Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol

1 We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paral ysis (M1360V) mutant alpha-subunits of hunan skeletal muscle sodium channel s. 2 Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR50 of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. W hen blockade was assessed at -100 mV, the ECR50 was reduced in R1448H (2 mM ) compared with both wild type (4.3 mM; P < 0.01) and M1360V (4.3 mM). 3 Membrane depolarization before the test depolarization significantly prom oted benzylalcohol-induced sodium channel blockade. The values of K-D for t he fast-inactivated state derived from benzylalcohol-induced shifts in stea dy-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448 H. In the presence of slow inactivation induced by 2.5 a depolarizing prepu lses, the ECI50 for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4 Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5 Benzylalcohol induced significant frequency-dependent block a t stimulating frequencies of 10, 50, and 100 Hz in all clones. 6 Our results clearly show that benzylalcohol is an effective blocker of mu scle sodium channels in conditions that are associated with membrane depola rization. Mutants that enter voltage-dependent inactivation at more hyperpo larized membrane potentials compared with wild type are more sensitive to i nhibitory effects at the normal resting potential.