Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia

S804F and V1293I

Donnella S. Green, Alfred L. George, Stephen C. Cannon

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

1. Missense mutations in the α-subunit of the human skeletal muscle sodium channel (hSkM1) have been detected in some heritable forms of myotonia. By recording Na+ currents from cells transfected with cDNA encoding either wild-type or mutant hSkM1, we characterized the functional consequences of two myotonia-associated mutations that lie at the cytoplasmic end of the sixth transmembrane segment in domain II (S804F) or domain III (V1293I). 2. Both mutations caused modest, but unequivocal, alterations in the voltage-dependent gating behaviour of hSkM1. For S804F, the abnormalities were limited to fast inactivation: the persistent Na+ current at the end of a 50 ms depolarization was increased 3-fold, the rate of inactivation from the open state was slowed 2-fold, and the voltage dependence of fast inactivation (h(∞)) was shifted by +3 mV. V1293I also disrupted fast inactivation, as evidenced by a 3-fold faster rate of recovery at hyperpolarized potentials (≤ -70 mV). Activation was altered as well for V1293I: the voltage dependence was shifted by -6 mV (hyperpolarized). 3. Slow inactivation was not altered by S804F or V12931. 4. We conclude that S804F and V1293I are not benign polymorphisms. Either mutation causes detectable alterations in channel gating and, in model simulations, the magnitude of the defects is sufficient to produce runs of myotonic discharges.

Original languageEnglish (US)
Pages (from-to)685-694
Number of pages10
JournalJournal of Physiology
Volume510
Issue number3
StatePublished - Aug 1 1998

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Myotonia
S 6
Sodium Channels
Missense Mutation
Mutation
Skeletal Muscle
Complementary DNA

ASJC Scopus subject areas

  • Physiology

Cite this

Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia : S804F and V1293I. / Green, Donnella S.; George, Alfred L.; Cannon, Stephen C.

In: Journal of Physiology, Vol. 510, No. 3, 01.08.1998, p. 685-694.

Research output: Contribution to journalArticle

Green, Donnella S. ; George, Alfred L. ; Cannon, Stephen C. / Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia : S804F and V1293I. In: Journal of Physiology. 1998 ; Vol. 510, No. 3. pp. 685-694.
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