Open AccessRegulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4–S5 linker in activation and slow inactivation
Author(s) -
Jinglei Xiao,
Vasyl Bondarenko,
Yali Wang,
Antonio Suma,
Marta M. Wells,
Qiang Chen,
Tommy S. Tillman,
Yan Luo,
Bo Yu,
William P. Dailey,
Roderic Eckenhoff,
Pei Tang,
Vincenzo Carnevale,
Michael L. Klein,
Yan Xu
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2102285118
Subject(s) - linker , sodium channel , biophysics , protein subunit , chemistry , gating , allosteric regulation , binding site , mechanism of action , helix (gastropod) , biochemistry , stereochemistry , biology , sodium , enzyme , in vitro , ecology , organic chemistry , snail , computer science , gene , operating system
Significance Voltage-gated sodium channels initiate electric signals in cell communications. The S4–S5 linker between the voltage-sensing and pore modules transmits depolarization signals to trigger channel activation. The mechanisms of this action, however, remain elusive. By combining biophysical and computational approaches, we identify a critical residue, T140, in the S4–S5 linker of the bacterial sodium channel NaChBac, which plays a pivotal role in channel activation and drug modulation of slow inactivation. Specifically, we discovered conformation-dependent drug binding at this site and unveiled a toggling mode of action by T140, which switches interaction partners with different S6 residues to regulate channel activation and slow inactivation. These observations suggest the possibility of conformation-specific drugs targeting the gating machinery of voltage-gated ion channels.