SODIUM-CHANNEL MUTATIONS IN PARAMYOTONIA-CONGENITA UNCOUPLE INACTIVATION FROM ACTIVATION

Mutations in the adult human skeletal muscle Na+ channel a subunit cau se the disease paramyotonia congenita. Two paramyotonia congenita muta tions, R1448H and R1448C, substitute histidine and cysteine for argini ne 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 th an wild-type channels and exhibit an enhanced rate of recovery from in activation. 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 cha nnels 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.