Molecular Modeling of Cardiac Sodium Channel with Mexiletine.

ABSTRACT: A sodium channel blocker mexiletine (MEX) is used to treat chronic pain, myotonia and some arrhythmias. Mutations in the pore domain (PD) of voltage-gated sodium channels differently affect tonic block (TB) and use-dependent block (UDB) by MEX. Previous studies identified several MEX-sensing residues in the hNav1.5 channel and demonstrated that the channel block by MEX increases with activation of the voltage-sensing domain III (VSD_III), whereas MEX stabilizes the activated state of VSD_III. Structural rationales for these observations are unclear. Here, Monte Carlo (MC) energy minimizations were used to dock MEX and its more potent analog, Thio-Me2, into the hNav1.5 cryo-EM structure with activated VSDs and presumably inactivated PD. Computations yielded two ensembles

SUBMITTER: Zhorov BS 

PROVIDER: S-EPMC9786191 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature