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(Circulation Research. 2002;90:e49.)
© 2002 American Heart Association, Inc.

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Isoform-Specific Modulation of Voltage-Gated Na⁺ Channels by Calmodulin

Isabelle Deschênes, Nathalie Neyroud, Deborah DiSilvestre, Eduardo Marbán, David T. Yue, Gordon F. Tomaselli

From the Department of Medicine, Institute of Molecular Cardiobiology, Division of Cardiology (I.D., N.N., D.D., E.M., G.F.T.), and the Department of Biomedical Engineering (D.T.Y.), The Johns Hopkins University, Baltimore, Md.

Correspondence to Gordon F. Tomaselli, MD, The Johns Hopkins University School of Medicine, 720 N Rutland Ave, 844 Ross Building, Baltimore, MD 21205. E-mail gtomasel{at}jhmi.edu

Abstract

Calmodulin (CaM) is a calcium-sensing protein that binds to Na⁺ channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (µ1) but not cardiac (hH1) Na⁺ channels. Mutant CaM₁₂₃₄ did not alter the voltage dependence or the kinetics of gating of either µ1 or hH1. Mutation of the highly conserved IQ motif in the carboxyl terminus of both isoforms (IQ/AA) slowed the kinetics of current decay and abolished the effect of wild-type CaM on µ1, but did not alter hH1 currents. The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both µ1 and hH1 channels. Inhibition of Ca²⁺/CaM kinase (CaM-K) slowed the current decay, the rate of entry into inactivation, and shifted the voltage dependence of hH1 in the depolarizing direction independent of CaM overexpression with no effect on µ1 Na⁺ channels. CaM signaling modulates Na⁺ currents in an isoform-specific manner, via direct interaction with skeletal muscle Na⁺ channels and through CaM-K in the case of the cardiac isoform. The full text of this article is available at http://www.circresaha.org.

Key Words: sodium channels • calmodulin • cardiac • skeletal muscle • Ca²⁺/calmodulin-dependent kinase

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