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Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L 858 F Na V 1.7 sodium channels
Author(s) -
Cregg R,
Cox J J,
Bennett D L H,
Wood J N,
Werdehausen R
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12788
Subject(s) - mexiletine , sodium channel , sodium channel blocker , erythromelalgia , chemistry , pharmacology , gating , patch clamp , biophysics , electrophysiology , medicine , anesthesia , sodium , biology , organic chemistry
Background and Purpose The non‐selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain‐of‐function SCN 9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L 858 F primary erythromelalgia Na V 1.7 mutation in vitro . Experimental Approach Human wild‐type and L 858 F ‐mutated Na V 1.7 channels were expressed in HEK293A cells. Whole‐cell currents were recorded by voltage‐clamp techniques to characterize the effect of mexiletine on channel gating properties. Key Results While the concentration‐dependent tonic block of peak currents by mexiletine was similar in wild‐type and L 858 F channels, phasic block was more pronounced in cells transfected with the L 858 F mutation. Moreover, mexiletine substantially shifted the pathologically‐hyperpolarized voltage‐dependence of steady‐state activation in L 858 F ‐mutated channels towards wild‐type values and the voltage‐dependence of steady‐state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents. Conclusion and Implications Mexiletine has a normalizing effect on the pathological gating properties of the L 858 F gain‐of‐function mutation in Na V 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain‐of‐function sodium channel disorders.