Voltage-dependent block of normal and mutant muscle sodium channels by 4-Chloro-m-Cresol

1 The effects of 4-Chloro-m-Cresol (4-CmC) were examined on heterologously expressed wild type (WT), Paramyotonia Congenita (R1448H) and Hyperkalemic Periodic Paralysis (M1360V) mutant alpha-subunits of human muscle sodium channels. 2 Block of rested sodium channels caused by 4-CmC was concentration-dependent with an ECR50 of 0.40 mM in WT, 0.45 mM in R1448H and 0.49 mM in M1360V. 3 Inactivation significantly promoted 4-CmC-induced sodium channel block in all clones indicated by 4-CmC-induced shifts of steady-state availability curves, reflecting a higher proportion of channel block at depolarized membrane potentials. Channel block was almost complete (>90%) at concentrations close to the ECR50 (0.5 mM) on application of an inactivating prepulse before the test pulse. 4 4-CmC accelerated the current decay following depolarization and prolonged recovery from inactivation in all clones. Of these, R1448H, the mutant which displayed severely impaired inactivation in the controls, responded to 4-CmC with the most pronounced acceleration of inactivation. Control experiments revealed enhanced recovery from inactivation in the mutants, which was restored to normal in 0.1 mM 4-CmC. 5 4-CmC induced no additional frequency-dependent block. 6 Our results clearly demonstrate that 4-CmC is as effective as lidocaine (Fan et al., 1996) in blocking muscle sodium channels. Low concentrations of the compound (less than or equal to ECR50) were able to restore pathologically accelerated recovery from inactivation and impaired inactivation in the mutants to the WT value.