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

J. F. Desaphy, A. De Luca, P. Tortorella, D. De Vito, A. L. George, Diana Conte Camerino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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 (INa) 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 INa with a potency following the order rank R1448C > WT ≈ 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 (α-[(2-methylphenoxy)methyl]-benzenemethanamine), behaved similarly but was ∼5 times more potent than mexiletine. Interestingly, the higher drug concentrations ameliorated the abnormally slower decay rate of myotonic INa. 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.

Original languageEnglish (US)
Pages (from-to)1849-1857
Number of pages9
Issue number10
StatePublished - Nov 27 2001

ASJC Scopus subject areas

  • Clinical Neurology

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