Single-channel analysis of inactivation-defective rat skeletal muscle sodium channels containing the F1304Q mutation

John H. Lawrence, David W. Orias, Jeffrey R. Balser, H. Bradley Nuss, Gordon F. Tomaselli, Brian O'Rourke, Eduardo Marban

Research output: Contribution to journalArticle

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Abstract

The intracellular linker between domains III and IV of the voltage- gated Na channel mediates fast inactivation. Targeted alteration of one or more of a triplet of hydrophobic amine acids within this linker region results in a marked slowing in the decay of ionic current. The mechanism of this defective inactivation was explored in rat skeletal muscle sodium channels (μ1) containing the F1304Q mutation in Xenopus laevis oocytes with and without coexpression of the rat brain β1 subunit. Cell-attached single- channel patch-clamp recordings revealed that the μ1-F1304Q channel reopens multiple times with open times that are prolonged compared with those of the wild-type channel. Coexpression of the β1 subunit stabilized a dominant nonbursting gating mode and accelerated the activation kinetics of μ1- F1304Q but did not modify mean open time or fast-inactivation kinetics. A Markov gating model incorporating separate fast- and slow-inactivation particles reproduced the results by assuming that the F1304Q mutation specifically influences transitions to and from fast-inactivated states. These affects are independent of interactions of the mutant channel with the β1 subunit and do not result from a change in modal gating behavior. These results indicate that F1304Q mutant channels can still enter the inactivated state but do so reversibly and with altered kinetics.

Original languageEnglish (US)
Pages (from-to)1285-1294
Number of pages10
JournalBiophysical Journal
Volume71
Issue number3
DOIs
StatePublished - Jan 1 1996
Externally publishedYes

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Sodium Channels
Skeletal Muscle
Mutation
Xenopus laevis
Oocytes
Amines
Acids
Brain

ASJC Scopus subject areas

  • Biophysics

Cite this

Single-channel analysis of inactivation-defective rat skeletal muscle sodium channels containing the F1304Q mutation. / Lawrence, John H.; Orias, David W.; Balser, Jeffrey R.; Nuss, H. Bradley; Tomaselli, Gordon F.; O'Rourke, Brian; Marban, Eduardo.

In: Biophysical Journal, Vol. 71, No. 3, 01.01.1996, p. 1285-1294.

Research output: Contribution to journalArticle

Lawrence, John H. ; Orias, David W. ; Balser, Jeffrey R. ; Nuss, H. Bradley ; Tomaselli, Gordon F. ; O'Rourke, Brian ; Marban, Eduardo. / Single-channel analysis of inactivation-defective rat skeletal muscle sodium channels containing the F1304Q mutation. In: Biophysical Journal. 1996 ; Vol. 71, No. 3. pp. 1285-1294.
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