Calcium-mediated dual-mode regulation of cardiac sodium channel gating

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

Research output: Contribution to journalArticle

Abstract

Intracellular Ca2+ ([Ca2+]i) can trigger dual-mode regulation of the voltage gated cardiac sodium channel (NaV1.5). 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 NaV1.5 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 (NaV1.54X) 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 NaV1.5 by [Ca2+]i is more pronounced after the truncation of the carboxyl terminus proximal to the IQ motif (NaV1.5Δ1885), which retains the EFL. Mutating the EFL (NaV1.54X) 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 (NaV1.5 4X-IQ/AA). The LQT3 EFL mutant channel NaV1.5 D1790G exhibits Ca2+ insensitivity and unmasking of CaM regulation of inactivation gating. The enhanced effect of CaM on Na V1.54X gating is associated with significantly greater fluorescence resonance energy transfer between enhanced cyan fluorescent protein-CaM and NaV1.54X channels than is observed with wild-type NaV1.5. Unlike other isoforms of the Na channel, the IQ-CaM interaction in the carboxyl terminus of NaV1.5 is latent under physiological conditions but may become manifest in the presence of disease causing mutations in the CT of NaV1.5 (particularly in the EFL), contributing to the production of potentially lethal ventricular arrhythmias.

Original languageEnglish (US)
Pages (from-to)870-878
Number of pages9
JournalCirculation Research
Volume104
Issue number7
DOIs
StatePublished - Apr 10 2009

Fingerprint

EF Hand Motifs
Sodium Channels
Calmodulin
Calcium
Mutation
NAV1.5 Voltage-Gated Sodium Channel
Fluorescence Resonance Energy Transfer
Cardiac Arrhythmias
Protein Isoforms

Keywords

  • Calmodulin
  • EF hand motif
  • FRET
  • Gated sodium channel
  • IQ motif
  • Voltage

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Biswas, S., Disilvestre, D., Tian, Y., Halperin, V. L., & Tomaselli, G. F. (2009). Calcium-mediated dual-mode regulation of cardiac sodium channel gating. Circulation Research, 104(7), 870-878. https://doi.org/10.1161/CIRCRESAHA.108.193565

Calcium-mediated dual-mode regulation of cardiac sodium channel gating. / Biswas, Subrata; Disilvestre, Deborah; Tian, Yanli; Halperin, Victoria L.; Tomaselli, Gordon F.

In: Circulation Research, Vol. 104, No. 7, 10.04.2009, p. 870-878.

Research output: Contribution to journalArticle

Biswas, S, Disilvestre, D, Tian, Y, Halperin, VL & Tomaselli, GF 2009, 'Calcium-mediated dual-mode regulation of cardiac sodium channel gating', Circulation Research, vol. 104, no. 7, pp. 870-878. https://doi.org/10.1161/CIRCRESAHA.108.193565
Biswas S, Disilvestre D, Tian Y, Halperin VL, Tomaselli GF. Calcium-mediated dual-mode regulation of cardiac sodium channel gating. Circulation Research. 2009 Apr 10;104(7):870-878. https://doi.org/10.1161/CIRCRESAHA.108.193565
Biswas, Subrata ; Disilvestre, Deborah ; Tian, Yanli ; Halperin, Victoria L. ; Tomaselli, Gordon F. / Calcium-mediated dual-mode regulation of cardiac sodium channel gating. In: Circulation Research. 2009 ; Vol. 104, No. 7. pp. 870-878.
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