The Human Ether-A-Go-Go-Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

doi:10.1124/jpet.114.217703

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	The Human Ether-A-Go-Go-Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels
	Li, Ping 1; Chen, Xueqin 1; Zhang, Qiansen 2; Zheng, Yueming 1; Jiang, Hualiang2 ; Yang, Huaiyu 2; Gao, Zhaobing1
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2014-12
卷号	351 期号:3 页码:596-604
ISSN号	0022-3565
DOI	10.1124/jpet.114.217703
文献子类	Article
英文摘要	Human ether-a-go-go-related gene (hERG) and KCNQ channels are two classes of voltage-gated potassium channels. Specific mutations have been identified that are causal for type II long QT (LQT2) syndrome, neonatal epilepsy, and benign familial neonatal convulsions. Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigating and treating the two diseases is likely more effective. In the current study, we found that NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)urea], a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4, and KCNQ2/Q3 channels, but not the cardiac KCNQ1. The effects of NS1643 on the KCNQ2 channel include left shifting of voltage for reaching 50% of the maximum conductance and slowing of deactivation. Analysis of the dose-response curve of NS1643 revealed an EC50 value of 2.44 +/- 0.25 mu M. A hydrophobic phenylalanine (F137) located at the middle region of the voltage-sensing domain was identified as critical for NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.
资助项目	State Key Program of Basic Research of China[2013CB910604] ; National Science and Technology Major Project on "Key New Drug Creation and Manufacturing Program"[2013ZX09103001-016] ; National Natural Science Foundation of China Grant for Excellent Key Laboratory[81123004] ; National Natural Science Foundation of China[61327014] ; National Natural Science Foundation of China[61175103] ; National Natural Science Foundation of China[81173027] ; Shanghai Municipal Science and Technology Commission[13JC1406700] ; External Cooperation Program of BIC, Chinese Academy of Sciences[1536631KYSB20130003]
WOS关键词	LONG-QT-SYNDROME ; GATED POTASSIUM CHANNELS ; K+ CHANNELS ; GATING-MODIFIER ; VOLTAGE SENSOR ; HERG CHANNEL ; PHARMACOLOGY ; PHYSIOLOGY ; MUTATIONS ; SEIZURES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000345219800013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276822]
专题	神经药理学研究国际科学家工作站中科院受体结构与功能重点实验室成果转移转化处新药研究国家重点实验室
通讯作者	Gao, Zhaobing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Li, Ping,Chen, Xueqin,Zhang, Qiansen,et al. The Human Ether-A-Go-Go-Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2014,351(3):596-604.
APA	Li, Ping.,Chen, Xueqin.,Zhang, Qiansen.,Zheng, Yueming.,Jiang, Hualiang.,...&Gao, Zhaobing.(2014).The Human Ether-A-Go-Go-Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,351(3),596-604.
MLA	Li, Ping,et al."The Human Ether-A-Go-Go-Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 351.3(2014):596-604.