Sodium channel, voltage gated, type V alpha subunit
Solution structure of the Nav1.5 inactivation gate.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; CDCD2; CMD1E; CMPD2; HB1; HB2; HBBD; HH1; ICCD; IVF; LQT3; Nav1.5; PFHB1; SSS1; VF1
External IDs IUPHAR: ChEMBL: GeneCards:
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.


  • Gene structure 1
    • Expression pattern 1.1
    • Splice variants 1.2
  • Protein structure and function 2
    • Sub-units and protein interaction partners 2.1
  • Genetics 3
    • SCN5A variations in the general population 3.1
  • NaV1.5 as a pharmacological target 4
  • See also 5
  • References 6
  • Further reading 7
  • External links 8

Gene structure

SCN5A is a highly conserved gene[2] located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28 exons, of which exon 1 and in part exon 2 form the 5’ untranslated region (5’UTR) and exon 28 the 3’ untranslated region (3’UTR) of the RNA. SCN5A is part of a family of 10 genes that encode different types of sodium channels, i.e. brain-type (NaV1.1, NaV1.2, NaV1.3, NaV1.6), neuronal channels (NaV1.7, NaV1.8 and NaV1.9), skeletal muscle channels (NaV1.4) and the cardiac sodium channel NaV1.5.

Expression pattern

SCN5A is mainly expressed in the heart, where expression is abundant in working myocardium and conduction tissue. In contrast, expression is low in the sinoatrial node and atrioventricular node.[3] Within the heart, a transmural expression gradient from subendocardium to subsendocardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium[3]

Splice variants

More than 10 different splice isoforms have been described for SCN5A, of which several harbour different functional properties. In the heart, two isoforms are mainly expressed (ratio 1:2), of which the least predominant one contains an extra glutamine at position 1077 (1077Q). Moreover, different isoforms are expressed during fetal life and adult, differing in the inclusion of an alternative exon 6.[4]

Protein structure and function

NaV1.5 is a large transmembrane protein with 4 repetitive transmembrane domains (DI-DIV), containing 6 transmembrane spanning sections each (S1-S6). The pore region of the channels, through which Na+-ions flow, are formed by the segments S5 and S6 of the 4 domains. Voltage sensing is mediated by the remaining segments, of which the positively charged S4 segments plays a fundamental role.[2][5]

NaV1.5 channels predominantly mediate the sodium current (INa) in cardiac cells. INa is responsible for the fast upstroke of the action potential, and as such plays a crucial role in impulse propagation through the heart. The conformational state of the channel, which is both voltage and time-dependent, determines whether the channel is opened or closed. At the resting membrane potential (around -85 mV), NaV1.5 channels are closed. Upon a stimulus (through conduction by a neighboring cell), the membrane depolarizes and NaV1.5 channels open through the outward movement of the S4 segments, leading to the initiation of the action potential. Simultaneously, a process called ‘fast inactivation’ results in closure of the channels within 1 ms. In physiological conditions, when inactivated, channels remain in closed state until the cell membrane repolarizes, where a recovery from inactivation is necessary before they become available for activation again. During the action potential, a very small fraction of sodium current persists and does not inactivate completely. This current is called ‘sustained current’, ‘late current’ or ‘INa,L’.[6][7] Also, some channels may reactivate during the repolarizing phase of the action potential at a range of potentials where inactivation is not complete and shows overlap with activation, generating the so-called “window current”.[8]

Sub-units and protein interaction partners

Trafficking, function and structure of NaV1.5 can be affected by the many protein interaction partners that have been identified to date (for an extensive review, see Abriel et al 2010).[9] Of these, the 4 sodium channel beta-subunits, encoded by the genes SCN1B, SCN2B, SCN3B and SCN4B, form an important category. In general, beta-subunits increase function of NaV1.5, either by change in intrinsic properties or by affecting the process of trafficking to the cell surface.

Apart from the beta-subunits, other proteins, such as calmodulin, calmodulin kinase II δc, ankyrin-G and plakophilin-2, are known to interact and modulate function of NaV1.5.[9] Some of these have also been linked to genetic and acquired cardiac diseases.[10][11]


Mutations in SCN5A, which could result in a loss and/or a gain-of-function of the channel, are associated with a spectrum of cardiac diseases. Pathogenic mutations generally exhibit a autosomal dominant inheritance pattern, although recessive forms of SCN5A mutations are also described. Also, mutations may act as a disease modifier, especially in families where lack of direct causality is reflected by complex inheritance patterns. It is important to note that a significant amount of individuals (2-7%) in the general population carry a rare (population frequency <1%),[12] protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. Interestingly, mutations that result in the same biophysical effect can give rise to different diseases.

To date, loss-of-function mutations have been associated with Brugada syndrome (BrS),[13][14][15] progressive cardiac conduction disease (Lev-Lenègre disease),[16][17] dilated cardiomyopathy (DCM),[18][19] sick sinus syndrome,[20] and atrial fibrillation.[21]

Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3[15][22] and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC)[19][23] Some gain-of-function mutations are also associated with AF and DCM.[24] Gain-of-function of NaV1.5 is generally reflected by an increase in INa,L, a slowed rate of inactivation or a shift in voltage dependence of activation or inactivation (resulting in an increased window-current).

SCN5A variations in the general population

Genetic variations in SCN5A, i.e. single nucleotide polymorphisms (SNPs) have been described in both coding and non-coding regions of the gene. These variations are typically present at relatively high frequencies within the general population. Genome Wide Association Studies (GWAS) have used this type of common genetic variation to identify genetic loci associated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detect loci involved in variation in electrocardiographic parameters (i.e. PR-, QRS- and QTc-interval duration) in the general population.[12] The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. Interestingly, these studies consistently identified the SCN5A-SCN10A genomic region on chromosome 3 to be associated with variation in QTc-interval, QRS duration and PR-interval.[12] These results indicate that genetic variation at the SCN5A locus is not only involved in disease #genetics but also plays a role in the variation in cardiac function between individuals in the general population.

NaV1.5 as a pharmacological target

The cardiac sodium channel NaV1.5 has since long been a common target in the pharmacologic treatment of arrhythmic events. Classically, sodium channel blockers that block the peak sodium current are classified as Class I anti-arrhythmic agents and further subdivided in class IA, IB and IC, depending on their ability to change the length of the cardiac action potential.[25][26] Use of such sodium channel blockers is among others indicated in patients with ventricular reentrant tachyarrhythmia in the setting of cardiac ischemia and in patients with atrial fibrillation in absence of structural heart disease.[26]

See also


  1. ^ ​; Rohl CA, Boeckman FA, Baker C, Scheuer T, Catterall WA, Klevit RE (January 1999). "Solution structure of the sodium channel inactivation gate". Biochemistry 38 (3): 855–61.  
  2. ^ a b Catterall WA (2014). "Sodium channels, inherited epilepsy, and antiepileptic drugs". Annual Review of Pharmacology and Toxicology 54: 317–38.  
  3. ^ a b Remme CA, Verkerk AO, Hoogaars WM, Aanhaanen WT, Scicluna BP, Annink C, van den Hoff MJ, Wilde AA, van Veen TA, Veldkamp MW, de Bakker JM, Christoffels VM, Bezzina CR (Sep 2009). "The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium". Basic Research in Cardiology 104 (5): 511–22.  
  4. ^ Schroeter A, Walzik S, Blechschmidt S, Haufe V, Benndorf K, Zimmer T (Jul 2010). "Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5". Journal of Molecular and Cellular Cardiology 49 (1): 16–24.  
  5. ^ Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, Aldrich RW, Belardinelli L, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Deschenes I, Grandi E, Hund TJ, Izu LT, Maier LS, Maltsev VA, Marionneau C, Mohler PJ, Rajamani S, Rasmusson RL, Sobie EA, Clancy CE, Bers DM (Mar 2015). "Na+ channel function, regulation, structure, trafficking and sequestration". The Journal of Physiology 593 (6): 1347–60.  
  6. ^ Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI (Dec 1998). "Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes". Circulation 98 (23): 2545–52.  
  7. ^ Sakmann BF, Spindler AJ, Bryant SM, Linz KW, Noble D (Nov 2000). "Distribution of a persistent sodium current across the ventricular wall in guinea pigs". Circulation Research 87 (10): 910–4.  
  8. ^ Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (Mar 1979). "The steady state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres". Pflügers Archiv 379 (2): 137–42.  
  9. ^ a b Abriel H (Jan 2010). "Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology". Journal of Molecular and Cellular Cardiology 48 (1): 2–11.  
  10. ^ Herren AW, Bers DM, Grandi E (Aug 2013). "Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias". American Journal of Physiology. Heart and Circulatory Physiology 305 (4): H431–45.  
  11. ^ Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, Novelli V, Kim C, Tirasawadichai T, Judge DP, Rothenberg E, Chen HS, Napolitano C, Priori SG, Delmar M (Mar 2014). "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype". Circulation 129 (10): 1092–103.  
  12. ^ a b c Lodder EM, Bezzina CR (Jan 2014). "Genomics of cardiac electrical function". Briefings in Functional Genomics 13 (1): 39–50.  
  13. ^ Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q (Mar 1998). "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation". Nature 392 (6673): 293–6.  
  14. ^ Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, van Der Hout AH, Mannens MM, Wilde AA (Dec 1999). "A single Na(+) channel mutation causing both long-QT and Brugada syndromes". Circulation Research 85 (12): 1206–13.  
  15. ^ a b Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, Wilders R, van Roon MA, Tan HL, Wilde AA, Carmeliet P, de Bakker JM, Veldkamp MW, Bezzina CR (Dec 2006). "Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD". Circulation 114 (24): 2584–94.  
  16. ^ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H (Sep 1999). "Cardiac conduction defects associate with mutations in SCN5A". Nature Genetics 23 (1): 20–1.  
  17. ^ Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR (Feb 2001). "A sodium-channel mutation causes isolated cardiac conduction disease". Nature 409 (6823): 1043–7.  
  18. ^ McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L (Oct 2004). "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia". Circulation 110 (15): 2163–7.  
  19. ^ a b Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, Barc J, Dina C, Bertaux G, Barthez O, Thauvin-Robinet C, Charron P, Fressart V, Maltret A, Villain E, Baron E, Mérot J, Turpault R, Coudière Y, Charpentier F, Schott JJ, Loussouarn G, Wilde AA, Wolf JE, Baró I, Kyndt F, Probst V (Jul 2012). "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". Journal of the American College of Cardiology 60 (2): 144–56.  
  20. ^ Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George AL (Oct 2003). "Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)". The Journal of Clinical Investigation 112 (7): 1019–28.  
  21. ^ Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, Ohno S, Nishio Y, Tsuji K, Itoh H, Kimura T, Kita T, Horie M (Oct 2008). "A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation". Journal of the American College of Cardiology 52 (16): 1326–34.  
  22. ^ Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (Mar 1995). "SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome". Cell 80 (5): 805–11.  
  23. ^ Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, Stockhammer K, Thompson T, Playford D, Subbiah R, Kuchar D, Aggarwal A, Vandenberg JI, Fatkin D (Oct 2012). "R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy". Journal of the American College of Cardiology 60 (16): 1566–73.  
  24. ^ Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (Jan 2005). "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation". Jama 293 (4): 447–54.  
  25. ^ Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (Feb 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". European Heart Journal 5 (2): 99–107.  
  26. ^ a b Balser JR (Apr 2001). "The cardiac sodium channel: gating function and molecular pharmacology". Journal of Molecular and Cellular Cardiology 33 (4): 599–613.  

Further reading

  • Viswanathan PC, Balser JR (Jan 2004). "Inherited sodium channelopathies: a continuum of channel dysfunction". Trends in Cardiovascular Medicine 14 (1): 28–35.  
  • Catterall WA, Goldin AL, Waxman SG (Dec 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews 57 (4): 397–409.  
  • Wolf CM, Berul CI (Apr 2006). "Inherited conduction system abnormalities--one group of diseases, many genes". Journal of Cardiovascular Electrophysiology 17 (4): 446–55.  

External links

  • GeneReviews/NIH/NCBI/UW entry on Brugada syndrome
  • GeneReviews/NIH/NCBI/UW entry on Romano-Ward Syndrome
  • SCN5A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)