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

被引:50
作者
Desaphy, JF
De Luca, A
Tortorella, P
De Vito, D
George, AL
Camerino, DC
机构
[1] Univ Bari, Fac Farm, Dipartimento Farmaco Biol, Unita Farmacol, I-70125 Bari, Italy
[2] Univ Bari, Fac Farm, Dept Pharmaco Biol, I-70125 Bari, Italy
[3] Vanderbilt Univ, Div Med Genet, Nashville, TN USA
关键词
D O I
10.1212/WNL.57.10.1849
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 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 (alpha-[(2-methylphenoxy)methyl]-benzenemethanamine), behaved similarly but was similar to5 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.
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页码:1849 / 1857
页数:9
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