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From the Unit of Pharmacology (Drs. Desaphy, De Luca, Tortorella, and Conte Camerino), Department of Pharmaco-Biology (Dr. De Vito), Faculty of Pharmacy, University of Bari, Italy; and Division of Genetic Medicine (Dr. George), Vanderbilt University, Nashville, TN.
Address correspondence and reprint requests to Dr. Diana Conte Camerino, Unità di Farmacologia, Dipartimento Farmaco-Biologico, Facoltà di Farmacia, Università di Bari, via Orabona 4Campus, 70125 Bari, Italy; e-mail: conte{at}farmbiol.uniba.it
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 (
-[(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.
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