title: Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.
abstract: OBJECTIVE
  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 SCN9a 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 L858F primary erythromelalgia NaV 1.7 mutation in vitro.
  
  
  METHODS
  Human wild-type and L858F-mutated NaV 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.
  
  
  RESULTS
  While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-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.
  
  
  CONCLUSIONS
  Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, UCL, London, UK; UCL Centre for Anaesthesia, Critical Care and Pain Medicine, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Cregg
authors.forename: J J
authors.initials: JJ
authors.lastname: Cox
authors.forename: D L H
authors.initials: DL
authors.lastname: Bennett
authors.forename: J N
authors.initials: JN
authors.lastname: Wood
authors.forename: R
authors.initials: R
authors.lastname: Werdehausen
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D004916:Erythromelalgia; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008801:Mexiletine / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D008801:Mexiletine