Review article
Channelopathies from mutations in the cardiac sodium channel protein complex

https://doi.org/10.1016/j.yjmcc.2013.03.017Get rights and content

Highlights

  • Sodium channel complex proteins (SCCPs) regulate the sodium current in the heart.

  • Arrhythmogenic mutations in SCCPs cause functional abnormalities called channelopathies.

  • The literature for established, potential, and arrythmogenic mutant SCCPs is reviewed.

Abstract

The cardiac sodium current underlies excitability in heart, and inherited abnormalities of the proteins regulating and conducting this current cause inherited arrhythmia syndromes. This review focuses on inherited mutations in non-pore forming proteins of sodium channel complexes that cause cardiac arrhythmia, and the deduced mechanisms by which they affect function and dysfunction of the cardiac sodium current. Defining the structure and function of these complexes and how they are regulated will contribute to understanding the possible roles for this complex in normal and abnormal physiology and homeostasis. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

Section snippets

INa in heart: Excitability, arrhythmogenesis, and sodium–calcium homeostasis

Sodium current (INa) underlies excitability in cardiac ventricular and atrial myocytes and also in specialized conduction tissue including Purkinje cells. Peak INa is a large inward current responsible for rapid upstroke of the action potential (phase 0) and for conduction in working myocardium. The INa flowing just milliseconds after the peak, here called “early INa”, decays rapidly but helps sustain the initial plateau (phase 1) during activation of the transient outward potassium current (Ito

Arrhythmia syndromes associated with mutations in SCCPs

This review focuses on those SCCPs for which putative mutations have been identified in arrhythmia patients and for which dysfunctional INa supports a plausible arrhythmogenic mechanism through either gain of function, loss of function, or both. Many of these SCCPs interact with other ion channels and may have multiple roles in cardiac myocytes, and thus the mutations may have additional arrhythmogenic mechanisms in addition to INa dysfunction.

Other cardiac SCCPs

Many cardiac SCCPs have been identified that modulate cardiac INa, but mutations in these proteins have yet to be discovered in patients with inherited arrhythmias of unknown origin. These SCCPs (listed in Table 2, with additional possible SCCPs discussed in the online supplement) are candidate genes for SCN5A channelopathies.

Comments and conclusions

Channelopathies caused by mutations in SCCPs, although relatively rare clinically, are “natural” experiments that give insight into the structure function of SCCs. For example, a function for GPD1L was completely unknown until associated with SCN5A and BrS [82]. Conversely, work associating SNTA1 with SCN5A [67] led to the discovery of LQT12 [87] and further definition of a particular SCC (Fig. 1A,D). Genotype-negative inherited arrhythmia patients (patients for which the causative gene and

Disclosures

None.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgment

This work was supported by the NIH NHLBI HL71092 and T32 HL07936.

References (135)

  • F. Potet et al.

    Functional interactions between distinct sodium channel cytoplasmic domains through the action of calmodulin

    J Biol Chem

    (Mar 27 2009)
  • C. Chen et al.

    Identification of the cysteine residue responsible for disulfide linkage of Na+ channel alpha and beta2 subunits

    J Biol Chem

    (Nov 9 2012)
  • W.A. Catterall

    Signaling complexes of voltage-gated sodium and calcium channels

    Neurosci Lett

    (Dec 10 2010)
  • D. Johnson et al.

    Isoform-specific effects of the beta2 subunit on voltage-gated sodium channel gating

    J Biol Chem

    (Sep 8 2006)
  • J. Kim et al.

    Calmodulin mediates Ca2+ sensitivity of sodium channels

    J Biol Chem

    (Oct 22 2004)
  • M.S. Olesen et al.

    SCN1Bb R214Q found in 3 patients: 1 with Brugada syndrome and 2 with lone atrial fibrillation

    Heart Rhythm

    (May 2012)
  • X. Lin et al.

    Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes

    Heart Rhythm

    (2011 Dec)
  • A.L. Goldin

    Mechanisms of sodium channel inactivation

    Curr Opin Neurobiol

    (Jun 2003)
  • J.A. Jansen et al.

    Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice

    Heart Rhythm

    (Apr 2012)
  • J.D. Malhotra et al.

    Tyrosine-phosphorylated and nonphosphorylated sodium channel beta1 subunits are differentially localized in cardiac myocytes

    J Biol Chem

    (Sep 24 2004)
  • P. Wang et al.

    Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population

    Biochem Biophys Res Commun

    (Jul 16 2010)
  • T.J. Kamp

    An electrifying iPSC disease model: long QT syndrome type 2 and heart cells in a dish

    Cell Stem Cell

    (Feb 4 2011)
  • B.H. Tan et al.

    Sudden infant death syndrome-associated mutations in the sodium channel beta subunits

    Heart Rhythm

    (Jun 2010)
  • C.R. Valdivia et al.

    Late Na currents affected by alpha subunit isoform and beta1 subunit co-expression in HEK293 cells

    J Mol Cell Cardiol

    (Aug 2002)
  • Y. Qu et al.

    Modulation of cardiac Na+ channel expression in Xenopus oocytes by β1 subunits

    J Biol Chem

    (Oct 27 1995)
  • C. Wang et al.

    Crystal structure of the ternary complex of a NaV C-terminal domain, a fibroblast growth factor homologous factor, and calmodulin

    Structure

    (Jul 3 2012)
  • Y.J. Ou et al.

    Syntrophin gamma 2 regulates SCN5A gating by a PDZ domain-mediated interaction

    J Biol Chem

    (Jan 17 2003)
  • L.B. Cronk et al.

    Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3

    Heart Rhythm

    (Feb 2007)
  • J.D. Malhotra et al.

    Structural requirements for interaction of sodium channel beta 1 subunits with ankyrin

    J Biol Chem

    (Jul 19 2002)
  • L. Wu et al.

    Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5

    J Biol Chem

    (Mar 14 2008)
  • J.C. Williams et al.

    The sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex

    J Biol Chem

    (Aug 18 2006)
  • T. Jespersen et al.

    Cardiac sodium channel Na(v)1.5 interacts with and is regulated by the protein tyrosine phosphatase PTPH1

    Biochem Biophys Res Commun

    (Oct 6 2006)
  • L.L. Isom et al.

    Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif

    Cell

    (Nov 3 1995)
  • J.D. Malhotra et al.

    Sodium channel beta subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell–cell contact

    J Biol Chem

    (Apr 14 2000)
  • M. Allouis et al.

    14-3-3 is a regulator of the cardiac voltage-gated sodium channel Nav1.5

    Circ Res

    (Jun 23 2006)
  • M.J. Dhar et al.

    Characterization of sodium channel alpha- and beta-subunits in rat and mouse cardiac myocytes

    Circulation

    (Mar 6 2001)
  • J.C. Makielski et al.

    Na(+) current in human ventricle: implications for sodium loading and homeostasis

    J Cardiovasc Electrophysiol

    (May 2006)
  • C. Antzelevitch

    The Brugada syndrome: ionic basis and arrhythmia mechanisms

    J Cardiovasc Electrophysiol

    (Feb 2001)
  • C.R. Valdivia et al.

    Increased late Na+ current from a canine heart failure model and from human heart failure

    Biophys J

    (2000)
  • V.A. Maltsev et al.

    Late Na+ current produced by human cardiac Na+ channel isoform Nav1.5 is modulated by its beta1 subunit

    J Physiol Sci

    (May 2009)
  • H.B. Nuss et al.

    Functional association of the β1 subunit with human cardiac (hH1) and rat skeletal muscle (μ1) sodium channel α subunits expressed in Xenopus oocytes

    J Gen Physiol

    (Dec 1995)
  • R. Ziane et al.

    Cell membrane expression of cardiac sodium channel Na(v)1.5 is modulated by alpha-actinin-2 interaction

    Biochemistry

    (Jan 12 2010)
  • H. Watanabe et al.

    Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans

    J Clin Invest

    (Jun 2008)
  • S.K. Maier et al.

    An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart

    Proc Natl Acad Sci U S A

    (Mar 19 2002)
  • J.S. Lowe et al.

    Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway

    J Cell Biol

    (Jan 14 2008)
  • P.J. Mohler et al.

    Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes

    Proc Natl Acad Sci U S A

    (Dec 14 2004)
  • P.B. Bennett et al.

    Molecular mechanism for an inherited cardiac arrhythmia

    Nature

    (1995)
  • T. Aiba et al.

    Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes

    Cardiovasc Res

    (Feb 1 2010)
  • H. Watanabe et al.

    Mutations in sodium channel beta1- and beta2-subunits associated with atrial fibrillation

    Circ Arrhythm Electrophysiol

    (Jun 2009)
  • Y. Ruan et al.

    Sodium channel mutations and arrhythmias

    Nat Rev Cardiol

    (May 2009)
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