Mexiletine is a class Ib antiarrhythmic drug and is also used clinically to reduce or prevent myotonia. In addition, mexiletine has neuroprotective effects in models of brain ischemia. We compared state-dependent affinities of mexiletine for Nav1.2, Nav1.4, and Nav1.5 and examined the effects of mutations of transmembrane segment S6 residues on mexiletine block of Nav1.5. Three channel isoforms had similar affinities of mexiletine for the rested state, and Nav1.4 and Nav1.5 had similar affinities for the open and inactivated states, while Nav1.2 had lower affinity for these states than Nav1.4 and Nav1.5. Mutational studies revealed that the largest affinity change was observed for an Ala substitution of Phe in domain IV S6. In our homology modeling based on the bacterial Na+ channel, mexiletine changed its location and orientation in the pore depending on the state of the channel, irrespective of the channel isoform. Mexiletine occurred in the upper part in the pore in the open state and lower in the closed state. High-affinity binding of mexiletine in the open states of Nav1.4 and Nav1.5 was caused by a π-π interaction with Phe, whereas mexiletine was located away from Phe in the open state of Nav1.2. These results provide crucial information on the mechanism of isoform differences in state-dependent block by local anesthetics and related drugs. Mexiletine at upper locations in the open state may effectively cause an electrostatic mechanism of block.
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.