Regulation and drug modulation of a voltage-gated sodium channel: Pivotal role of the S4–S5 linker in activation and slow inactivation
Jinglei Xiao, Vasyl Bondarenko, Yali Wang, Antonio Suma, Marta M. Wells, Qiang Chen, Tommy S. Tillman, Yan Luo, Buwei Yu, William P. Dailey, Roderic G. Eckenhoff, Pei Tang, Vincenzo Carnevale, Michael L. Klein, Yan Xu
Abstract
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.