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1.A.1.10.4
The skeletal muscle Na+ channel, NaV1.4 of 1836 aas and 24 TMSs. Mutations in charged residues in the S4 segment cause hypokalemic periodic paralysis (HypoPP)) due to sustained sarcolemmal depolarization (Struyk and Cannon 2007; Sokolov et al., 2007; Groome et al. 2014). Also causes myotonia; regulated by calmodulin which binds to the C-terminus of Nav1.4 (Biswas et al., 2008). NaV1.4 gating pores are permeable to guanidine as well as Na+ and H+ (Sokolov et al., 2010). The R669H mutation allows transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K+ channel S4 sites (Struyk and Cannon 2007).  The mechanism of inactivation involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the beta1 subunit (Sánchez-Solano et al. 2016).

Accession Number:P35499
Protein Name:Voltage-gated sodium channel subunit alpha Nav1.4
Length:1836
Molecular Weight:208061.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:18
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate Na+

Cross database links:

Genevestigator: P35499
HEGENOM: HBG358468
RefSeq: NP_000325.4   
Entrez Gene ID: 6329   
Pfam: PF00520    PF06512   
OMIM: 168300  phenotype
170400  phenotype
170500  phenotype
603967  gene+phenotype
608390  phenotype
KEGG: hsa:6329   

Gene Ontology

GO:0001518 C:voltage-gated sodium channel complex
GO:0005248 F:voltage-gated sodium channel activity
GO:0006936 P:muscle contraction
GO:0006814 P:sodium ion transport
GO:0055085 P:transmembrane transport

References (40)

[1] “Primary structure of the adult human skeletal muscle voltage-dependent sodium channel.”  George A.L. Jr.et.al.   1315496
[2] “Sequence and genomic structure of the human adult skeletal muscle sodium channel alpha subunit gene on 17q.”  Wang J.et.al.   1310396
[3] “Myasthenic syndrome caused by mutation of the SCN4A sodium channel.”  Tsujino A.et.al.   12766226
[4] “The genomic structure of the human skeletal muscle sodium channel gene.”  McClatchey A.I.et.al.   1339144
[5] “DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.”  Zody M.C.et.al.   16625196
[6] “Temperature-sensitive mutations in the III-IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita.”  McClatchey A.I.et.al.   1310898
[7] “Identification of a mutation in the gene causing hyperkalemic periodic paralysis.”  Ptacek L.J.et.al.   1659948
[8] “A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis.”  Rojas C.V.et.al.   1659668
[9] “Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel.”  McClatchey A.I.et.al.   1338909
[10] “Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita.”  Ptacek L.J.et.al.   1316765
[11] “Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis.”  Ptacek L.J.et.al.   8388676
[12] “Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker.”  Lerche H.et.al.   8308722
[13] “A novel SCN4A mutation causing myotonia aggravated by cold and potassium.”  Heine R.et.al.   8242056
[14] “Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis.”  Ptacek L.J.et.al.   8058156
[15] “Hyperkalemic periodic paralysis with cardiac dysrhythmia: a novel sodium channel mutation?”  Baquero J.L.et.al.   7695243
[16] “Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile).”  Koch M.C.et.al.   8580427
[17] “A novel muscle sodium channel mutation causes painful congenital myotonia.”  Rosenfeld J.et.al.   9392583
[18] “A novel mutation in the gene for the adult skeletal muscle sodium channel alpha-subunit (SCN4A) that causes paramyotonia congenita of von Eulenburg.”  Sasaki R.et.al.   10369308
[19] “Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia.”  Wang D.W.et.al.   10218481
[20] “A novel sodium channel mutation in a family with hypokalemic periodic paralysis.”  Bulman D.E.et.al.   10599760
[21] “Clinical, electrophysiological, and molecular genetic studies in a new family with paramyotonia congenita.”  Davies N.P.et.al.   10727489
[22] “Temperature-sensitive sodium channelopathy with heat-induced myotonia and cold-induced paralysis.”  Sugiura Y.et.al.   10851391
[23] “Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.”  Jurkat-Rott K.et.al.   10944223
[24] “Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis.”  Bendahhou S.et.al.   11558801
[25] “Sodium channel gene mutations in hypokalemic periodic paralysis: an uncommon cause in the UK.”  Davies N.P.et.al.   11591859
[26] “New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis.”  Vicart S.et.al.   15596759
[27] “A1152D mutation of the Na+ channel causes paramyotonia congenita and emphasizes the role of DIII/S4-S5 linker in fast inactivation.”  Bouhours M.et.al.   15790667
[28] “Cold extends electromyography distinction between ion channel mutations causing myotonia.”  Fournier E.et.al.   16786525
[29] “Autosomal dominant monosymptomatic myotonia permanens.”  Colding-Joergensen E.et.al.   16832098
[30] “The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis.”  Kim J.-B.et.al.   18162704
[31] “A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene.”  Schoser B.G.H.et.al.   17212350
[32] “A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians.”  Rossignol E.et.al.   17998485
[33] “Severe neonatal non-dystrophic myotonia secondary to a novel mutation of the voltage-gated sodium channel (SCN4A) gene.”  Gay S.et.al.   18203179
[34] “Mutations of sodium channel alpha-subunit genes in Chinese patients with normokalemic periodic paralysis.”  Xiuhai G.et.al.   18046642
[35] “Differential effects of paramyotonia congenita mutations F1473S and F1705I on sodium channel gating.”  Groome J.R.et.al.   18690054
[36] “What causes paramyotonia in the United Kingdom? Common and new SCN4A mutations revealed.”  Matthews E.et.al.   18166706
[37] “A novel dominant mutation of the Nav1.4 alpha-subunit domain I leading to sodium channel myotonia.”  Petitprez S.et.al.   19015483
[38] “Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians.”  Dupre N.et.al.   18337100
[39] “Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis.”  Matthews E.et.al.   19118277
[40] “Tubular aggregates in paralysis periodica paramyotonica with T704M mutation of SCN4A.”  Luan X.et.al.   19077043

External Searches:

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  • 2° Structure (Network Protein Sequence Analysis)

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Predict TMSs (Predict number of transmembrane segments)
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FASTA formatted sequence
1:	MARPSLCTLV PLGPECLRPF TRESLAAIEQ RAVEEEARLQ RNKQMEIEEP ERKPRSDLEA 
61:	GKNLPMIYGD PPPEVIGIPL EDLDPYYSNK KTFIVLNKGK AIFRFSATPA LYLLSPFSVV 
121:	RRGAIKVLIH ALFSMFIMIT ILTNCVFMTM SDPPPWSKNV EYTFTGIYTF ESLIKILARG 
181:	FCVDDFTFLR DPWNWLDFSV IMMAYLTEFV DLGNISALRT FRVLRALKTI TVIPGLKTIV 
241:	GALIQSVKKL SDVMILTVFC LSVFALVGLQ LFMGNLRQKC VRWPPPFNDT NTTWYSNDTW 
301:	YGNDTWYGNE MWYGNDSWYA NDTWNSHASW ATNDTFDWDA YISDEGNFYF LEGSNDALLC 
361:	GNSSDAGHCP EGYECIKTGR NPNYGYTSYD TFSWAFLALF RLMTQDYWEN LFQLTLRAAG 
421:	KTYMIFFVVI IFLGSFYLIN LILAVVAMAY AEQNEATLAE DKEKEEEFQQ MLEKFKKHQE 
481:	ELEKAKAAQA LEGGEADGDP AHGKDCNGSL DTSQGEKGAP RQSSSGDSGI SDAMEELEEA 
541:	HQKCPPWWYK CAHKVLIWNC CAPWLKFKNI IHLIVMDPFV DLGITICIVL NTLFMAMEHY 
601:	PMTEHFDNVL TVGNLVFTGI FTAEMVLKLI AMDPYEYFQQ GWNIFDSIIV TLSLVELGLA 
661:	NVQGLSVLRS FRLLRVFKLA KSWPTLNMLI KIIGNSVGAL GNLTLVLAII VFIFAVVGMQ 
721:	LFGKSYKECV CKIALDCNLP RWHMHDFFHS FLIVFRILCG EWIETMWDCM EVAGQAMCLT 
781:	VFLMVMVIGN LVVLNLFLAL LLSSFSADSL AASDEDGEMN NLQIAIGRIK LGIGFAKAFL 
841:	LGLLHGKILS PKDIMLSLGE ADGAGEAGEA GETAPEDEKK EPPEEDLKKD NHILNHMGLA 
901:	DGPPSSLELD HLNFINNPYL TIQVPIASEE SDLEMPTEEE TDTFSEPEDS KKPPQPLYDG 
961:	NSSVCSTADY KPPEEDPEEQ AEENPEGEQP EECFTEACVQ RWPCLYVDIS QGRGKKWWTL 
1021:	RRACFKIVEH NWFETFIVFM ILLSSGALAF EDIYIEQRRV IRTILEYADK VFTYIFIMEM 
1081:	LLKWVAYGFK VYFTNAWCWL DFLIVDVSII SLVANWLGYS ELGPIKSLRT LRALRPLRAL 
1141:	SRFEGMRVVV NALLGAIPSI MNVLLVCLIF WLIFSIMGVN LFAGKFYYCI NTTTSERFDI 
1201:	SEVNNKSECE SLMHTGQVRW LNVKVNYDNV GLGYLSLLQV ATFKGWMDIM YAAVDSREKE 
1261:	EQPQYEVNLY MYLYFVIFII FGSFFTLNLF IGVIIDNFNQ QKKKLGGKDI FMTEEQKKYY 
1321:	NAMKKLGSKK PQKPIPRPQN KIQGMVYDLV TKQAFDITIM ILICLNMVTM MVETDNQSQL 
1381:	KVDILYNINM IFIIIFTGEC VLKMLALRQY YFTVGWNIFD FVVVILSIVG LALSDLIQKY 
1441:	FVSPTLFRVI RLARIGRVLR LIRGAKGIRT LLFALMMSLP ALFNIGLLLF LVMFIYSIFG 
1501:	MSNFAYVKKE SGIDDMFNFE TFGNSIICLF EITTSAGWDG LLNPILNSGP PDCDPNLENP 
1561:	GTSVKGDCGN PSIGICFFCS YIIISFLIVV NMYIAIILEN FNVATEESSE PLGEDDFEMF 
1621:	YETWEKFDPD ATQFIAYSRL SDFVDTLQEP LRIAKPNKIK LITLDLPMVP GDKIHCLDIL 
1681:	FALTKEVLGD SGEMDALKQT MEEKFMAANP SKVSYEPITT TLKRKHEEVC AIKIQRAYRR 
1741:	HLLQRSMKQA SYMYRHSHDG SGDDAPEKEG LLANTMSKMY GHENGNSSSP SPEEKGEAGD 
1801:	AGPTMGLMPI SPSDTAWPPA PPPGQTVRPG VKESLV