Mexiletine Block of Voltage-Gated Sodium Channels: Isoform- and State-Dependent Drug–Pore Interactions

Abstract

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 Na v 1.2, Na v 1.4, and Na v 1.5 and examined the effects of mutations of transmembrane segment S6 residues on mexiletine block of Na v 1.5. Three channel isoforms had similar affinities of mexiletine for the rested state, and Na v 1.4 and Na v 1.5 had similar affinities for the open and inactivated states, while Na v 1.2 had lower affinity for these states than Na v 1.4 and Na v 1.5. 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 1 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 Na v 1.4 and Na v 1.5 was caused by a p-p interaction with Phe, whereas mexiletine was located away from Phe in the open state of Na v 1.2. 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.

ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling

“…Different compounds and toxins have been found as state-dependent modulators for ion channels. For instance, mexiletine preferentially blocks the Na V 1.5 sodium channel when the DIII-VSD is activated, and protoxin-II shows higher affinity to resting VSD states of Na V 1.7 sodium channel (Nakagawa et al, 2019; Xu et al, 2019; Zhu et al, 2019), while roscovitine facilitates the inactivation and shows less effect on activation of Ca V 1.2 calcium channel (Yarotskyy et al, 2010; Yazawa et al, 2011). We previously found that the IO state is more sensitive to the blocker XE991 than the AO state (Zaydman et al, 2014).…”

Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome

“…Residues in S6 segments of DⅠ, DⅢ, and DⅣ, but not DⅡ, have been reported to affect local anesthetic binding (Yarov‐Yarovoy et al., 2002). Recently, Nakagawa et al reported that residues in DⅠS6, DⅢS6, and DⅣS6, but not DⅡS6, are major determinants to affect the affinity of MEX, which is supported by structural studies revealing that L1462 in DⅢS6 and F1760 in DⅣS6 face the inner pore, while N406 in DⅠS6 faces away from the pore (Nakagawa et al., 2019). Considering the fact that most SCN5A trafficking‐deficient mutations rescued by MEX are located at pore‐S6 regions in DⅠ, DⅢ, and DⅣ, but not DⅡ, it is conceivable that MEX binding to the pore‐S6 region of unmatured trafficking‐deficient mutant channels may stabilize the pore of the channel, then promote protein folding at ER, thereby facilitating the exit of mutant channels from the ER to Golgi apparatus.…”

Characterization of a novel LQT3 variant with a selective efficacy of mexiletine treatment

“…In our study, we demonstrate that A1656D mutation differently responds to three Na + channel blockers and that the distinct effectiveness is well correlated with the specific therapeutic responsiveness of the patient. It has been demonstrated that the structurally diverse antiarrhythmic drugs including flecainide, ranolazine and mexiletine, share overlapping binding sites in the inner-pore region of Nav1.5, which is lined by the S6 transmembrane helices and P-loop turns 36,37 . However, the variable responsiveness of the Y1767C Nav1.5 mutation to mexiletine, flecainide, and ranolazine might reflect differences in the underlying mechanisms of drug binding and Na + channel inhibition 38 .…”