The Journal of General Physiology
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Published online February 11, 2008
doi:10.1085/jgp.200709863
The Journal of General Physiology, Vol. 131, No. 3, 197-209
The Rockefeller University Press, 0022-1295 $30.00
© 2008 Biswas et al.
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ARTICLE

 Calmodulin Regulation of NaV1.4 Current: Role of Binding to the Carboxyl Terminus



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

Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Correspondence to Gordon F. Tomaselli: gtomasel{at}jhmi.edu

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.

I. Deschênes' present address is Metro Health Medical Center, Case Western Reserve University, Cleveland, OH 44106.

Abbreviations used in this paper: CaM, calmodulin; CT, carboxy terminus; DIC, differential interference contrast; FRET, fluorescence resonance energy transfer; NaV, voltage-gated sodium channel.


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