A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel

doi:10.3389/fphar.2018.00150

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	A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel
	Bai, Fang 1,2,3,6; Pi, Xiaoping 3,4; Li, Ping 3; Zhou, Pingzheng 3; Yang, Huaiyu 3; Wang, Xicheng 1,2; Li, Min 5; Gao, Zhaobing3,4 ; Jiang, Hualiang3,4
刊名	FRONTIERS IN PHARMACOLOGY
	2018-03-09
卷号	9
关键词	KCNQ2 potassium channel hill equation thermodynamic model patch clamp electrophysiology activators
ISSN号	1663-9812
DOI	10.3389/fphar.2018.00150
文献子类	Article
英文摘要	Ion channels are important therapeutic targets, and their pharmacology is becoming increasingly important. However, knowledge of the mechanism of interaction of the activators and ion channels is still limited due to the complexity of the mechanisms. A statistical thermodynamic model has been developed in this study to characterize the cooperative binding of activators to ion channels. By fitting experimental concentration-response data, the model gives eight parameters for revealing the mechanism of an activator potentiating an ion channel, i.e., the binding affinity (KA), the binding cooperative coefficients for two to four activator molecules interacting with one channel (gamma, mu, and gamma), and the channel conductance coefficients for four activator binding configurations of the channel ( a, b, c, and d). Values for the model parameters and the mechanism underlying the interaction of ztz240, a proven KCNQ2 activator, with the wild-type channel have been obtained and revealed by fitting the concentration-response data of this activator potentiating the outward current amplitudes of KCNQ2. With these parameters, our model predicted an unexpected bi-sigmoid concentration-response curve of ztz240 activation of the WT-F137A mutant heteromeric channel that was in good agreement with the experimental data determined in parallel in this study, lending credence to the assumptions on which the model is based and to the model itself. Our model can provide a better fit to the measured data than the Hill equation and estimates the binding affinity, as well as the cooperative coefficients for the binding of activators and conductance coefficients for binding states, which validates its use in studying ligand-channel interaction mechanisms.
资助项目	National Basic Research Program of China[2015CB910304] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[91313000] ; National Natural Science Foundation of China[61433017] ; National Natural Science Foundation of China[81773707] ; Shanghai Science and Technology Innovation Fund[15431901500] ; Welch Foundation[C-1792]
WOS关键词	GATED POTASSIUM CHANNELS ; MOLECULAR DETERMINANTS ; VOLTAGE-SENSOR ; K+ CHANNELS ; RETIGABINE ; EPILEPSY ; DOMAIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000427040500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279856]
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新药研究国家重点实验室药物发现与设计中心
通讯作者	Gao, Zhaobing; Jiang, Hualiang
作者单位	1.Dalian Univ Technol, Dept Engn Mech, State Key Lab Struct Anal Ind Equipment, Dalian, Peoples R China; 2.Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, Dalian, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res,CAS Key Lab Receptor Res, Shanghai, Peoples R China; 4.Univ Chinese Acad Sci, Beijing, Peoples R China; 5.Johns Hopkins Univ, Dept Neurosci, Baltimore, MD USA; 6.Rice Univ, Ctr Theoret Biol Phys, Houston, TX USA
推荐引用方式 GB/T 7714	Bai, Fang,Pi, Xiaoping,Li, Ping,et al. A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel[J]. FRONTIERS IN PHARMACOLOGY,2018,9.
APA	Bai, Fang.,Pi, Xiaoping.,Li, Ping.,Zhou, Pingzheng.,Yang, Huaiyu.,...&Jiang, Hualiang.(2018).A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel.FRONTIERS IN PHARMACOLOGY,9.
MLA	Bai, Fang,et al."A Statistical Thermodynamic Model for Ligands Interacting With Ion Channels: Theoretical Model and Experimental Validation of the KCNQ2 Channel".FRONTIERS IN PHARMACOLOGY 9(2018).