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1.A.1.10.3
Ca2+-regulated heart Na+ channel, Nav1.5, SCN5A or INa channel of 2016 aas. The COOH terminus functions in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it (Glaaser et al., 2006); regulated by ProTx-II Toxin (Smith et al. 2007), telethonin, the titin cap protein (167aas; secreted protein; O15273) (Mazzone et al., 2008), and the Mog1 protein, a central component of the channel complex (Wu et al., 2008). Nav1.5, the principal Na+ channel in the heart, possesses an ankyrin binding site, and direct interaction with ankyrin-G is required for the expression of Nav1.5 at the cardiomyocyte cell surface (Bennett and Healy, 2008; Lowe et al., 2008). Mutations cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes (Mazzone et al., 2008; Kapplinger et al. 2010; Wang et al. 2015). SCN5A mutations causing arrhythmic dilated cardiomyopathy, commonly localized to the voltage-sensing mechanism, and giving rise to gating pore currents (currents that go through the voltage sensor) have been identified (McNair et al., 2011; Moreau et al., 2014).  Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death (Sheikh and Ranjan 2014) and (Kapplinger et al. 2015). Mutations causing disease have been identified (Qureshi et al. 2015). These give rise to arrhythias and cardiomyopathies (Moreau et al. 2015).  Mutations that cause relative resistance to slow inactivation have been identified (Chancey et al. 2007).  Green tea catechins are potential anti-arrhythmics because of the significant effect of Epigallocatechin-3-Gallate (E3G) on  cardiac sodium channelopathies that display a hyperexcitability phenotype (Boukhabza et al. 2016 ().

Accession Number:Q14524
Protein Name:Nav1.5 aka Scn5A
Length:2016
Molecular Weight:226940.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:18
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Na+

Cross database links:

Genevestigator: Q14524
RefSeq: NP_000326.2    NP_001092874.1    NP_001092875.1    NP_001153632.1    NP_001153633.1    NP_932173.1   
Entrez Gene ID: 6331   
Pfam: PF00520    PF06512   
OMIM: 108770  phenotype
113900  phenotype
272120  phenotype
600163  gene
601144  phenotype
601154  phenotype
603829  phenotype
603830  phenotype
608567  phenotype
KEGG: hsa:6331   

Gene Ontology

GO:0001518 C:voltage-gated sodium channel complex
GO:0005515 F:protein binding
GO:0005248 F:voltage-gated sodium channel activity
GO:0008015 P:blood circulation
GO:0006936 P:muscle contraction
GO:0008016 P:regulation of heart contraction
GO:0006814 P:sodium ion transport
GO:0055085 P:transmembrane transport

References (79)

[1] “Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.”  Gellens M.E.et.al.   1309946
[2] “SCN5A is expressed in human jejunal circular smooth muscle cells.”  Ou Y.et.al.   12358675
[3] “A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels.”  Makielski J.C.et.al.   14500339
[4] “A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation.”  Ye B.et.al.   12454206
[5] “Tetrodotoxin-resistant Na+ channels in human neuroblastoma cells are encoded by new variants of Nav1.5/SCN5A.”  Ou S.-W.et.al.   16115203
[6] “The DNA sequence, annotation and analysis of human chromosome 3.”  Muzny D.M.et.al.   16641997
[7] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[8] “Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination.”  van Bemmelen M.X.et.al.   15217910
[9] “Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins.”  Rougier J.-S.et.al.   15548568
[10] “Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.”  Dichgans M.et.al.   16054936
[11] “GPD1L links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel SCN5A.”  Valdivia C.R.et.al.   19666841
[12] “Analysis of four novel variants of Nav1.5/SCN5A cloned from the brain.”  Wang J.et.al.   19376164
[13] “SCN5A channelopathies - An update on mutations and mechanisms.”  Zimmer T.et.al.   19027780
[14] “SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.”  Wang Q.et.al.   7889574
[15] “Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia.”  Wang Q.et.al.   8541846
[16] “Molecular mechanism for an inherited cardiac arrhythmia.”  Bennett P.B.et.al.   7651517
[17] “Novel LQT-3 mutation affects Na+ channel activity through interactions between alpha- and beta1-subunits.”  An R.H.et.al.   9686753
[18] “A de novo missense mutation of human cardiac Na(+) channel exhibiting novel molecular mechanisms of long QT syndrome.”  Makita N.et.al.   9506831
[19] “Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome.”  Benhorin J.et.al.   10627139
[20] “Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.”  Chen Q.et.al.   9521325
[21] “Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.”  Wattanasirichaigoon D.et.al.   10508990
[22] “Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome.”  Rook M.B.et.al.   10690282
[23] “Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel.”  Wei J.et.al.   10377081
[24] “Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent.”  Dumaine R.et.al.   10532948
[25] “A single Na(+) channel mutation causing both long-QT and Brugada syndromes.”  Bezzina C.R.et.al.   10590249
[26] “Cardiac conduction defects associate with mutations in SCN5A.”  Schott J.-J.et.al.   10471492
[27] “Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit.”  Makita N.et.al.   10618304
[28] “Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.”  Splawski I.et.al.   10973849
[29] “A novel SCN5A mutation associated with idiopathic ventricular fibrillation without typical ECG findings of Brugada syndrome.”  Akai J.et.al.   10940383
[30] “A molecular link between the sudden infant death syndrome and the long-QT syndrome.”  Schwartz P.J.et.al.   10911008
[31] “Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel.”  Abriel H.et.al.   11304498
[32] “Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes.”  Rivolta I.et.al.   11410597
[33] “Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family.”  Kyndt F.et.al.   11748104
[34] “Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome.”  Ackerman M.J.et.al.   11710892
[35] “A sodium-channel mutation causes isolated cardiac conduction disease.”  Tan H.L.et.al.   11234013
[36] “Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients.”  Smits J.P.P.et.al.   12106943
[37] “Clinical, genetic and biophysical characterisation of SCN5A mutations associated with atrioventricular conduction block.”  Wang D.W.et.al.   11804990
[38] “Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism.”  Clancy C.E.et.al.   11889015
[39] “Natural history of Brugada syndrome: insights for risk stratification and management.”  Priori S.G.et.al.   11901046
[40] “Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.”  Yang P.et.al.   11997281
[41] “Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome.”  Vatta M.et.al.   11823453
[42] “SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family.”  Chen S.et.al.   12471205
[43] “Novel mutations in domain I of SCN5A cause Brugada syndrome.”  Vatta M.et.al.   12051963
[44] “A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction.”  Rivolta I.et.al.   12209021
[45] “Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia.”  Splawski I.et.al.   12193783
[46] “A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill.”  Groenewegen W.A.et.al.   12522116
[47] “Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system.”  Bezzina C.R.et.al.   12574143
[48] “A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating.”  Wehrens X.H.et.al.   12673799
[49] “A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation.”  Viswanathan P.C.et.al.   12569159
[50] “Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).”  Benson D.W.et.al.   14523039
[51] “A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs.”  Valdivia C.R.et.al.   15023552
[52] “SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia.”  McNair W.P.et.al.   15466643
[53] “Genetic analysis of the cardiac sodium channel gene SCN5A in Koreans with Brugada syndrome.”  Shin D.-J.et.al.   15338453
[54] “Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes.”  Mohler P.J.et.al.   15579534
[55] “Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties.”  Amin A.S.et.al.   16266370
[56] “Double SCN5A mutation underlying asymptomatic Brugada syndrome.”  Yokoi H.et.al.   15851320
[57] “High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.”  Makiyama T.et.al.   16325048
[58] “A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation.”  Keller D.I.et.al.   16616735
[59] “Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.”  Millat G.et.al.   16922724
[60] “Novel SCN5A gene mutations associated with Brugada syndrome: V95I, A1649V and delF1617.”  Liang P.et.al.   17081365
[61] “A novel LQT-3 mutation disrupts an inactivation gate complex with distinct rate-dependent phenotypic consequences.”  Bankston J.R.et.al.   18708744
[62] “A sodium channel pore mutation causing Brugada syndrome.”  Pfahnl A.E.et.al.   17198989
[63] “A novel and lethal de novo LQT-3 mutation in a newborn with distinct molecular pharmacology and therapeutic response.”  Bankston J.R.et.al.   18060054
[64] “Gene (SCN5A) mutation analysis of a Chinese family with Brugada syndrome.”  Tian L.et.al.   18341814
[65] “Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel.”  Zhang Y.et.al.   18616619
[66] “Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation.”  Bebarova M.et.al.   18456723
[67] “Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.”  Petitprez S.et.al.   18252757
[68] “Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.”  Barajas-Martinez H.M.et.al.   18599870
[69] “Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.”  Darbar D.et.al.   18378609
[70] “A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation.”  Benito B.et.al.   18929331
[71] “In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: compound effects of hERG pore region mutation and SCN5A N-terminus variant.”  Lin M.-T.et.al.   18848812
[72] “A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation.”  Makiyama T.et.al.   18929244
[73] “The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome.”  Makita N.et.al.   18451998
[74] “SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia.”  Shan L.et.al.   18368697
[75] “Cardiac ion channel gene mutations in sudden infant death syndrome.”  Otagiri T.et.al.   18596570
[76] “Sodium channel mutation in irritable bowel syndrome: evidence for an ion channelopathy.”  Saito Y.A.et.al.   19056759
[77] “Biophysical characterization of a new SCN5A mutation S1333Y in a SIDS infant linked to long QT syndrome.”  Huang H.et.al.   19302788
[78] “Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.”  Meregalli P.G.et.al.   19251209
[79] “Distinct functional defect of three novel Brugada syndrome related cardiac sodium channel mutations.”  Hsueh C.H.et.al.   19272188
Structure:
2KBI   2L53   4DCK   4DJC   4JQ0   4OVN     

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MANFLLPRGT SSFRRFTRES LAAIEKRMAE KQARGSTTLQ ESREGLPEEE APRPQLDLQA 
61:	SKKLPDLYGN PPQELIGEPL EDLDPFYSTQ KTFIVLNKGK TIFRFSATNA LYVLSPFHPI 
121:	RRAAVKILVH SLFNMLIMCT ILTNCVFMAQ HDPPPWTKYV EYTFTAIYTF ESLVKILARG 
181:	FCLHAFTFLR DPWNWLDFSV IIMAYTTEFV DLGNVSALRT FRVLRALKTI SVISGLKTIV 
241:	GALIQSVKKL ADVMVLTVFC LSVFALIGLQ LFMGNLRHKC VRNFTALNGT NGSVEADGLV 
301:	WESLDLYLSD PENYLLKNGT SDVLLCGNSS DAGTCPEGYR CLKAGENPDH GYTSFDSFAW 
361:	AFLALFRLMT QDCWERLYQQ TLRSAGKIYM IFFMLVIFLG SFYLVNLILA VVAMAYEEQN 
421:	QATIAETEEK EKRFQEAMEM LKKEHEALTI RGVDTVSRSS LEMSPLAPVN SHERRSKRRK 
481:	RMSSGTEECG EDRLPKSDSE DGPRAMNHLS LTRGLSRTSM KPRSSRGSIF TFRRRDLGSE 
541:	ADFADDENST AGESESHHTS LLVPWPLRRT SAQGQPSPGT SAPGHALHGK KNSTVDCNGV 
601:	VSLLGAGDPE ATSPGSHLLR PVMLEHPPDT TTPSEEPGGP QMLTSQAPCV DGFEEPGARQ 
661:	RALSAVSVLT SALEELEESR HKCPPCWNRL AQRYLIWECC PLWMSIKQGV KLVVMDPFTD 
721:	LTITMCIVLN TLFMALEHYN MTSEFEEMLQ VGNLVFTGIF TAEMTFKIIA LDPYYYFQQG 
781:	WNIFDSIIVI LSLMELGLSR MSNLSVLRSF RLLRVFKLAK SWPTLNTLIK IIGNSVGALG 
841:	NLTLVLAIIV FIFAVVGMQL FGKNYSELRD SDSGLLPRWH MMDFFHAFLI IFRILCGEWI 
901:	ETMWDCMEVS GQSLCLLVFL LVMVIGNLVV LNLFLALLLS SFSADNLTAP DEDREMNNLQ 
961:	LALARIQRGL RFVKRTTWDF CCGLLRQRPQ KPAALAAQGQ LPSCIATPYS PPPPETEKVP 
1021:	PTRKETRFEE GEQPGQGTPG DPEPVCVPIA VAESDTDDQE EDEENSLGTE EESSKQQESQ 
1081:	PVSGGPEAPP DSRTWSQVSA TASSEAEASA SQADWRQQWK AEPQAPGCGE TPEDSCSEGS 
1141:	TADMTNTAEL LEQIPDLGQD VKDPEDCFTE GCVRRCPCCA VDTTQAPGKV WWRLRKTCYH 
1201:	IVEHSWFETF IIFMILLSSG ALAFEDIYLE ERKTIKVLLE YADKMFTYVF VLEMLLKWVA 
1261:	YGFKKYFTNA WCWLDFLIVD VSLVSLVANT LGFAEMGPIK SLRTLRALRP LRALSRFEGM 
1321:	RVVVNALVGA IPSIMNVLLV CLIFWLIFSI MGVNLFAGKF GRCINQTEGD LPLNYTIVNN 
1381:	KSQCESLNLT GELYWTKVKV NFDNVGAGYL ALLQVATFKG WMDIMYAAVD SRGYEEQPQW 
1441:	EYNLYMYIYF VIFIIFGSFF TLNLFIGVII DNFNQQKKKL GGQDIFMTEE QKKYYNAMKK 
1501:	LGSKKPQKPI PRPLNKYQGF IFDIVTKQAF DVTIMFLICL NMVTMMVETD DQSPEKINIL 
1561:	AKINLLFVAI FTGECIVKLA ALRHYYFTNS WNIFDFVVVI LSIVGTVLSD IIQKYFFSPT 
1621:	LFRVIRLARI GRILRLIRGA KGIRTLLFAL MMSLPALFNI GLLLFLVMFI YSIFGMANFA 
1681:	YVKWEAGIDD MFNFQTFANS MLCLFQITTS AGWDGLLSPI LNTGPPYCDP TLPNSNGSRG 
1741:	DCGSPAVGIL FFTTYIIISF LIVVNMYIAI ILENFSVATE ESTEPLSEDD FDMFYEIWEK 
1801:	FDPEATQFIE YSVLSDFADA LSEPLRIAKP NQISLINMDL PMVSGDRIHC MDILFAFTKR 
1861:	VLGESGEMDA LKIQMEEKFM AANPSKISYE PITTTLRRKH EEVSAMVIQR AFRRHLLQRS 
1921:	LKHASFLFRQ QAGSGLSEED APEREGLIAY VMSENFSRPL GPPSSSSISS TSFPPSYDSV 
1981:	TRATSDNLQV RGSDYSHSED LADFPPSPDR DRESIV