Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation

Mohamed Chahine, Alfred L. George, Ming Zhou, Sen Ji, Weijing Sun, Robert L. Barchi, Richard Horn

Research output: Contribution to journalArticlepeer-review

291 Scopus citations

Abstract

Mutations in the adult human skeletal muscle Na + channel a 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 RI 448H 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.

Original languageEnglish (US)
Pages (from-to)281-294
Number of pages14
JournalNeuron
Volume12
Issue number2
DOIs
StatePublished - Feb 1994
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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