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An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG

文献类型：期刊论文

作者Liu, Zhipei1,8; Wang, Feng8,9; Yuan, Hui8,9; Tian, Fuyun1,8; Yang, Chuanyan1,6,7,8; Hu, Fei1,8; Liu, Yiyao8; Tang, Meiqin5,8; Ping, Meixuan1,4,8; Kang, Chunlan5,8
刊名BMC BIOLOGY
出版日期2024-02-05
卷号22期号:1页码:14
关键词hERG K525N Gating Polarity Voltage-Sensing Domain LQT2
DOI10.1186/s12915-024-01833-0
通讯作者Gao, Zhaobing(zbgao@simm.ac.cn) ; Li, Ping(lipingt@simm.ac.cn)
英文摘要BackgroundCyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the "opposite" voltage-sensing properties of hERG and HCN remains unknown.ResultsWe found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y.ConclusionsOur data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.
WOS关键词MOLECULAR DETERMINANTS ; K+ CHANNEL ; POTASSIUM CHANNELS ; S4-S5 LINKER ; UNRELATED PATIENTS ; SENSOR MOVEMENTS ; XENOPUS-OOCYTES ; S4 DOMAIN ; ACTIVATION ; INACTIVATION
资助项目National Natural Science Foundation of China
WOS研究方向Life Sciences & Biomedicine - Other Topics
语种英语
出版者BMC
WOS记录号WOS:001158151100003
源URL[http://119.78.100.183/handle/2S10ELR8/309225]  
专题中国科学院上海药物研究所
通讯作者Gao, Zhaobing; Li, Ping
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai 201203, Peoples R China
2.Guangzhou Univ Chinese Med, Zhongshan Tradit Chinese Med Hosp, Pharmacol Lab, Zhongshan 528401, Peoples R China
3.Guizhou Med Univ, Sch Pharmaceut Sci, Guiyang 550025, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou 510515, Peoples R China
6.China Pharmaceut Univ, Clin Pharm, Nanjing 210009, Peoples R China
7.China Pharmaceut Univ, Sch Basic Med, Nanjing 210009, Peoples R China
8.Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
9.Zunyi Med Univ, Sch Pharm, Zunyi 563000, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Zhipei,Wang, Feng,Yuan, Hui,et al. An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG[J]. BMC BIOLOGY,2024,22(1):14.
APA Liu, Zhipei.,Wang, Feng.,Yuan, Hui.,Tian, Fuyun.,Yang, Chuanyan.,...&Li, Ping.(2024).An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG.BMC BIOLOGY,22(1),14.
MLA Liu, Zhipei,et al."An LQT2-related mutation in the voltage-sensing domain is involved in switching the gating polarity of hERG".BMC BIOLOGY 22.1(2024):14.

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来源：上海药物研究所

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