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Front. Pharmacol. | doi: 10.3389/fphar.2018.00150

A statistical thermodynamic model for ligands interacting with ion channels: theoretical model and experimental validation of the KCNQ2 channel

 Fang Bai1,  Xiaoping Pi1, Ping Li1, Pingzheng Zhou1, Huaiyu Yang1, Xicheng Wang1, Min Li2,  Zhaobing Gao1* and  Hualiang Jiang1*
  • 1Shanghai Institute of Materia Medica (CAS), China
  • 2Department of Neuroscience, Johns Hopkins University, United States

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 (y, μ and v), 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.

Keywords: KCNQ2 Potassium Channel, Hill equation, Thermodynamic model, patch clamp electrophysiology, activator

Received: 07 Jan 2018; Accepted: 13 Feb 2018.

Edited by:

Jianfeng Pei, Peking University, China

Reviewed by:

Francesco Miceli, University of Naples Federico II, Italy
Zhuqing Zhang, University of Chinese Academy of Sciences (UCAS), China  

Copyright: © 2018 Bai, Pi, Li, Zhou, Yang, Wang, Li, Gao and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Zhaobing Gao, Shanghai Institute of Materia Medica (CAS), Shanghai, China, zbgao@simm.ac.cn
Prof. Hualiang Jiang, Shanghai Institute of Materia Medica (CAS), Shanghai, China, hljiang@simm.ac.cn