State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells

doi:10.1038/aps.2010.84

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	State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells
	Chen, Wei-hai 1,2; Wang, Wen-yi 1; Zhang, Jie 1; Yang, Ding 1,2; Wang, Yi-ping1
刊名	ACTA PHARMACOLOGICA SINICA
	2010-08
卷号	31 期号:8 页码:915-922
关键词	changrolin human ether-a-go-go-related gene torsades de pointes whole-cell patch-clamp anti-arrhythmic agent
ISSN号	1671-4083
DOI	10.1038/aps.2010.84
文献子类	Article
英文摘要	Aim: To study the effect of changrolin on the K+ channels encoded by the human ether-a-go-go-related gene (hERG). Methods: hERG channels were heterologously stably expressed in human embryonic kidney 293 cells, and the hERG K+ currents were recorded using a standard whole-cell patch-clamp technique. Results: Changrolin inhibited hERG channels in a concentration-dependent and reversible manner (IC50=18.23 mu mol/L, 95% CI: 9.27-35.9 mu mol/L; Hill coefficient=-0.9446). In addition, changrolin shifted the activation curve of hERG channels by 14.3 +/- 1.5 mV to more negative potentials (P<0.01, n=9) but did not significantly affect the steady-state inactivation of hERG (n=5, P>0.05). The relative block of hERG channels by changrolin was close to zero at the time point of channel opening by the depolarizing voltage step and quickly increased afterwards. The maximal block was achieved in the inactivated state, with no further development of the open channel block. In the "envelope of tails" experiments, the time constants of activation were found to be 287.8 +/- 46.2 ms and 174.2 +/- 18.4 ms, respectively, for the absence and presence of 30 mu mol/L changrolin (P<0.05, n=7). The onset of inactivation was accelerated significantly by changrolin between -40 mV and +60 mV (P<0.05, n=7). Conclusion: The results demonstrate that changrolin is a potent hERG blocker that preferentially binds to hERG channels in the open and inactivated states.
资助项目	National Basic Research Program of China[2009CB930300] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM 0907KF-02]
WOS关键词	TORSADES-DE-POINTES ; POTASSIUM CHANNELS ; PROLONGATION ; DERIVATIVES ; BINDING ; DRUGS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:3971249
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000280617100004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278803]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Wang, Yi-ping
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Wei-hai,Wang, Wen-yi,Zhang, Jie,et al. State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells[J]. ACTA PHARMACOLOGICA SINICA,2010,31(8):915-922.
APA	Chen, Wei-hai,Wang, Wen-yi,Zhang, Jie,Yang, Ding,&Wang, Yi-ping.(2010).State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells.ACTA PHARMACOLOGICA SINICA,31(8),915-922.
MLA	Chen, Wei-hai,et al."State-dependent blockade of human ether-a-go-go-related gene (hERG) K+ channels by changrolin in stably transfected HEK293 cells".ACTA PHARMACOLOGICA SINICA 31.8(2010):915-922.