Sodium channel mutations in paramyotoniacongenita uncouple inactivation from activation

Author(s): Chahine M, George AL Jr, Zhou M, Ji S, Sun W, et al.

Abstract

Mutations in the adult human skeletal muscle Na+ channel alpha subunit cause the disease paramyotonia congenita. Two paramyotonia congenita mutations, R1448H and R1448C, substitute histidine and cysteine for arginine in the S4 segment of domain 4. These mutations, expressed in a cell line, have only small effects on the activation of Na+ currents, but mutant channels inactivate more slowly with less voltage dependence than wild-type channels and exhibit an enhanced rate of recovery from inactivation. Increase of extracellular pH made the rate of inactivation of R1448H similar to that of R1448C, suggesting that this residue has an extracellular location and that its charge is important for normal inactivation. Analysis of single-channel data reveals that mutant channels inactivate normally from closed states, but poorly from the open state. The data suggest a critical role for the S4 helix of domain 4 in coupling between activation and inactivation.

Similar Articles

Sodium channelopathies of skeletal muscle result from gain or loss of function

Author(s): Jurkat-Rott K, Holzherr B, Fauler M, Lehmann-Horn F

The skeletal muscle sodium and chloride channel diseases

Author(s): Hudson AJ, Ebers GC, Bulman DE

Primary structure of the adult human skeletal muscle voltage-dependent sodium channel

Author(s): George AL Jr, Komisarof J, Kallen RG, Barchi RL

A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation

Author(s): West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, et al.

Cooperative effect of S4-S5 loops in domains D3 and D4 on fast inactivation of the Na+ channel

Author(s): Popa MO, Alekov AK, Bail S, Lehmann-Horn F, Lerche H

Sodium channel mutations in paramyotoniacongenita exhibit similar biophysical phenotypes in vitro

Author(s): Yang N, Ji S, Zhou M, Ptácek LJ, Barchi RL, et al.

Thr1313Met mutation in skeletal muscle sodium channels in a Japanese family with paramyotoniacongenita

Author(s): Kinoshita M, Sasaki R, Nagano T, Matsuda A, Nakamura S, et al.

Voltage-gated ion channels and hereditary disease

Author(s): Lehmann-Horn F, Jurkat-Rott K