Jump to content

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:PDBeRCSB
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
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Sodium channel protein type 5 subunit alpha,also known asNaV1.5is anintegral membrane proteinandtetrodotoxin-resistant voltage-gatedsodium channelsubunit. NaV1.5 is found primarily incardiac muscle,where it mediates the fast influx of Na+-ions (INa) across thecell membrane,resulting in the fastdepolarizationphase of the cardiacaction potential.As such, it plays a major role inimpulse propagation through the heart.A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraphgenetics).SCN5Ais thegenethat encodes thecardiac sodium channelNaV1.5.

Gene structure[edit]

SCN5A is a highly conserved gene[5]located on human chromosome 3, where it spans more than 100 kb. The gene consists of 28exons,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 10genesthat encode different types of sodium channels, i.e. brain-type (NaV1.1,NaV1.2,NaV1.3,NaV1.6), neuronal channels (NaV1.7,NaV1.8andNaV1.9), skeletal muscle channels (NaV1.4) and the cardiac sodium channel NaV1.5.

Expression pattern[edit]

SCN5A is mainly expressed in the heart, where expression is abundant in workingmyocardiumand conduction tissue. In contrast, expression is low in thesinoatrial nodeandatrioventricular node.[6]Within the heart, a transmural expression gradient from subendocardium to subsepicardium is present, with higher expression of SCN5A in theendocardiumas compared to theepicardium.[6]SCN5A is also expressed in the gastrointestinal tract.[7]

Splice variants[edit]

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[edit]

NaV1.5 is a largetransmembrane proteinwith 4 repetitivetransmembrane 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 sensingis 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. INais 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[edit]

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 genesSCN1B,SCN2B,SCN3BandSCN4B,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 ascalmodulin,calmodulin kinase II δc,ankyrin-Gandplakophilin-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[edit]

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 withBrugada 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 forLong 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 withAFandDCM.[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 haveIrritable 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, insmooth muscleof thecolonand pacemaker cells.[7]Researchers managed to treat a case of IBS-C withmexiletineto restore Nav1.5 channels, reversing constipation andabdominal pain.[30][unreliable medical source][31]

SCN5A variations in the general population[edit]

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 identifygenetic lociassociated with variability in phenotypic traits. In the cardiovascular field this powerful technique has been used to detectlociinvolved in variation inelectrocardiographic parameters(i.e.PR-,QRS-andQTc-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.

NaV1.5 as a pharmacological target[edit]

The cardiac sodium channel NaV1.5 has long been a common target in thepharmacologic treatmentof arrhythmic events. Classically,sodium channel blockersthat 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 withventricular reentrant tachyarrhythmiain the setting of cardiac ischemia and in patients withatrial fibrillationin absence of structural heart disease.[33]

See also[edit]

Notes[edit]

References[edit]

  1. ^abcGRCh38: Ensembl release 89: ENSG00000183873–Ensembl,May 2017
  2. ^abcGRCm38: 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.
  5. ^abCatterall WA (2014)."Sodium channels, inherited epilepsy, and antiepileptic drugs".Annual Review of Pharmacology and Toxicology.54:317–38.doi:10.1146/annurev-pharmtox-011112-140232.PMID24392695.
  6. ^abRemme 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 (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): 511–22.doi:10.1007/s00395-009-0012-8.PMC2722719.PMID19255801.
  7. ^abcBeyder A, Farrugia G (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.PMC5142191.PMID27514480.
  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.PMID20398673.
  9. ^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 (March 2015)."Na+ channel function, regulation, structure, trafficking and sequestration".The Journal of Physiology.593(6): 1347–60.doi:10.1113/jphysiol.2014.281428.PMC4376415.PMID25772290.
  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): 2545–52.doi:10.1161/01.cir.98.23.2545.PMID9843461.
  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): 910–4.doi:10.1161/01.res.87.10.910.PMID11073887.
  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): 137–42.doi:10.1007/bf00586939.PMID571107.S2CID9145214.
  13. ^abAbriel 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.PMID19744495.
  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): H431–45.doi:10.1152/ajpheart.00306.2013.PMC3891248.PMID23771687.
  15. ^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 (March 2014)."Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype".Circulation.129(10): 1092–103.doi:10.1161/CIRCULATIONAHA.113.003077.PMC3954430.PMID24352520.
  16. ^abcLodder EM, Bezzina CR (January 2014). "Genomics of cardiac electrical function".Briefings in Functional Genomics.13(1): 39–50.doi:10.1093/bfgp/elt029.PMID23956259.
  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): 293–6.Bibcode:1998Natur.392..293C.doi:10.1038/32675.PMID9521325.S2CID4315426.
  18. ^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 (December 1999)."A single Na(+) channel mutation causing both long-QT and Brugada syndromes".Circulation Research.85(12): 1206–13.doi:10.1161/01.res.85.12.1206.PMID10590249.
  19. ^abRemme 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 (December 2006). "Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD".Circulation.114(24): 2584–94.doi:10.1161/CIRCULATIONAHA.106.653949.PMID17145985.S2CID10008930.
  20. ^Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H (September 1999). "Cardiac conduction defects associate with mutations in SCN5A".Nature Genetics.23(1): 20–1.doi:10.1038/12618.PMID10471492.S2CID7595466.
  21. ^Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR (February 2001). "A sodium-channel mutation causes isolated cardiac conduction disease".Nature.409(6823): 1043–7.Bibcode:2001Natur.409.1043T.doi:10.1038/35059090.PMID11234013.S2CID4422570.
  22. ^McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L (October 2004)."SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia".Circulation.110(15): 2163–7.doi:10.1161/01.CIR.0000144458.58660.BB.PMID15466643.
  23. ^abLaurent 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 (July 2012)."Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy".Journal of the American College of Cardiology.60(2): 144–56.doi:10.1016/j.jacc.2012.02.052.PMID22766342.
  24. ^Benson DW, Wang DW, Dyment M, Knilans TK, Fish FA, Strieper MJ, Rhodes TH, George 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): 1019–28.doi:10.1172/JCI18062.PMC198523.PMID14523039.
  25. ^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 (October 2008)."A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation".Journal of the American College of Cardiology.52(16): 1326–34.doi:10.1016/j.jacc.2008.07.013.PMID18929244.
  26. ^Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL,Moss AJ,Towbin JA, Keating MT (March 1995)."SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome".Cell.80(5): 805–11.doi:10.1016/0092-8674(95)90359-3.PMID7889574.S2CID15418443.
  27. ^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 (October 2012)."R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy".Journal of the American College of Cardiology.60(16): 1566–73.doi:10.1016/j.jacc.2012.05.050.PMID22999724.
  28. ^Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL (January 2005)."Sodium channel mutations and susceptibility to heart failure and atrial fibrillation".JAMA.293(4): 447–54.doi:10.1001/jama.293.4.447.PMC2039897.PMID15671429.
  29. ^Verstraelen TE, Ter Bekke RM, Volders PG, Masclee AA, Kruimel JW (2015). "The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders".Neurogastroenterology & Motility.27(7): 906–13.doi:10.1111/nmo.12569.PMID25898860.S2CID5055360.
  30. ^Beyder A, Mazzone A, Strege PR, Tester DJ, Saito YA, Bernard CE, Enders FT, Ek WE, Schmidt PT, Dlugosz A, Lindberg G, Karling P, Ohlsson B, Gazouli M, Nardone G, Cuomo R, Usai-Satta P, Galeazzi F, Neri M, Portincasa P, Bellini M, Barbara G, Camilleri M, Locke GR, Talley NJ, D'Amato M, Ackerman MJ, Farrugia G (June 2014)."Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome".Gastroenterology.146(7): 1659–68.doi:10.1053/j.gastro.2014.02.054.PMC4096335.PMID24613995.
  31. ^Beyder A, Strege PR, Bernard CE, Mazzone A, Tester DJ, Saito YA, Camilleri M, Locke GR, Talley NJ (1 September 2013)."Mexiletine rescues dysfunction of the Nav1.5 mutation A997t and restores bowel function in a patient with irritable bowel syndrome (ibs)".Neurogastroenterology & Motility.25.ISSN1350-1925.
  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.PMID6723689.
  33. ^abBalser 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.PMID11273715.S2CID35893248.

Further reading[edit]

External links[edit]

Retrieved from "https://en.wikipedia.org/w/index.php?title=SCN5A&oldid=1234038629"