Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation

Michihiro Tateyama, Ilaria Rivolta, Colleen E Clancy, Robert S. Kass

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Mutations associated with sodium channel-linked inherited Long-QT syndrome often result in a gain of channel function by disrupting channel inactivation. A small fraction of channels fail to inactivate (burst) at depolarized potentials where normal (wild type) channels fully inactivate. These noninactivating channels give rise to a sustained macroscopic current. We studied the effects of protein kinase A stimulation on sustained current in wild type and three disease-linked C-terminal mutant channels (D1790G, Y1795C, and Y1795H). We show that protein kinase A stimulation differentially affects gating in the mutant channels. Wild type, Y1795C, and Y1795H channels are insensitive to protein kinase A stimulation, whereas "bursting" in the D1790G mutant is markedly enhanced by protein kinase A-dependent phosphorylation. Our results suggest that the charge at position 1790 of the C terminus of the channel modulates the response of the cardiac sodium channel to protein kinase A stimulation and that phosphorylation of residue 36 in the N terminus and residue 525 in the cytoplasmic linker joining domains I and II of the channel α subunit facilitate destabilization of inactivation and thereby increase sustained current.

Original languageEnglish (US)
Pages (from-to)46718-46726
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number47
DOIs
StatePublished - Nov 21 2003
Externally publishedYes

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Sodium Channels
Cyclic AMP-Dependent Protein Kinases
Modulation
Mutation
Phosphorylation
Long QT Syndrome
Joining

ASJC Scopus subject areas

  • Biochemistry

Cite this

Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation. / Tateyama, Michihiro; Rivolta, Ilaria; Clancy, Colleen E; Kass, Robert S.

In: Journal of Biological Chemistry, Vol. 278, No. 47, 21.11.2003, p. 46718-46726.

Research output: Contribution to journalArticle

Tateyama, Michihiro ; Rivolta, Ilaria ; Clancy, Colleen E ; Kass, Robert S. / Modulation of Cardiac Sodium Channel Gating by Protein Kinase A Can Be Altered by Disease-linked Mutation. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 47. pp. 46718-46726.
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AU - Kass, Robert S.

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