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SCN5A

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
From Wikipedia, the free encyclopedia

SCN5A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSCN5A, CDCD2, CMD1E, CMPD2, HB1, HB2, HBBD, HH1, ICCD, IVF, LQT3, Nav1.5, PFHB1, SSS1, VF1, sodium voltage-gated channel alpha subunit 5
External IDsOMIM: 600163; MGI: 98251; HomoloGene: 22738; GeneCards: SCN5A; OMA:SCN5A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6331

20271

Ensembl

ENSG00000183873

ENSMUSG00000032511

UniProt

Q14524

Q9JJV9

RefSeq (mRNA)

NM_001253860
NM_021544

RefSeq (protein)

NP_001240789
NP_067519

Location (UCSC)Chr 3: 38.55 – 38.65 MbChr 9: 119.31 – 119.41 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sodium channel protein type 5 subunit alpha, also known as 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

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SCN5A is a highly conserved gene[5] 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

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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.[6] Within the heart, a transmural expression gradient from subendocardium to subsepicardium is present, with higher expression of SCN5A in the endocardium as compared to the epicardium.[6] SCN5A is also expressed in the gastrointestinal tract.[7]

Splice variants

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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.[8]

Protein structure and function

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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.[5][9]

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 a few milliseconds. 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’.[10][11] 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".[12]

Sub-units and protein interaction partners

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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).[13] 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.[13] Some of these have also been linked to genetic and acquired cardiac diseases.[14][15]

Genetics

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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 an autosomal dominant inheritance pattern, although compound heterozygote 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. A significant number of individuals (2-7%) in the general population carry a rare (population frequency <1%),[16] protein-altering variant in the gene, highlighting the complexity of linking mutations directly with observed phenotypes. 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),[17][18][19] progressive cardiac conduction disease (Lev-Lenègre disease),[20][21] dilated cardiomyopathy (DCM),[22][23] sick sinus syndrome,[24] and atrial fibrillation.[25]

Mutations resulting in a gain-of-function are causal for Long QT syndrome type 3[19][26] and are also more recently implicated in multifocal ectopic Purkinje-related premature contractions (MEPPC)[23][27] Some gain-of-function mutations are also associated with AF and DCM.[28] 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 mutations are believed to be found in a disproportionate number of people who have Irritable Bowel Syndrome, particularly the constipation-predominant variant (IBS-C).[7][29] The resulting defect leads to disruption in bowel function, by affecting the Nav1.5 channel, in smooth muscle of the colon and pacemaker cells.[7] Researchers managed to treat a case of IBS-C with mexiletine to restore Nav1.5 channels, reversing constipation and abdominal pain.[30][unreliable medical source][31]

SCN5A variations in the general population

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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.[16] The rationale behind this technique is that common genetic variation present in the general population can influence cardiac conduction in non-diseased individuals. 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.[16] 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.

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The cardiac sodium channel NaV1.5 has 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.[32][33] 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.[33]

See also

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Notes

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000183873 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032511 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ^ a b Remme CA, Verkerk AO, Hoogaars WM, Aanhaanen WT, Scicluna BP, Annink C, et al. (September 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): 511–522. doi:10.1007/s00395-009-0012-8. PMC 2722719. PMID 19255801.
  7. ^ a b c Beyder A, Farrugia G (October 2016). "Ion channelopathies in functional GI disorders". American Journal of Physiology. Gastrointestinal and Liver Physiology. 311 (4): G581–G586. doi:10.1152/ajpgi.00237.2016. PMC 5142191. PMID 27514480.
  8. ^ Schroeter A, Walzik S, Blechschmidt S, Haufe V, Benndorf K, Zimmer T (July 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. doi:10.1016/j.yjmcc.2010.04.004. PMID 20398673.
  9. ^ Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Abriel H, et al. (March 2015). "Na+ channel function, regulation, structure, trafficking and sequestration". The Journal of Physiology. 593 (6): 1347–1360. doi:10.1113/jphysiol.2014.281428. PMC 4376415. PMID 25772290.
  10. ^ Maltsev VA, Sabbah HN, Higgins RS, Silverman N, Lesch M, Undrovinas AI (December 1998). "Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes". Circulation. 98 (23): 2545–2552. doi:10.1161/01.cir.98.23.2545. PMID 9843461.
  11. ^ Sakmann BF, Spindler AJ, Bryant SM, Linz KW, Noble D (November 2000). "Distribution of a persistent sodium current across the ventricular wall in guinea pigs". Circulation Research. 87 (10): 910–914. doi:10.1161/01.res.87.10.910. PMID 11073887.
  12. ^ Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (March 1979). "The steady state TTX-sensitive ("window") sodium current in cardiac Purkinje fibres". Pflügers Archiv. 379 (2): 137–142. doi:10.1007/bf00586939. PMID 571107. S2CID 9145214.
  13. ^ a b Abriel H (January 2010). "Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology". Journal of Molecular and Cellular Cardiology. 48 (1): 2–11. doi:10.1016/j.yjmcc.2009.08.025. PMID 19744495.
  14. ^ Herren AW, Bers DM, Grandi E (August 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–H445. doi:10.1152/ajpheart.00306.2013. PMC 3891248. PMID 23771687.
  15. ^ Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H, et al. (March 2014). "Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype". Circulation. 129 (10): 1092–1103. doi:10.1161/CIRCULATIONAHA.113.003077. PMC 3954430. PMID 24352520.
  16. ^ a b c Lodder EM, Bezzina CR (January 2014). "Genomics of cardiac electrical function". Briefings in Functional Genomics. 13 (1): 39–50. doi:10.1093/bfgp/elt029. PMID 23956259.
  17. ^ Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. (March 1998). "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation". Nature. 392 (6673): 293–296. Bibcode:1998Natur.392..293C. doi:10.1038/32675. PMID 9521325. S2CID 4315426.
  18. ^ Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, et al. (December 1999). "A single Na(+) channel mutation causing both long-QT and Brugada syndromes". Circulation Research. 85 (12): 1206–1213. doi:10.1161/01.res.85.12.1206. PMID 10590249.
  19. ^ a b Remme CA, Verkerk AO, Nuyens D, van Ginneken AC, van Brunschot S, Belterman CN, et al. (December 2006). "Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD". Circulation. 114 (24): 2584–2594. doi:10.1161/CIRCULATIONAHA.106.653949. PMID 17145985. S2CID 10008930.
  20. ^ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, et al. (September 1999). "Cardiac conduction defects associate with mutations in SCN5A". Nature Genetics. 23 (1): 20–21. doi:10.1038/12618. PMID 10471492. S2CID 7595466.
  21. ^ Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, et al. (February 2001). "A sodium-channel mutation causes isolated cardiac conduction disease". Nature. 409 (6823): 1043–1047. Bibcode:2001Natur.409.1043T. doi:10.1038/35059090. PMID 11234013. S2CID 4422570.
  22. ^ McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, et al. (October 2004). "SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia". Circulation. 110 (15): 2163–2167. doi:10.1161/01.CIR.0000144458.58660.BB. PMID 15466643.
  23. ^ a b Laurent G, Saal S, Amarouch MY, Béziau DM, Marsman RF, Faivre L, et al. (July 2012). "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". Journal of the American College of Cardiology. 60 (2): 144–156. doi:10.1016/j.jacc.2012.02.052. PMID 22766342.
  24. ^ Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, et al. (October 2003). "Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)". The Journal of Clinical Investigation. 112 (7): 1019–1028. doi:10.1172/JCI18062. PMC 198523. PMID 14523039.
  25. ^ Makiyama T, Akao M, Shizuta S, Doi T, Nishiyama K, Oka Y, et al. (October 2008). "A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation". Journal of the American College of Cardiology. 52 (16): 1326–1334. doi:10.1016/j.jacc.2008.07.013. PMID 18929244.
  26. ^ Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. (March 1995). "SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome". Cell. 80 (5): 805–811. doi:10.1016/0092-8674(95)90359-3. PMID 7889574. S2CID 15418443.
  27. ^ Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, et al. (October 2012). "R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy". Journal of the American College of Cardiology. 60 (16): 1566–1573. doi:10.1016/j.jacc.2012.05.050. PMID 22999724.
  28. ^ Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, et al. (January 2005). "Sodium channel mutations and susceptibility to heart failure and atrial fibrillation". JAMA. 293 (4): 447–454. doi:10.1001/jama.293.4.447. PMC 2039897. PMID 15671429.
  29. ^ Verstraelen TE, Ter Bekke RM, Volders PG, Masclee AA, Kruimel JW (July 2015). "The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders". Neurogastroenterology and Motility. 27 (7): 906–913. doi:10.1111/nmo.12569. PMID 25898860. S2CID 5055360.
  30. ^ Beyder A, Mazzone A, Strege PR, Tester DJ, Saito YA, Bernard CE, et al. (June 2014). "Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome". Gastroenterology. 146 (7): 1659–1668. doi:10.1053/j.gastro.2014.02.054. PMC 4096335. PMID 24613995.
  31. ^ Beyder A, Strege PR, Bernard CE, Mazzone A, Tester DJ, Saito YA, et al. (September 2013). "Mexiletine rescues dysfunction of the Nav1.5 mutation A997t and restores bowel function in a patient with irritable bowel syndrome (IBS)". Neurogastroenterology and Motility. Vol. 25. Hoboken NJ: Wiley-Blackwell. p. 6.
  32. ^ Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (February 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". European Heart Journal. 5 (2): 99–107. doi:10.1093/oxfordjournals.eurheartj.a061633. PMID 6723689.
  33. ^ a b Balser JR (April 2001). "The cardiac sodium channel: gating function and molecular pharmacology". Journal of Molecular and Cellular Cardiology. 33 (4): 599–613. doi:10.1006/jmcc.2000.1346. PMID 11273715. S2CID 35893248.

Further reading

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  • Viswanathan PC, Balser JR (January 2004). "Inherited sodium channelopathies: a continuum of channel dysfunction". Trends in Cardiovascular Medicine. 14 (1): 28–35. doi:10.1016/j.tcm.2003.10.001. PMID 14720472.
  • Catterall WA, Goldin AL, Waxman SG (December 2005). "International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels". Pharmacological Reviews. 57 (4): 397–409. doi:10.1124/pr.57.4.4. PMID 16382098. S2CID 7332624.
  • Wolf CM, Berul CI (April 2006). "Inherited conduction system abnormalities--one group of diseases, many genes". Journal of Cardiovascular Electrophysiology. 17 (4): 446–455. doi:10.1111/j.1540-8167.2006.00427.x. PMID 16643374. S2CID 21847457.
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