Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models

doi:10.1126/scitranslmed.aaw8434

	Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models
	Liao, Ping 6; Qiu, Yunguang 2,7,8; Mo, Yiqing 3; Fu, Jie 3; Song, Zhenpeng 6; Huang, Lu 6; Bai, Suwen 4; Wang, Yang 4; Zhu, Jia-Jie 5; Tian, Fuyun 7,8
刊名	SCIENCE TRANSLATIONAL MEDICINE
	2019-11-20
卷号	11 期号:519 页码:12
ISSN号	1946-6234
DOI	10.1126/scitranslmed.aaw8434
通讯作者	Jiang, Ruotian(ruotianjiang@scu.edu.cn) ; Yang, Huaiyu(hyyang@bio.ecnu.edu.cn)
英文摘要	The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.
资助项目	National Science and Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; National Natural Science Foundation of China[21422208] ; National Natural Science Foundation of China[31600832] ; Thousand Talents Plan in Sichuan Province ; 1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University[ZY2016101] ; ECNU[44300-19311-542500/006] ; Fundamental Research Funds for the Central Universities[2018SCUH0086] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501] ; State Key Laboratory of Bioorganic and Natural Products Chemistry
WOS关键词	DOMAIN POTASSIUM CHANNEL ; ION-CHANNEL ; PAIN ; TASK-3 ; TASK-1/TASK-3 ; HETERODIMERS ; ANTAGONIST ; EXPRESSION ; CHALLENGES ; RECEPTOR
WOS研究方向	Cell Biology ; Research & Experimental Medicine
语种	英语
出版者	AMER ASSOC ADVANCEMENT SCIENCE
WOS记录号	WOS:000497975000005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282085]
专题	中国科学院上海药物研究所
通讯作者	Jiang, Ruotian; Yang, Huaiyu
作者单位	1.Soochow Univ, Coll Pharmaceut Sci, Suzhou 215123, Jiangsu, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China 4.Anhui Med Univ, Dept Physiol, Hefei 230032, Anhui, Peoples R China 5.Shanghai Jiao Tong Univ, Sch Med, Collaborat Innovat Ctr Brain Sci, Dept Anat & Physiol, Shanghai 200025, Peoples R China 6.Sichuan Univ, Natl Local Joint Engn Res Ctr Translat Med Anesth, Lab Anesthesia & Crit Care Med, West China Hosp,Dept Anesthesiol, Chengdu 610000, Sichuan, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Materia Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 9.Soochow Univ, Jiangsu Key Lab Neuropsychiat Dis, Suzhou 215123, Jiangsu, Peoples R China 10.Shanghai Univ, Sch Life Sci, Cardiac Regenerat & Ageing Lab, Shanghai 200444, Peoples R China
推荐引用方式 GB/T 7714	Liao, Ping,Qiu, Yunguang,Mo, Yiqing,et al. Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models[J]. SCIENCE TRANSLATIONAL MEDICINE,2019,11(519):12.
APA	Liao, Ping.,Qiu, Yunguang.,Mo, Yiqing.,Fu, Jie.,Song, Zhenpeng.,...&Yang, Huaiyu.(2019).Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models.SCIENCE TRANSLATIONAL MEDICINE,11(519),12.
MLA	Liao, Ping,et al."Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models".SCIENCE TRANSLATIONAL MEDICINE 11.519(2019):12.