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(Circulation Research. 2009;104:870.)
© 2009 American Heart Association, Inc.

Cellular Biology

Calcium-Mediated Dual-Mode Regulation of Cardiac Sodium Channel Gating

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

From the Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, Md.

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

Intracellular Ca²⁺ ([Ca²⁺]_i) can trigger dual-mode regulation of the voltage gated cardiac sodium channel (Na_V1.5). The channel components of the Ca²⁺ regulatory system are the calmodulin (CaM)-binding IQ motif and the Ca²⁺ sensing EF hand–like (EFL) motif in the carboxyl terminus of the channel. Mutations in either motif have been associated with arrhythmogenic changes in expressed Na_V1.5 currents. Increases in [Ca²⁺]_i shift the steady-state inactivation of Na_V1.5 in the depolarizing direction and slow entry into inactivated states. Mutation of the EFL (Na_V1.5_4X) shifts inactivation in the hyperpolarizing direction compared with the wild-type channel and eliminates the Ca²⁺ sensitivity of inactivation gating. Modulation of the steady-state availability of Na_V1.5 by [Ca²⁺]_i is more pronounced after the truncation of the carboxyl terminus proximal to the IQ motif (Na_V1.5₁₈₈₅), which retains the EFL. Mutating the EFL (Na_V1.5_4X) unmasks CaM-mediated regulation of the kinetics and voltage dependence of inactivation. This latent CaM modulation of inactivation is eliminated by mutation of the IQ motif (Na_V1.5_4X-IQ/AA). The LQT3 EFL mutant channel Na_V1.5_D1790G exhibits Ca²⁺ insensitivity and unmasking of CaM regulation of inactivation gating. The enhanced effect of CaM on Na_V1.5_4X gating is associated with significantly greater fluorescence resonance energy transfer between enhanced cyan fluorescent protein–CaM and Na_V1.5_4X channels than is observed with wild-type Na_V1.5. Unlike other isoforms of the Na channel, the IQ-CaM interaction in the carboxyl terminus of Na_V1.5 is latent under physiological conditions but may become manifest in the presence of disease causing mutations in the CT of Na_V1.5 (particularly in the EFL), contributing to the production of potentially lethal ventricular arrhythmias.

Key Words: voltage-gated sodium channel • EF hand motif • IQ motif • calmodulin • FRET

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