Premium
Voltage‐dependent block of normal and mutant muscle sodium channels by 4‐Chloro‐m‐Cresol
Author(s) -
Haeseler G,
Leuwer M,
Kavan J,
Würz A,
Dengler R,
Piepenbrock S
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702896
Subject(s) - sodium channel , chemistry , sodium , depolarization , sodium channel blocker , biophysics , membrane potential , mutant , tetrodotoxin , patch clamp , medicine , endocrinology , biochemistry , biology , receptor , organic chemistry , gene
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 α‐subunits of human muscle sodium channels. Block of rested sodium channels caused by 4‐CmC was concentration‐dependent with an ECR 50 of 0.40 m M in WT, 0.45 m M in R1448H and 0.49 m M in M1360V. 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 ECR 50 (0.5 m M ) on application of an inactivating prepulse before the test pulse. 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 m M 4‐CmC. 4‐CmC induced no additional frequency‐dependent block. 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 (ECR 50 ) were able to restore pathologically accelerated recovery from inactivation and impaired inactivation in the mutants to the WT value.British Journal of Pharmacology (1999) 128 , 1259–1267; doi: 10.1038/sj.bjp.0702896