Calmodulin regulation of NaV1.4 current: Role of binding to the carboxyl terminus

Subrata Biswas, Isabelle Deschênes, Deborah DiSilvestre, Yanli Tian, Victoria L. Halperin, Gordon F. Tomaselli

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Calmodulin (CaM) regulates steady-state inactivation of sodium currents (NaV1.4) in skeletal muscle. Defects in Na current inactivation are associated with pathological muscle conditions such as myotonia and paralysis. The mechanisms of CaM modulation of expression and function of the Na channel are incompletely understood. A physical association between CaM and the intact C terminus of NaV1.4 has not previously been demonstrated. FRET reveals channel conformation-independent association of CaM with the C terminus of NaV1.4 (CT-NaV1.4) in mammalian cells. Mutation of the NaV1.4 CaM-binding IQ motif (NaV1.4IQ/AA ) reduces cell surface expression of NaV1.4 channels and eliminates CaM modulation of gating. Truncations of the CT that include the IQ region abolish Na current. NaV1.4 channels with one CaM fused to the CT by variable length glycine linkers exhibit CaM modulation of gating only with linker lengths that allowed CaM to reach IQ region. Thus one CaM is sufficient to modulate Na current, and CaM acts as an ancillary subunit of NaV1.4 channels that binds to the CT in a conformation-independent fashion, modulating the voltage dependence of inactivation and facilitating trafficking to the surface membrane.

Original languageEnglish (US)
Pages (from-to)197-209
Number of pages13
JournalJournal of General Physiology
Volume131
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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Calmodulin
Myotonia
Paralysis
Glycine
Skeletal Muscle
Sodium
Muscles
Mutation
Membranes

ASJC Scopus subject areas

  • Physiology

Cite this

Calmodulin regulation of NaV1.4 current : Role of binding to the carboxyl terminus. / Biswas, Subrata; Deschênes, Isabelle; DiSilvestre, Deborah; Tian, Yanli; Halperin, Victoria L.; Tomaselli, Gordon F.

In: Journal of General Physiology, Vol. 131, No. 3, 01.03.2008, p. 197-209.

Research output: Contribution to journalArticle

Biswas, Subrata ; Deschênes, Isabelle ; DiSilvestre, Deborah ; Tian, Yanli ; Halperin, Victoria L. ; Tomaselli, Gordon F. / Calmodulin regulation of NaV1.4 current : Role of binding to the carboxyl terminus. In: Journal of General Physiology. 2008 ; Vol. 131, No. 3. pp. 197-209.
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