Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative

Neurology. 2001 Nov 27;57(10):1849-57. doi: 10.1212/wnl.57.10.1849.


Background: Myotonia and periodic paralysis caused by sodium channel mutations show variable responses to the anti-myotonic drug mexiletine.

Objective: To investigate whether variability among sodium channel mutants results from differences in drug binding affinity or in channel gating.

Methods: Whole-cell sodium currents (I(Na)) were recorded in tsA201 cells expressing human wild-type (WT) and mutant skeletal muscle sodium channels (A1156T, hyperkalemic periodic paralysis; R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia).

Results: At a holding potential (hp) of -120 mV, mexiletine produced a tonic (TB, 0.33 Hz) and a use-dependent (UDB, 10 Hz) block of peak I(Na) with a potency following the order rank R1448C > WT approximately equal A1156T > G1306E. Yet, when assayed from an hp of -180 mV, TB and UDB by mexiletine were similar for the four channels. The different midpoints of channel availability curves found for the four channels track the half-maximum inhibitory value (IC50) measured at -120 mV. Thus differences in the partitioning of channels between the closed and fast-inactivated states underlie the different IC50 measured at a given potential. The mexiletine-derivative, Me7 (alpha-[(2-methylphenoxy)methyl]-benzenemethanamine), behaved similarly but was approximately 5 times more potent than mexiletine. Interestingly, the higher drug concentrations ameliorated the abnormally slower decay rate of myotonic I(Na).

Conclusions: These results explain the basis of the apparent difference in block of mutant sodium channels by mexiletine and Me7, opening the way to a more rationale drug use and to design more potent drugs able to correct specifically the biophysical defect of the mutation in individual myotonic patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Transformed
  • DNA Mutational Analysis
  • Dose-Response Relationship, Drug
  • Humans
  • Ion Channel Gating / drug effects*
  • Ion Channel Gating / genetics
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mexiletine / analogs & derivatives*
  • Mexiletine / pharmacology*
  • Mutation / genetics*
  • Myotonic Disorders / genetics*
  • Myotonic Disorders / physiopathology
  • Paralyses, Familial Periodic / genetics*
  • Paralyses, Familial Periodic / physiopathology
  • Patch-Clamp Techniques
  • Protein-Serine-Threonine Kinases / genetics
  • Saccharomyces cerevisiae Proteins*
  • Sodium Channels / drug effects
  • Sodium Channels / genetics*
  • Structure-Activity Relationship


  • Saccharomyces cerevisiae Proteins
  • Sodium Channels
  • Mexiletine
  • SKM1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases