacological probe for research focused on defining TASK-3 channel function(s). In addition, we identified two distant clusters of residues as determinants of NPBA activation providing new molecular clues for the understanding of the gating mechanism of K2P channels.
资助项目	National Science Fund of Distinguished Young Scholars[81825021] ; National Natural Science Foundation of China[81773707] ; National Natural Science Foundation of China[61433017] ; Strategic Leading Science and Technology Projects of Chinese Academy of Sciences[XDA12040211] ; Strategic Leading Science and Technology Projects of Chinese Academy of Sciences[XDA12050308]
WOS关键词	POTASSIUM CHANNELS ; K+ CHANNEL ; MUTATION ; DELETION ; TREK-1
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000472623500003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289391]
专题	中国科学院上海药物研究所
通讯作者	Gao, Zhaobing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Johns Hopkins Univ, Dept Neurosci, High Throughput Biol Ctr, Baltimore, MD USA 4.Johns Hopkins Univ, Sch Med, Johns Hopkins Ion Channel Ctr, Baltimore, MD USA 5.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Tian, Fuyun,Qiu, Yunguang,Lan, Xi,et al. A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues[J]. MOLECULAR PHARMACOLOGY,2019,96(1):26-35.
APA	Tian, Fuyun,Qiu, Yunguang,Lan, Xi,Li, Min,Yang, Huaiyu,&Gao, Zhaobing.(2019).A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues.MOLECULAR PHARMACOLOGY,96(1),26-35.
MLA	Tian, Fuyun,et al."A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues".MOLECULAR PHARMACOLOGY 96.1(2019):26-35.