SCN9A_HUMAN
ID SCN9A_HUMAN Reviewed; 1988 AA.
AC Q15858; A1BUH5; Q6B4R9; Q6B4S0; Q6B4S1; Q70HX1; Q70HX2; Q8WTU1; Q8WWN4;
DT 23-NOV-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-APR-2011, sequence version 3.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Sodium channel protein type 9 subunit alpha {ECO:0000305};
DE AltName: Full=Neuroendocrine sodium channel {ECO:0000303|PubMed:7720699};
DE Short=hNE-Na {ECO:0000303|PubMed:7720699};
DE AltName: Full=Peripheral sodium channel 1;
DE Short=PN1 {ECO:0000250|UniProtKB:O08562};
DE AltName: Full=Sodium channel protein type IX subunit alpha;
DE AltName: Full=Voltage-gated sodium channel subunit alpha Nav1.7;
GN Name=SCN9A {ECO:0000312|HGNC:HGNC:10597}; Synonyms=NENA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION IN VOLTAGE-EVOKED
RP DEPOLARIZATION, SUBCELLULAR LOCATION, SUBUNIT, TISSUE SPECIFICITY, AND
RP VARIANT ARG-1161.
RC TISSUE=Thyroid;
RX PubMed=7720699; DOI=10.1002/j.1460-2075.1995.tb07091.x;
RA Klugbauer N., Lacinova L., Flockerzi V., Hofmann F.;
RT "Structure and functional expression of a new member of the tetrodotoxin-
RT sensitive voltage-activated sodium channel family from human neuroendocrine
RT cells.";
RL EMBO J. 14:1084-1090(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), INVOLVEMENT IN CONGENITAL
RP INSENSITIVITY TO PAIN, FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, AND VARIANT
RP ARG-1161.
RX PubMed=17167479; DOI=10.1038/nature05413;
RA Cox J.J., Reimann F., Nicholas A.K., Thornton G., Roberts E., Springell K.,
RA Karbani G., Jafri H., Mannan J., Raashid Y., Al-Gazali L., Hamamy H.,
RA Valente E.M., Gorman S., Williams R., McHale D.P., Wood J.N., Gribble F.M.,
RA Woods C.G.;
RT "An SCN9A channelopathy causes congenital inability to experience pain.";
RL Nature 444:894-898(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 136-674 (ISOFORMS 1; 2; 3 AND 4), AND TISSUE
RP SPECIFICITY.
RC TISSUE=Spinal ganglion;
RX PubMed=15302875; DOI=10.1074/jbc.m406387200;
RA Raymond C.K., Castle J.C., Garrett-Engele P.W., Armour C.D., Kan Z.G.,
RA Tsinoremas N.T., Johnson J.M.;
RT "Expression of alternatively spliced sodium channel alpha-subunit genes:
RT unique splicing patterns are observed in dorsal root ganglia.";
RL J. Biol. Chem. 279:46234-46241(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 150-264 AND 1340-1400.
RA Diss J.K.J., Fraser S.P., Coombes R.C., Djamgoz M.B.A.;
RT "Upregulation of voltage-gated Na+ channel expression and metastatic
RT potential in human breast cancer: correlative studies on cell lines and
RT biopsy tissues.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 840-958, AND VARIANTS PERYTHM THR-859
RP AND HIS-869.
RX PubMed=14985375; DOI=10.1136/jmg.2003.012153;
RA Yang Y., Wang Y., Li S., Xu Z., Li H., Ma L., Fan J., Bu D., Liu B.,
RA Fan Z., Wu G., Jin J., Ding B., Zhu X., Shen Y.;
RT "Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients
RT with primary erythermalgia.";
RL J. Med. Genet. 41:171-174(2004).
RN [7]
RP TISSUE SPECIFICITY.
RX PubMed=9169448; DOI=10.1074/jbc.272.23.14805;
RA Sangameswaran L., Fish L.M., Koch B.D., Rabert D.K., Delgado S.G.,
RA Ilnicka M., Jakeman L.B., Novakovic S., Wong K., Sze P., Tzoumaka E.,
RA Stewart G.R., Herman R.C., Chan H., Eglen R.M., Hunter J.C.;
RT "A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in
RT rat and human dorsal root ganglia.";
RL J. Biol. Chem. 272:14805-14809(1997).
RN [8]
RP FUNCTION IN VOLTAGE-EVOKED DEPOLARIZATION, AND TISSUE SPECIFICITY.
RX PubMed=15178348; DOI=10.1016/j.febslet.2004.04.092;
RA Jo T., Nagata T., Iida H., Imuta H., Iwasawa K., Ma J., Hara K., Omata M.,
RA Nagai R., Takizawa H., Nagase T., Nakajima T.;
RT "Voltage-gated sodium channel expressed in cultured human smooth muscle
RT cells: involvement of SCN9A.";
RL FEBS Lett. 567:339-343(2004).
RN [9]
RP SUBUNIT, INTERACTION WITH THE SPIDER TOXINS HUWENTOXIN-IV AND PROTOXIN-II,
RP AND MUTAGENESIS OF GLU-829.
RX PubMed=20855463; DOI=10.1124/mol.110.066332;
RA Xiao Y., Blumenthal K., Jackson J.O. II, Liang S., Cummins T.R.;
RT "The tarantula toxins ProTx-II and huwentoxin-IV differentially interact
RT with human Nav1.7 voltage sensors to inhibit channel activation and
RT inactivation.";
RL Mol. Pharmacol. 78:1124-1134(2010).
RN [10]
RP SUBUNIT, INTERACTION WITH THE SPIDER HUWENTOXIN-IV, AND MUTAGENESIS OF
RP GLU-764; GLU-822; LEU-825 AND ASP-827.
RX PubMed=21659528; DOI=10.1074/jbc.m111.246876;
RA Xiao Y., Jackson J.O. II, Liang S., Cummins T.R.;
RT "Common molecular determinants of tarantula huwentoxin-IV inhibition of Na+
RT channel voltage sensors in domains II and IV.";
RL J. Biol. Chem. 286:27301-27310(2011).
RN [11]
RP SUBUNIT, INTERACTION WITH THE SCORPION ALPHA-TOXIN CVIV4, AND MUTAGENESIS
RP OF ASP-1597 AND GLU-1600.
RX PubMed=21887265; DOI=10.1371/journal.pone.0023520;
RA Rowe A.H., Xiao Y., Scales J., Linse K.D., Rowe M.P., Cummins T.R.,
RA Zakon H.H.;
RT "Isolation and characterization of CvIV4: a pain inducing alpha-scorpion
RT toxin.";
RL PLoS ONE 6:E23520-E23520(2011).
RN [12]
RP ACTIVITY REGULATION, AND MUTAGENESIS OF 1409-THR-ILE-1410.
RX PubMed=23077250; DOI=10.1073/pnas.1206952109;
RA Walker J.R., Novick P.A., Parsons W.H., McGregor M., Zablocki J.,
RA Pande V.S., Du Bois J.;
RT "Marked difference in saxitoxin and tetrodotoxin affinity for the human
RT nociceptive voltage-gated sodium channel (Nav1.7) [corrected].";
RL Proc. Natl. Acad. Sci. U.S.A. 109:18102-18107(2012).
RN [13]
RP ERRATUM OF PUBMED:23077250.
RA Walker J.R., Novick P.A., Parsons W.H., McGregor M., Zablocki J.,
RA Pande V.S., Du Bois J.;
RL Proc. Natl. Acad. Sci. U.S.A. 109:21551-21551(2012).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, SUBUNIT, PHOSPHORYLATION AT SER-1490, AND
RP MUTAGENESIS OF SER-1490.
RX PubMed=25240195; DOI=10.1016/j.febslet.2014.09.011;
RA Tan Z.Y., Priest B.T., Krajewski J.L., Knopp K.L., Nisenbaum E.S.,
RA Cummins T.R.;
RT "Protein kinase C enhances human sodium channel hNav1.7 resurgent currents
RT via a serine residue in the domain III-IV linker.";
RL FEBS Lett. 588:3964-3969(2014).
RN [15]
RP SUBUNIT, AND INTERACTION WITH THE CONOTOXIN GVIIJ.
RX PubMed=24497506; DOI=10.1073/pnas.1324189111;
RA Gajewiak J., Azam L., Imperial J., Walewska A., Green B.R.,
RA Bandyopadhyay P.K., Raghuraman S., Ueberheide B., Bern M., Zhou H.M.,
RA Minassian N.A., Hagan R.H., Flinspach M., Liu Y., Bulaj G., Wickenden A.D.,
RA Olivera B.M., Yoshikami D., Zhang M.M.;
RT "A disulfide tether stabilizes the block of sodium channels by the
RT conotoxin muO[section sign]-GVIIJ.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:2758-2763(2014).
RN [16]
RP SUBUNIT, AND INTERACTION WITH THE SPIDER BETA/DELTA-THERAPHOTOXIN-PRE1A.
RX PubMed=28428547; DOI=10.1038/s41598-017-01129-0;
RA Wingerd J.S., Mozar C.A., Ussing C.A., Murali S.S., Chin Y.K.,
RA Cristofori-Armstrong B., Durek T., Gilchrist J., Vaughan C.W., Bosmans F.,
RA Adams D.J., Lewis R.J., Alewood P.F., Mobli M., Christie M.J., Rash L.D.;
RT "The tarantula toxin beta/delta-TRTX-Pre1a highlights the importance of the
RT S1-S2 voltage-sensor region for sodium channel subtype selectivity.";
RL Sci. Rep. 7:974-988(2017).
RN [17]
RP TISSUE SPECIFICITY.
RX PubMed=31647222; DOI=10.1021/acs.bioconjchem.9b00612;
RA Gonzales J., Demetrio de Souza Franca P., Jiang Y., Pirovano G.,
RA Kossatz S., Guru N., Yarilin D., Agwa A.J., Schroeder C.I., Patel S.G.,
RA Ganly I., King G.F., Reiner T.;
RT "Fluorescence imaging of peripheral nerves by a Nav1.7-targeted inhibitor
RT cystine knot peptide.";
RL Bioconj. Chem. 30:2879-2888(2019).
RN [18] {ECO:0000312|PDB:5EK0}
RP X-RAY CRYSTALLOGRAPHY (3.53 ANGSTROMS) OF 1527-1559 AND 1581-1622,
RP FUNCTION, SUBCELLULAR LOCATION, AND DOMAIN.
RX PubMed=26680203; DOI=10.1126/science.aac5464;
RA Ahuja S., Mukund S., Deng L., Khakh K., Chang E., Ho H., Shriver S.,
RA Young C., Lin S., Johnson J.P. Jr., Wu P., Li J., Coons M., Tam C.,
RA Brillantes B., Sampang H., Mortara K., Bowman K.K., Clark K.R., Estevez A.,
RA Xie Z., Verschoof H., Grimwood M., Dehnhardt C., Andrez J.C., Focken T.,
RA Sutherlin D.P., Safina B.S., Starovasnik M.A., Ortwine D.F., Franke Y.,
RA Cohen C.J., Hackos D.H., Koth C.M., Payandeh J.;
RT "Structural basis of Nav1.7 inhibition by an isoform-selective small-
RT molecule antagonist.";
RL Science 350:0-0(2015).
RN [19] {ECO:0000312|PDB:6N4Q, ECO:0000312|PDB:6N4R}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 758-788 AND 813-843 IN
RP COMPLEX WITH THE SPIDER PROTOXIN-II, AND MUTAGENESIS OF ILE-778; LEU-823;
RP PHE-824; LEU-825; ALA-826 AND ASP-827.
RX PubMed=30661758; DOI=10.1016/j.cell.2018.12.018;
RA Xu H., Li T., Rohou A., Arthur C.P., Tzakoniati F., Wong E., Estevez A.,
RA Kugel C., Franke Y., Chen J., Ciferri C., Hackos D.H., Koth C.M.,
RA Payandeh J.;
RT "Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin.";
RL Cell 176:702-715(2019).
RN [20] {ECO:0000312|PDB:6J8G, ECO:0000312|PDB:6J8H, ECO:0000312|PDB:6J8I, ECO:0000312|PDB:6J8J}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.2 ANGSTROMS) OF MUTANT LYS-406 IN
RP COMPLEX WITH SCN1B; SCN2B; PROTOTOXIN-II; TETRODOTOXIN; HUWENTOXIN-IV AND
RP SAXITOXIN, GLYCOSYLATION AT ASN-283; ASN-1352; ASN-1366 AND ASN-1375,
RP SUBUNIT, DISULFIDE BOND, AND MUTAGENESIS OF GLU-406.
RX PubMed=30765606; DOI=10.1126/science.aaw2493;
RA Shen H., Liu D., Wu K., Lei J., Yan N.;
RT "Structures of human Nav1.7 channel in complex with auxiliary subunits and
RT animal toxins.";
RL Science 363:1303-1308(2019).
RN [21]
RP CHARACTERIZATION OF VARIANTS PERYTHM THR-859 AND HIS-869, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=15385606; DOI=10.1523/jneurosci.2695-04.2004;
RA Cummins T.R., Dib-Hajj S.D., Waxman S.G.;
RT "Electrophysiological properties of mutant Nav1.7 sodium channels in a
RT painful inherited neuropathy.";
RL J. Neurosci. 24:8232-8236(2004).
RN [22]
RP VARIANT PERYTHM THR-241.
RX PubMed=16216943; DOI=10.1001/archneur.62.10.1587;
RA Michiels J.J., te Morsche R.H.M., Jansen J.B.M.J., Drenth J.P.H.;
RT "Autosomal dominant erythermalgia associated with a novel mutation in the
RT voltage-gated sodium channel alpha subunit Nav1.7.";
RL Arch. Neurol. 62:1587-1590(2005).
RN [23]
RP VARIANT PERYTHM VAL-1460, AND CHARACTERIZATION OF VARIANT PERYTHM VAL-1460.
RX PubMed=15958509; DOI=10.1093/brain/awh514;
RA Dib-Hajj S.D., Rush A.M., Cummins T.R., Hisama F.M., Novella S.,
RA Tyrrell L., Marshall L., Waxman S.G.;
RT "Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces
RT bursting of sensory neurons.";
RL Brain 128:1847-1854(2005).
RN [24]
RP VARIANTS PERYTHM SER-216; LYS-395; THR-859 AND PHE-869, AND VARIANT
RP ARG-1161.
RX PubMed=15955112; DOI=10.1111/j.0022-202x.2005.23737.x;
RA Drenth J.P., te Morsche R.H., Guillet G., Taieb A., Kirby R.L.,
RA Jansen J.B.;
RT "SCN9A mutations define primary erythermalgia as a neuropathic disorder of
RT voltage gated sodium channels.";
RL J. Invest. Dermatol. 124:1333-1338(2005).
RN [25]
RP VARIANT PERYTHM PHE-869, AND CHARACTERIZATION OF VARIANT PERYTHM PHE-869.
RX PubMed=16392115; DOI=10.1002/ana.20776;
RA Han C., Rush A.M., Dib-Hajj S.D., Li S., Xu Z., Wang Y., Tyrrell L.,
RA Wang X., Yang Y., Waxman S.G.;
RT "Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7.";
RL Ann. Neurol. 59:553-558(2006).
RN [26]
RP CHARACTERIZATION OF VARIANT PERYTHM SER-216, FUNCTION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=16988069; DOI=10.1212/01.wnl.0000231514.33603.1e;
RA Choi J.S., Dib-Hajj S.D., Waxman S.G.;
RT "Inherited erythermalgia: limb pain from an S4 charge-neutral Na
RT channelopathy.";
RL Neurology 67:1563-1567(2006).
RN [27]
RP VARIANTS PEPD CYS-1007; PHE-1309; ASP-1309; PHE-1310; THR-1472; VAL-1473;
RP ILE-1475 AND LYS-1638, CHARACTERIZATION OF VARIANTS PEPD THR-1472; ILE-1475
RP AND LYS-1638, AND FUNCTION.
RX PubMed=17145499; DOI=10.1016/j.neuron.2006.10.006;
RA Fertleman C.R., Baker M.D., Parker K.A., Moffatt S., Elmslie F.V.,
RA Abrahamsen B., Ostman J., Klugbauer N., Wood J.N., Gardiner R.M., Rees M.;
RT "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants
RT underlie distinct channel defects and phenotypes.";
RL Neuron 52:767-774(2006).
RN [28]
RP CHARACTERIZATION OF VARIANT PERYTHM HIS-869.
RX PubMed=16702558; DOI=10.1073/pnas.0602813103;
RA Rush A.M., Dib-Hajj S.D., Liu S., Cummins T.R., Black J.A., Waxman S.G.;
RT "A single sodium channel mutation produces hyper- or hypoexcitability in
RT different types of neurons.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:8245-8250(2006).
RN [29]
RP VARIANT PERYTHM GLU-1643, CHARACTERIZATION OF VARIANT PERYTHM GLU-1643,
RP VARIANT PEPD GLU-1643, AND CHARACTERIZATION OF VARIANT PEPD GLU-1643.
RX PubMed=18945915; DOI=10.1523/jneurosci.3443-08.2008;
RA Estacion M., Dib-Hajj S.D., Benke P.J., Te Morsche R.H., Eastman E.M.,
RA Macala L.J., Drenth J.P., Waxman S.G.;
RT "NaV1.7 gain-of-function mutations as a continuum: A1632E displays
RT physiological changes associated with erythromelalgia and paroxysmal
RT extreme pain disorder mutations and produces symptoms of both disorders.";
RL J. Neurosci. 28:11079-11088(2008).
RN [30]
RP VARIANT PERYTHM ARG-10, CHARACTERIZATION OF VARIANTS PERYTHM ARG-10 AND
RP THR-859, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19369487; DOI=10.1093/brain/awp078;
RA Han C., Dib-Hajj S.D., Lin Z., Li Y., Eastman E.M., Tyrrell L., Cao X.,
RA Yang Y., Waxman S.G.;
RT "Early- and late-onset inherited erythromelalgia: genotype-phenotype
RT correlation.";
RL Brain 132:1711-1722(2009).
RN [31]
RP VARIANTS VAL-62; GLN-149; MET-228; ASN-490; LYS-519; TYR-641; ARG-666;
RP MET-695; TYR-710; VAL-750; PHE-1134; GLN-1171 AND VAL-1278.
RX PubMed=19763161; DOI=10.1371/journal.pgen.1000649;
RA Singh N.A., Pappas C., Dahle E.J., Claes L.R., Pruess T.H., De Jonghe P.,
RA Thompson J., Dixon M., Gurnett C., Peiffer A., White H.S., Filloux F.,
RA Leppert M.F.;
RT "A role of SCN9A in human epilepsies, as a cause of febrile seizures and as
RT a potential modifier of Dravet syndrome.";
RL PLoS Genet. 5:E1000649-E1000649(2009).
RN [32]
RP VARIANTS CIP GLN-907 AND 1381-ARG--LEU-1385 DEL, AND CHARACTERIZATION OF
RP VARIANTS CIP GLN-907 AND 1381-ARG--LEU-1385 DEL.
RX PubMed=20635406; DOI=10.1002/humu.21325;
RA Cox J.J., Sheynin J., Shorer Z., Reimann F., Nicholas A.K., Zubovic L.,
RA Baralle M., Wraige E., Manor E., Levy J., Woods C.G., Parvari R.;
RT "Congenital insensitivity to pain: novel SCN9A missense and in-frame
RT deletion mutations.";
RL Hum. Mutat. 31:E1670-E1686(2010).
RN [33]
RP VARIANT PEPD PRO-1623, AND CHARACTERIZATION OF VARIANT PEPD PRO-1623.
RX PubMed=25285947; DOI=10.1097/aln.0000000000000476;
RA Suter M.R., Bhuiyan Z.A., Laedermann C.J., Kuntzer T., Schaller M.,
RA Stauffacher M.W., Roulet E., Abriel H., Decosterd I., Wider C.;
RT "p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a
RT cold sensitive paroxysmal extreme pain disorder.";
RL Anesthesiology 122:414-423(2015).
RN [34]
RP VARIANT PERYTHM THR-1643, CHARACTERIZATION OF VARIANT PERYTHM THR-1643,
RP MUTAGENESIS OF ALA-1643, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24311784; DOI=10.1074/jbc.m113.502211;
RA Eberhardt M., Nakajima J., Klinger A.B., Neacsu C., Huhne K.,
RA O'Reilly A.O., Kist A.M., Lampe A.K., Fischer K., Gibson J., Nau C.,
RA Winterpacht A., Lampert A.;
RT "Inherited pain: sodium channel Nav1.7 A1632T mutation causes
RT erythromelalgia due to a shift of fast inactivation.";
RL J. Biol. Chem. 289:1971-1980(2014).
RN [35]
RP LACK OF INVOLVEMENT IN EPILEPSY AND FEBRILE SEIZURES, AND VARIANT TYR-641.
RX PubMed=33216760; DOI=10.1371/journal.pgen.1009161;
RA Fasham J., Leslie J.S., Harrison J.W., Deline J., Williams K.B., Kuhl A.,
RA Scott Schwoerer J., Cross H.E., Crosby A.H., Baple E.L.;
RT "No association between SCN9A and monogenic human epilepsy disorders.";
RL PLoS Genet. 16:e1009161-e1009161(2020).
CC -!- FUNCTION: Mediates the voltage-dependent sodium ion permeability of
CC excitable membranes. Assuming opened or closed conformations in
CC response to the voltage difference across the membrane, the protein
CC forms a sodium-selective channel through which Na(+) ions may pass in
CC accordance with their electrochemical gradient (PubMed:7720699,
CC PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606,
CC PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It
CC is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699).
CC Plays a role in pain mechanisms, especially in the development of
CC inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487,
CC PubMed:24311784). {ECO:0000269|PubMed:15178348,
CC ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16988069,
CC ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:17167479,
CC ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784,
CC ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203,
CC ECO:0000269|PubMed:7720699}.
CC -!- ACTIVITY REGULATION: Inhibited by tetrodotoxin (PubMed:23077250).
CC Weakly inhibited by saxitoxin (PubMed:23077250).
CC {ECO:0000269|PubMed:23077250}.
CC -!- SUBUNIT: The sodium channel complex consists of a large, channel-
CC forming alpha subunit (SCN9A) regulated by one or more beta subunits
CC (SCN1B, SCN2B, SCN3B and SCN4B) (PubMed:7720699, PubMed:17167479,
CC PubMed:25240195). SCN1B and SCN3B are non-covalently associated with
CC SCN2A. SCN2B and SCN4B are disulfide-linked to SCN2A. Interacts with
CC NEDD4 and NEDD4L (By similarity). Interacts with the scorpion alpha-
CC toxin CvIV4 (PubMed:21887265). Interacts with the conotoxin GVIIJ
CC (PubMed:24497506). Interacts with the spider huwentoxin-IV (through the
CC extracellular loop S3-S4 of repeat II) (PubMed:20855463,
CC PubMed:21659528, PubMed:30661758, PubMed:30765606). Interacts with the
CC spider protoxin-II (through the extracellular loop S3-S4 of repeats II
CC and IV) (PubMed:20855463, PubMed:21659528, PubMed:30661758,
CC PubMed:30765606). Interacts with the spider beta/delta-theraphotoxin-
CC Pre1a (PubMed:28428547). {ECO:0000250|UniProtKB:Q62205,
CC ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:21659528,
CC ECO:0000269|PubMed:21887265, ECO:0000269|PubMed:24497506,
CC ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:28428547,
CC ECO:0000269|PubMed:30661758, ECO:0000269|PubMed:30765606,
CC ECO:0000269|PubMed:7720699}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15385606,
CC ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487,
CC ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195,
CC ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}; Multi-pass
CC membrane protein {ECO:0000250|UniProtKB:D0E0C2}. Cell projection,
CC neuron projection {ECO:0000250|UniProtKB:O08562}. Note=In neurite
CC terminals. {ECO:0000250|UniProtKB:O08562}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q15858-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15858-2; Sequence=VSP_012028;
CC Name=3;
CC IsoId=Q15858-3; Sequence=VSP_012029;
CC Name=4;
CC IsoId=Q15858-4; Sequence=VSP_012028, VSP_012029;
CC -!- TISSUE SPECIFICITY: Expressed strongly in dorsal root ganglion, with
CC only minor levels elsewhere in the body, smooth muscle cells, MTC cell
CC line and C-cell carcinoma. Also expressed in vagus nerves within the
CC head and neck region (PubMed:31647222). Isoform 1 is expressed
CC preferentially in the central and peripheral nervous system. Isoform 2
CC is expressed preferentially in the dorsal root ganglion.
CC {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15302875,
CC ECO:0000269|PubMed:31647222, ECO:0000269|PubMed:7720699,
CC ECO:0000269|PubMed:9169448}.
CC -!- DOMAIN: The sequence contains 4 internal repeats, each with 5
CC hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged
CC segment (S4). Segments S4 are probably the voltage-sensors and are
CC characterized by a series of positively charged amino acids at every
CC third position. {ECO:0000305}.
CC -!- PTM: Phosphorylation at Ser-1490 by PKC in a highly conserved
CC cytoplasmic loop increases peak sodium currents.
CC {ECO:0000269|PubMed:25240195}.
CC -!- PTM: Ubiquitinated by NEDD4L; which may promote its endocytosis. Does
CC not seem to be ubiquitinated by NEDD4. {ECO:0000250|UniProtKB:Q62205}.
CC -!- DISEASE: Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal
CC dominant disease characterized by recurrent episodes of severe pain
CC associated with redness and warmth in the feet or hands.
CC {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15385606,
CC ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509,
CC ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115,
CC ECO:0000269|PubMed:16702558, ECO:0000269|PubMed:16988069,
CC ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487,
CC ECO:0000269|PubMed:24311784}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Indifference to pain, congenital, autosomal recessive (CIP)
CC [MIM:243000]: A disorder characterized by congenital inability to
CC perceive any form of pain, in any part of the body. All other sensory
CC modalities are preserved and the peripheral and central nervous systems
CC are apparently intact. Patients perceive the sensations of touch, warm
CC and cold temperature, proprioception, tickle and pressure, but not
CC painful stimuli. There is no evidence of a motor or sensory neuropathy,
CC either axonal or demyelinating. {ECO:0000269|PubMed:20635406}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Paroxysmal extreme pain disorder (PEPD) [MIM:167400]:
CC Autosomal dominant paroxysmal disorder of pain and autonomic
CC dysfunction. The distinctive features are paroxysmal episodes of
CC burning pain in the rectal, ocular, and mandibular areas accompanied by
CC autonomic manifestations such as skin flushing.
CC {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915,
CC ECO:0000269|PubMed:25285947}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the sodium channel (TC 1.A.1.10) family.
CC Nav1.7/SCN9A subfamily. {ECO:0000305}.
CC -!- CAUTION: SCN9A has been originally reported to be involved in
CC generalized epilepsy with febrile seizures plus
CC (GEFS+)(PubMed:19763161). However, it has later been shown that SCN9A
CC variants are not a likely cause of autosomal dominant febrile
CC seizures/febrile seizures plus and other monogenic seizure phenotypes
CC (PubMed:33216760). {ECO:0000269|PubMed:19763161,
CC ECO:0000269|PubMed:33216760}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=SCN9A entry;
CC URL="https://en.wikipedia.org/wiki/SCN9A";
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Silent pain - Issue 102 of
CC February 2009;
CC URL="https://web.expasy.org/spotlight/back_issues/102";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X82835; CAA58042.1; -; mRNA.
DR EMBL; DQ857292; ABI51981.1; -; mRNA.
DR EMBL; AC074101; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107082; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC108146; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AY682084; AAT85833.1; -; mRNA.
DR EMBL; AY682085; AAT85834.1; -; mRNA.
DR EMBL; AY682086; AAT85835.1; -; mRNA.
DR EMBL; AJ310882; CAC84550.1; -; mRNA.
DR EMBL; AJ310883; CAC84551.1; -; mRNA.
DR EMBL; AJ310897; CAC84537.1; -; mRNA.
DR EMBL; AJ580918; CAE45644.1; -; Genomic_DNA.
DR EMBL; AJ580919; CAE45645.1; -; Genomic_DNA.
DR CCDS; CCDS46441.1; -. [Q15858-3]
DR PIR; S54771; S54771.
DR RefSeq; NP_002968.1; NM_002977.3.
DR RefSeq; XP_005246814.1; XM_005246757.2.
DR RefSeq; XP_011509918.1; XM_011511616.2. [Q15858-1]
DR RefSeq; XP_011509919.1; XM_011511617.2. [Q15858-2]
DR RefSeq; XP_011509920.1; XM_011511618.2. [Q15858-4]
DR PDB; 5EK0; X-ray; 3.53 A; A/B/C/D=1527-1559, A/B/C/D=1581-1622.
DR PDB; 6J8G; EM; 3.20 A; A=1-1988.
DR PDB; 6J8H; EM; 3.20 A; A=1-1988.
DR PDB; 6J8I; EM; 3.20 A; A=1-1988.
DR PDB; 6J8J; EM; 3.20 A; A=1-1988.
DR PDB; 6N4Q; EM; 3.60 A; A/B/C/D=758-788, A/B/C/D=813-843.
DR PDB; 6N4R; EM; 4.20 A; A/B/C/D=758-788, A/B/C/D=813-843.
DR PDB; 6NT3; EM; 3.40 A; A=257-275, A=1501-1631.
DR PDB; 6NT4; EM; 3.50 A; A=257-275, A=1501-1631.
DR PDB; 6VXO; EM; 3.50 A; A/C/D/E=817-835.
DR PDB; 6W6O; EM; 3.20 A; A/D/F/H=817-835.
DR PDB; 7K48; EM; 3.60 A; A/B/C/D=751-790, A/B/C/D=817-841.
DR PDBsum; 5EK0; -.
DR PDBsum; 6J8G; -.
DR PDBsum; 6J8H; -.
DR PDBsum; 6J8I; -.
DR PDBsum; 6J8J; -.
DR PDBsum; 6N4Q; -.
DR PDBsum; 6N4R; -.
DR PDBsum; 6NT3; -.
DR PDBsum; 6NT4; -.
DR PDBsum; 6VXO; -.
DR PDBsum; 6W6O; -.
DR PDBsum; 7K48; -.
DR AlphaFoldDB; Q15858; -.
DR SMR; Q15858; -.
DR BioGRID; 112239; 6.
DR IntAct; Q15858; 5.
DR MINT; Q15858; -.
DR STRING; 9606.ENSP00000386306; -.
DR BindingDB; Q15858; -.
DR ChEMBL; CHEMBL4296; -.
DR DrugBank; DB09088; Amylocaine.
DR DrugBank; DB13746; Bioallethrin.
DR DrugBank; DB05541; Brivaracetam.
DR DrugBank; DB00564; Carbamazepine.
DR DrugBank; DB00907; Cocaine.
DR DrugBank; DB13269; Dichlorobenzyl alcohol.
DR DrugBank; DB13961; Fish oil.
DR DrugBank; DB06218; Lacosamide.
DR DrugBank; DB00555; Lamotrigine.
DR DrugBank; DB00281; Lidocaine.
DR DrugBank; DB00776; Oxcarbazepine.
DR DrugBank; DB11186; Pentoxyverine.
DR DrugBank; DB09345; Pramocaine.
DR DrugBank; DB01069; Promethazine.
DR DrugBank; DB09342; Propoxycaine.
DR DrugBank; DB00243; Ranolazine.
DR DrugBank; DB06201; Rufinamide.
DR DrugBank; DB09085; Tetracaine.
DR DrugBank; DB00273; Topiramate.
DR DrugBank; DB00313; Valproic acid.
DR DrugBank; DB00909; Zonisamide.
DR DrugCentral; Q15858; -.
DR GuidetoPHARMACOLOGY; 584; -.
DR TCDB; 1.A.1.10.5; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; Q15858; 5 sites.
DR iPTMnet; Q15858; -.
DR PhosphoSitePlus; Q15858; -.
DR BioMuta; SCN9A; -.
DR DMDM; 327478559; -.
DR EPD; Q15858; -.
DR jPOST; Q15858; -.
DR MassIVE; Q15858; -.
DR PaxDb; Q15858; -.
DR PeptideAtlas; Q15858; -.
DR PRIDE; Q15858; -.
DR ProteomicsDB; 60797; -. [Q15858-1]
DR ProteomicsDB; 60798; -. [Q15858-2]
DR ProteomicsDB; 60799; -. [Q15858-3]
DR ABCD; Q15858; 2 sequenced antibodies.
DR Antibodypedia; 33781; 467 antibodies from 39 providers.
DR DNASU; 6335; -.
DR Ensembl; ENST00000303354.11; ENSP00000304748.7; ENSG00000169432.19. [Q15858-1]
DR Ensembl; ENST00000409672.5; ENSP00000386306.1; ENSG00000169432.19. [Q15858-3]
DR Ensembl; ENST00000642356.2; ENSP00000495601.1; ENSG00000169432.19. [Q15858-1]
DR Ensembl; ENST00000645907.1; ENSP00000495983.1; ENSG00000169432.19. [Q15858-4]
DR GeneID; 6335; -.
DR KEGG; hsa:6335; -.
DR MANE-Select; ENST00000642356.2; ENSP00000495601.1; NM_001365536.1; NP_001352465.1.
DR UCSC; uc002udr.2; human. [Q15858-1]
DR CTD; 6335; -.
DR DisGeNET; 6335; -.
DR GeneCards; SCN9A; -.
DR GeneReviews; SCN9A; -.
DR HGNC; HGNC:10597; SCN9A.
DR HPA; ENSG00000169432; Tissue enhanced (brain).
DR MalaCards; SCN9A; -.
DR MIM; 133020; phenotype.
DR MIM; 167400; phenotype.
DR MIM; 243000; phenotype.
DR MIM; 603415; gene.
DR neXtProt; NX_Q15858; -.
DR OpenTargets; ENSG00000169432; -.
DR Orphanet; 88642; Congenital insensitivity to pain-anosmia-neuropathic arthropathy.
DR Orphanet; 33069; Dravet syndrome.
DR Orphanet; 36387; Generalized epilepsy with febrile seizures-plus.
DR Orphanet; 970; Hereditary sensory and autonomic neuropathy type 2.
DR Orphanet; 46348; Paroxysmal extreme pain disorder.
DR Orphanet; 90026; Primary erythromelalgia.
DR Orphanet; 306577; Sodium channelopathy-related small fiber neuropathy.
DR PharmGKB; PA35010; -.
DR VEuPathDB; HostDB:ENSG00000169432; -.
DR eggNOG; KOG2301; Eukaryota.
DR GeneTree; ENSGT00940000161368; -.
DR HOGENOM; CLU_000540_5_0_1; -.
DR InParanoid; Q15858; -.
DR OMA; SKYMTDV; -.
DR OrthoDB; 56920at2759; -.
DR PhylomeDB; Q15858; -.
DR TreeFam; TF323985; -.
DR PathwayCommons; Q15858; -.
DR Reactome; R-HSA-445095; Interaction between L1 and Ankyrins.
DR Reactome; R-HSA-5576892; Phase 0 - rapid depolarisation.
DR Reactome; R-HSA-9717207; Sensory perception of sweet, bitter, and umami (glutamate) taste.
DR SignaLink; Q15858; -.
DR SIGNOR; Q15858; -.
DR BioGRID-ORCS; 6335; 4 hits in 1074 CRISPR screens.
DR ChiTaRS; SCN9A; human.
DR GeneWiki; Nav1.7; -.
DR GenomeRNAi; 6335; -.
DR Pharos; Q15858; Tclin.
DR PRO; PR:Q15858; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q15858; protein.
DR Bgee; ENSG00000169432; Expressed in sural nerve and 120 other tissues.
DR ExpressionAtlas; Q15858; baseline and differential.
DR Genevisible; Q15858; HS.
DR GO; GO:0030424; C:axon; ISS:ARUK-UCL.
DR GO; GO:0005887; C:integral component of plasma membrane; IMP:UniProtKB.
DR GO; GO:0001518; C:voltage-gated sodium channel complex; IBA:GO_Central.
DR GO; GO:0031402; F:sodium ion binding; IEA:Ensembl.
DR GO; GO:0005244; F:voltage-gated ion channel activity; IEA:UniProtKB-KW.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; IDA:UniProtKB.
DR GO; GO:0061368; P:behavioral response to formalin induced pain; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0086010; P:membrane depolarization during action potential; IBA:GO_Central.
DR GO; GO:0045759; P:negative regulation of action potential; IEA:Ensembl.
DR GO; GO:0019228; P:neuronal action potential; IBA:GO_Central.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0019233; P:sensory perception of pain; IMP:UniProtKB.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006814; P:sodium ion transport; TAS:ProtInc.
DR CDD; cd13433; Na_channel_gate; 1.
DR Gene3D; 1.20.120.350; -; 4.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR InterPro; IPR001696; Na_channel_asu.
DR InterPro; IPR044564; Na_chnl_inactivation_gate.
DR InterPro; IPR010526; Na_trans_assoc.
DR InterPro; IPR024583; Na_trans_cytopl.
DR InterPro; IPR028803; SCN9A.
DR InterPro; IPR043203; VGCC_Ca_Na.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR10037; PTHR10037; 1.
DR PANTHER; PTHR10037:SF221; PTHR10037:SF221; 1.
DR Pfam; PF00520; Ion_trans; 4.
DR Pfam; PF06512; Na_trans_assoc; 1.
DR Pfam; PF11933; Na_trans_cytopl; 1.
DR PRINTS; PR00170; NACHANNEL.
DR SMART; SM00015; IQ; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Disease variant; Disulfide bond; Epilepsy; Glycoprotein; Ion channel;
KW Ion transport; Membrane; Phosphoprotein; Reference proteome; Repeat;
KW Sodium; Sodium channel; Sodium transport; Transmembrane;
KW Transmembrane helix; Transport; Ubl conjugation; Voltage-gated channel.
FT CHAIN 1..1988
FT /note="Sodium channel protein type 9 subunit alpha"
FT /id="PRO_0000048502"
FT TOPO_DOM 1..126
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 127..145
FT /note="Helical; Name=S1 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 146..152
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 153..173
FT /note="Helical; Name=S2 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 174..187
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 188..205
FT /note="Helical; Name=S3 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 206..211
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 212..228
FT /note="Helical; Name=S4 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 229..247
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 248..267
FT /note="Helical; Name=S5 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 268..346
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 347..371
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 372..378
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 379..399
FT /note="Helical; Name=S6 of repeat I"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 400..744
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 745..763
FT /note="Helical; Name=S1 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 764..774
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 775..794
FT /note="Helical; Name=S2 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 795..808
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 809..828
FT /note="Helical; Name=S3 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 829..830
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 831..848
FT /note="Helical; Name=S4 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 849..864
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 865..883
FT /note="Helical; Name=S5 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 884..912
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 913..933
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 934..946
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 947..967
FT /note="Helical; Name=S6 of repeat II"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 968..1193
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1194..1211
FT /note="Helical; Name=S1 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1212..1224
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1225..1243
FT /note="Helical; Name=S2 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1244..1257
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1258..1276
FT /note="Helical; Name=S3 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1277..1284
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1285..1303
FT /note="Helical; Name=S4 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1304..1320
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1321..1340
FT /note="Helical; Name=S5 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1341..1392
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 1393..1414
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1415..1431
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1432..1453
FT /note="Helical; Name=S6 of repeat III"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1454..1516
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1517..1534
FT /note="Helical; Name=S1 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1535..1545
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1546..1564
FT /note="Helical; Name=S2 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1565..1576
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1577..1594
FT /note="Helical; Name=S3 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1595..1607
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1608..1624
FT /note="Helical; Name=S4 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1625..1643
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 1644..1661
FT /note="Helical; Name=S5 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1662..1683
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT INTRAMEM 1684..1706
FT /note="Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1707..1736
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 1737..1759
FT /note="Helical; Name=S6 of repeat IV"
FT /evidence="ECO:0000250|UniProtKB:D0E0C2"
FT TOPO_DOM 1760..1988
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REPEAT 112..410
FT /note="I"
FT /evidence="ECO:0000305"
FT REPEAT 726..989
FT /note="II"
FT /evidence="ECO:0000305"
FT REPEAT 1180..1488
FT /note="III"
FT /evidence="ECO:0000305"
FT REPEAT 1497..1795
FT /note="IV"
FT /evidence="ECO:0000305"
FT DOMAIN 1889..1918
FT /note="IQ"
FT REGION 26..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 461..543
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 565..611
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1102..1148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1934..1988
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 26..51
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 486..529
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 565..592
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 594..610
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1117..1131
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1934..1960
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1961..1988
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 822
FT /note="Is directly targeted by the spider protoxin-II"
FT /evidence="ECO:0000269|PubMed:30661758"
FT SITE 827
FT /note="Is directly targeted by the spider protoxin-II"
FT /evidence="ECO:0000269|PubMed:30661758"
FT MOD_RES 1490
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000269|PubMed:25240195"
FT CARBOHYD 209
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 283
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT CARBOHYD 1352
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT CARBOHYD 1366
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT CARBOHYD 1375
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 275..324
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 895
FT /note="Interchain; with SCN2B or SCN4B"
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 895
FT /note="Interchain; with the conotoxin GVIIJ (when the
FT channel is not linked to SCN2B or SCN4B; the bond to SCN2B
FT or SCN4B protects the channel from the inhibition by
FT toxin)"
FT /evidence="ECO:0000250|UniProtKB:P04775"
FT DISULFID 897..903
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 935..944
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 1350..1370
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT DISULFID 1715..1730
FT /evidence="ECO:0000269|PubMed:30765606,
FT ECO:0007744|PDB:6J8G, ECO:0007744|PDB:6J8H,
FT ECO:0007744|PDB:6J8I, ECO:0007744|PDB:6J8J"
FT VAR_SEQ 200..229
FT /note="YLTEFVNLGNVSALRTFRVLRALKTISVIP -> YVTEFVDLGNVSALRTFR
FT VLRALKTISVIP (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:15302875"
FT /id="VSP_012028"
FT VAR_SEQ 648..658
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:15302875,
FT ECO:0000303|PubMed:17167479, ECO:0000303|PubMed:7720699"
FT /id="VSP_012029"
FT VARIANT 10
FT /note="Q -> R (in PERYTHM; causes a hyperpolarizing shift
FT of -5.3 mV for the midpoint of activation which is smaller
FT than that seen in other mutations causing early-onset
FT erythromelalgia mutations; also causes a faster rate of
FT activation and slower deactivation compared to wild-type;
FT expression of the mutant protein induced hyperexcitability
FT in dorsal root ganglion neurons but the increase is smaller
FT than that produced by Thr-859; dbSNP:rs267607030)"
FT /evidence="ECO:0000269|PubMed:19369487"
FT /id="VAR_064595"
FT VARIANT 62
FT /note="I -> V (found in a patient with febrile seizures;
FT unknown pathological significance; dbSNP:rs121908920)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064596"
FT VARIANT 149
FT /note="P -> Q (found in a patient with febrile seizures;
FT unknown pathological significance; dbSNP:rs121908921)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064597"
FT VARIANT 216
FT /note="F -> S (in PERYTHM; hyperpolarizes the voltage
FT dependence of activation by 11 mV, accelerates activation,
FT slows deactivation and enhances the response to slow, small
FT depolarizations; dbSNP:rs80356469)"
FT /evidence="ECO:0000269|PubMed:15955112,
FT ECO:0000269|PubMed:16988069"
FT /id="VAR_064598"
FT VARIANT 228
FT /note="I -> M (in dbSNP:rs71428908)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064599"
FT VARIANT 241
FT /note="S -> T (in PERYTHM; dbSNP:rs80356470)"
FT /evidence="ECO:0000269|PubMed:16216943"
FT /id="VAR_032014"
FT VARIANT 395
FT /note="N -> K (in PERYTHM; dbSNP:rs80356471)"
FT /evidence="ECO:0000269|PubMed:15955112"
FT /id="VAR_064600"
FT VARIANT 490
FT /note="S -> N (in dbSNP:rs58022607)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064602"
FT VARIANT 519
FT /note="E -> K (in dbSNP:rs187453572)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064603"
FT VARIANT 641
FT /note="N -> Y (found in patients with febrile seizures
FT plus; unknown pathological significance;
FT dbSNP:rs121908918)"
FT /evidence="ECO:0000269|PubMed:19763161,
FT ECO:0000269|PubMed:33216760"
FT /id="VAR_064604"
FT VARIANT 666
FT /note="K -> R (in dbSNP:rs121908919)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064605"
FT VARIANT 695
FT /note="I -> M (in dbSNP:rs199588089)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064606"
FT VARIANT 710
FT /note="C -> Y (found in a patient with severe myoclonic
FT epilepsy in infancy; unknown pathological significance;
FT dbSNP:rs201709980)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064607"
FT VARIANT 750
FT /note="I -> V (in dbSNP:rs182650126)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064608"
FT VARIANT 859
FT /note="I -> T (in PERYTHM; sporadic; activated at more
FT negative potentials; slower inactivation kinetics than
FT wild-type channels; dbSNP:rs80356474)"
FT /evidence="ECO:0000269|PubMed:14985375,
FT ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:15955112,
FT ECO:0000269|PubMed:19369487"
FT /id="VAR_019947"
FT VARIANT 869
FT /note="L -> F (in PERYTHM; causes a hyperpolarizing shift
FT in channel activation, a depolarizing shift of inactivation
FT and an 18-fold increase in deactivation time compared to
FT wild-type; the mean ramp current amplitude in response to
FT slow depolarization is higher in the mutant channels;
FT dbSNP:rs80356476)"
FT /evidence="ECO:0000269|PubMed:15955112,
FT ECO:0000269|PubMed:16392115"
FT /id="VAR_064609"
FT VARIANT 869
FT /note="L -> H (in PERYTHM; activated at more negative
FT potentials; slower inactivation kinetics than wild-type
FT channels; dbSNP:rs80356475)"
FT /evidence="ECO:0000269|PubMed:14985375,
FT ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16702558"
FT /id="VAR_019948"
FT VARIANT 907
FT /note="R -> Q (in CIP; significant reduction in membrane
FT localization of the mutant protein compared to the wild-
FT type; complete loss of function of the sodium channel;
FT dbSNP:rs1024152367)"
FT /evidence="ECO:0000269|PubMed:20635406"
FT /id="VAR_064610"
FT VARIANT 932
FT /note="M -> L (in dbSNP:rs12478318)"
FT /id="VAR_030444"
FT VARIANT 943
FT /note="M -> L (in dbSNP:rs12478318)"
FT /id="VAR_055646"
FT VARIANT 1007
FT /note="R -> C (in PEPD; dbSNP:rs121908910)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032015"
FT VARIANT 1134
FT /note="L -> F (in dbSNP:rs200160858)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064611"
FT VARIANT 1161
FT /note="W -> R (in dbSNP:rs6746030)"
FT /evidence="ECO:0000269|PubMed:15955112,
FT ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:7720699"
FT /id="VAR_019949"
FT VARIANT 1171
FT /note="E -> Q (found in a patient with severe myoclonic
FT epilepsy in infancy; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064612"
FT VARIANT 1278
FT /note="L -> V (in dbSNP:rs180922748)"
FT /evidence="ECO:0000269|PubMed:19763161"
FT /id="VAR_064613"
FT VARIANT 1309
FT /note="V -> D (in PEPD; dbSNP:rs121908911)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032016"
FT VARIANT 1309
FT /note="V -> F (in PEPD; dbSNP:rs121908912)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032017"
FT VARIANT 1310
FT /note="V -> F (in PEPD; dbSNP:rs121908913)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032018"
FT VARIANT 1381..1385
FT /note="Missing (in CIP; significant reduction in membrane
FT localization of the mutant protein compared to the wild-
FT type; complete loss of function of the sodium channel)"
FT /evidence="ECO:0000269|PubMed:20635406"
FT /id="VAR_064614"
FT VARIANT 1460
FT /note="F -> V (in PERYTHM; produces a hyperpolarizing shift
FT in channel activation and a depolarizing shift in steady-
FT state activation; dbSNP:rs80356478)"
FT /evidence="ECO:0000269|PubMed:15958509"
FT /id="VAR_032019"
FT VARIANT 1472
FT /note="I -> T (in PEPD; reduction in fast inactivation
FT leading to persistent sodium current; dbSNP:rs121908914)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032020"
FT VARIANT 1473
FT /note="F -> V (in PEPD; dbSNP:rs1553474394)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032021"
FT VARIANT 1475
FT /note="T -> I (in PEPD; reduction in fast inactivation
FT leading to persistent sodium current; dbSNP:rs121908915)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032022"
FT VARIANT 1623
FT /note="L -> P (in PEPD; depolarizes the voltage-dependence
FT of channel activation and steady-state fast inactivation;
FT increases ramp current; dbSNP:rs1131691776)"
FT /evidence="ECO:0000269|PubMed:25285947"
FT /id="VAR_072279"
FT VARIANT 1638
FT /note="M -> K (in PEPD; reduction in fast inactivation
FT leading to persistent sodium current)"
FT /evidence="ECO:0000269|PubMed:17145499"
FT /id="VAR_032023"
FT VARIANT 1643
FT /note="A -> E (in PERYTHM and PEPD; hyperpolarizes voltage-
FT dependence of channel activation; depolarizes the voltage-
FT dependence of steady-state fast inactivation; slows channel
FT deactivation; enhances persistent and resurgent current;
FT enhances neuronal hyperexcitability in dorsal root ganglion
FT neurons; dbSNP:rs879253994)"
FT /evidence="ECO:0000269|PubMed:18945915,
FT ECO:0000269|PubMed:24311784"
FT /id="VAR_072280"
FT VARIANT 1643
FT /note="A -> T (in PERYTHM; no effect on voltage-dependence
FT of channel activation; depolarizes the voltage dependence
FT of steady-state fast inactivation; accelerates channel
FT deactivation; no increase in persistent and resurgent
FT currents; enhances neuronal hyperexcitability in dorsal
FT root ganglion neurons)"
FT /evidence="ECO:0000269|PubMed:24311784"
FT /id="VAR_072281"
FT VARIANT 1919
FT /note="D -> G (in dbSNP:rs3750904)"
FT /id="VAR_019950"
FT MUTAGEN 406
FT /note="E->K: Hyperpolarizes the voltage dependence of
FT activation by 10.6 mV and prolonges fast-inactivation
FT duration when coexpressed with SCN1B and SCN2B."
FT /evidence="ECO:0000269|PubMed:30765606"
FT MUTAGEN 764
FT /note="E->Q: 5-fold less blocked by the spider huwentoxin-
FT IV."
FT /evidence="ECO:0000269|PubMed:21659528"
FT MUTAGEN 778
FT /note="I->A: 5-fold less inhibited by the spider protoxin-
FT II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 822
FT /note="E->A: No change in inhibition (IC(50)) by the spider
FT protoxin-II, but has a significant impact on channel
FT activation by shifiting the V(50) towart 0 mV when targeted
FT by protoxin-II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 822
FT /note="E->Q: 18-fold less blocked by the spider huwentoxin-
FT IV."
FT /evidence="ECO:0000269|PubMed:21659528"
FT MUTAGEN 823
FT /note="L->A: 9-fold less inhibited by the spider protoxin-
FT II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 824
FT /note="F->A: 4-fold less inhibited by the spider protoxin-
FT II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 824
FT /note="F->C: Less inhibited by the spider protoxin-II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 825
FT /note="L->A: No change in inhibition by the spider
FT protoxin-II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 825
FT /note="L->C: 19-fold less blocked by the spider huwentoxin-
FT IV."
FT /evidence="ECO:0000269|PubMed:21659528"
FT MUTAGEN 826
FT /note="A->L: 8-fold less inhibited by the spider protoxin-
FT II."
FT /evidence="ECO:0000269|PubMed:30661758"
FT MUTAGEN 827
FT /note="D->A: 13-fold less blocked by the spider huwentoxin-
FT IV, 3-fold less inhibited by the spider protoxin-II, and
FT has a significant impact on channel activation by shifiting
FT the V(50) towart 0 mV when targeted by protoxin-II."
FT /evidence="ECO:0000269|PubMed:21659528,
FT ECO:0000269|PubMed:30661758"
FT MUTAGEN 829
FT /note="E->C: 400-fold less blocked by the spider
FT huwentoxin-IV."
FT /evidence="ECO:0000269|PubMed:20855463"
FT MUTAGEN 1409..1410
FT /note="TI->MD: Important increase in inhibition by
FT saxitoxin and little increase in inhibition by
FT tetrodotoxin."
FT /evidence="ECO:0000269|PubMed:23077250"
FT MUTAGEN 1490
FT /note="S->A: Abolishes stimulation by agents that stimulate
FT PKC activity."
FT /evidence="ECO:0000269|PubMed:25240195"
FT MUTAGEN 1490
FT /note="S->D,E: Increases current amplitude."
FT /evidence="ECO:0000269|PubMed:25240195"
FT MUTAGEN 1597
FT /note="D->A: Decrease of the inhibition of fast
FT inactivation produced by the scorpion alpha-toxin CvIV4 on
FT this channel."
FT /evidence="ECO:0000269|PubMed:21887265"
FT MUTAGEN 1600
FT /note="E->Q: Decrease of the inhibition of fast
FT inactivation produced by the scorpion alpha-toxin CvIV4 on
FT this channel."
FT /evidence="ECO:0000269|PubMed:21887265"
FT MUTAGEN 1643
FT /note="A->D: Depolarizes the voltage-dependence of steady-
FT state fast inactivation; enhances persistent current."
FT /evidence="ECO:0000269|PubMed:24311784"
FT MUTAGEN 1643
FT /note="A->K: No effect on voltage-dependence of steady-
FT state fast inactivation."
FT /evidence="ECO:0000269|PubMed:24311784"
FT MUTAGEN 1643
FT /note="A->V: No effect on voltage-dependence of steady-
FT state fast inactivation."
FT /evidence="ECO:0000269|PubMed:24311784"
FT CONFLICT 267
FT /note="F -> S (in Ref. 4; AAT85834)"
FT /evidence="ECO:0000305"
FT CONFLICT 301
FT /note="K -> R (in Ref. 4; AAT85835)"
FT /evidence="ECO:0000305"
FT CONFLICT 309
FT /note="S -> P (in Ref. 4; AAT85834)"
FT /evidence="ECO:0000305"
FT CONFLICT 420
FT /note="E -> G (in Ref. 4; AAT85834)"
FT /evidence="ECO:0000305"
FT CONFLICT 430
FT /note="L -> P (in Ref. 4; AAT85834)"
FT /evidence="ECO:0000305"
FT CONFLICT 501
FT /note="S -> P (in Ref. 4; AAT85835)"
FT /evidence="ECO:0000305"
FT CONFLICT 610
FT /note="P -> T (in Ref. 4; AAT85835)"
FT /evidence="ECO:0000305"
FT CONFLICT 642
FT /note="G -> R (in Ref. 4; AAT85835)"
FT /evidence="ECO:0000305"
FT HELIX 115..123
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 126..143
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 152..175
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 178..180
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 181..185
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 187..203
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 210..214
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 219..227
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 231..244
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 246..267
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 270..272
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 273..278
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 281..283
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 286..292
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 296..302
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 317..321
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 328..332
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 337..341
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 344..346
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 347..358
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 363..374
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 376..378
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 379..389
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 391..416
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 727..739
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 743..745
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 746..761
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 770..798
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 800..805
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 807..822
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 825..827
FT /evidence="ECO:0007829|PDB:6W6O"
FT HELIX 833..836
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 837..846
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 850..863
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 864..866
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 867..895
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 896..899
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 901..904
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 910..912
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 913..924
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 928..939
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 941..971
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1177..1190
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1192..1211
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1214..1217
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1220..1254
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1257..1278
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1287..1290
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1291..1299
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1300..1303
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1305..1343
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1349..1352
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 1353..1356
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1361..1363
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1367..1376
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1378..1383
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1386..1391
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1392..1404
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1408..1417
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1434..1444
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1446..1466
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 1467..1469
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1472..1474
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1476..1487
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1503..1513
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1515..1533
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1541..1569
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1571..1575
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1577..1602
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1606..1613
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1614..1616
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1617..1620
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1623..1626
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1628..1639
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1641..1666
FT /evidence="ECO:0007829|PDB:6J8G"
FT STRAND 1676..1683
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1684..1695
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 1696..1699
FT /evidence="ECO:0007829|PDB:6J8I"
FT HELIX 1700..1708
FT /evidence="ECO:0007829|PDB:6J8G"
FT TURN 1712..1714
FT /evidence="ECO:0007829|PDB:6J8G"
FT HELIX 1733..1767
FT /evidence="ECO:0007829|PDB:6J8G"
SQ SEQUENCE 1988 AA; 226372 MW; 1BAEB8F32EBF5438 CRC64;
MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS SDLEAGKQLP
FIYGDIPPGM VSEPLEDLDP YYADKKTFIV LNKGKTIFRF NATPALYMLS PFSPLRRISI
KILVHSLFSM LIMCTILTNC IFMTMNNPPD WTKNVEYTFT GIYTFESLVK ILARGFCVGE
FTFLRDPWNW LDFVVIVFAY LTEFVNLGNV SALRTFRVLR ALKTISVIPG LKTIVGALIQ
SVKKLSDVMI LTVFCLSVFA LIGLQLFMGN LKHKCFRNSL ENNETLESIM NTLESEEDFR
KYFYYLEGSK DALLCGFSTD SGQCPEGYTC VKIGRNPDYG YTSFDTFSWA FLALFRLMTQ
DYWENLYQQT LRAAGKTYMI FFVVVIFLGS FYLINLILAV VAMAYEEQNQ ANIEEAKQKE
LEFQQMLDRL KKEQEEAEAI AAAAAEYTSI RRSRIMGLSE SSSETSKLSS KSAKERRNRR
KKKNQKKLSS GEEKGDAEKL SKSESEDSIR RKSFHLGVEG HRRAHEKRLS TPNQSPLSIR
GSLFSARRSS RTSLFSFKGR GRDIGSETEF ADDEHSIFGD NESRRGSLFV PHRPQERRSS
NISQASRSPP MLPVNGKMHS AVDCNGVVSL VDGRSALMLP NGQLLPEVII DKATSDDSGT
TNQIHKKRRC SSYLLSEDML NDPNLRQRAM SRASILTNTV EELEESRQKC PPWWYRFAHK
FLIWNCSPYW IKFKKCIYFI VMDPFVDLAI TICIVLNTLF MAMEHHPMTE EFKNVLAIGN
LVFTGIFAAE MVLKLIAMDP YEYFQVGWNI FDSLIVTLSL VELFLADVEG LSVLRSFRLL
RVFKLAKSWP TLNMLIKIIG NSVGALGNLT LVLAIIVFIF AVVGMQLFGK SYKECVCKIN
DDCTLPRWHM NDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVYMM VMVIGNLVVL
NLFLALLLSS FSSDNLTAIE EDPDANNLQI AVTRIKKGIN YVKQTLREFI LKAFSKKPKI
SREIRQAEDL NTKKENYISN HTLAEMSKGH NFLKEKDKIS GFGSSVDKHL MEDSDGQSFI
HNPSLTVTVP IAPGESDLEN MNAEELSSDS DSEYSKVRLN RSSSSECSTV DNPLPGEGEE
AEAEPMNSDE PEACFTDGCV WRFSCCQVNI ESGKGKIWWN IRKTCYKIVE HSWFESFIVL
MILLSSGALA FEDIYIERKK TIKIILEYAD KIFTYIFILE MLLKWIAYGY KTYFTNAWCW
LDFLIVDVSL VTLVANTLGY SDLGPIKSLR TLRALRPLRA LSRFEGMRVV VNALIGAIPS
IMNVLLVCLI FWLIFSIMGV NLFAGKFYEC INTTDGSRFP ASQVPNRSEC FALMNVSQNV
RWKNLKVNFD NVGLGYLSLL QVATFKGWTI IMYAAVDSVN VDKQPKYEYS LYMYIYFVVF
IIFGSFFTLN LFIGVIIDNF NQQKKKLGGQ DIFMTEEQKK YYNAMKKLGS KKPQKPIPRP
GNKIQGCIFD LVTNQAFDIS IMVLICLNMV TMMVEKEGQS QHMTEVLYWI NVVFIILFTG
ECVLKLISLR HYYFTVGWNI FDFVVVIISI VGMFLADLIE TYFVSPTLFR VIRLARIGRI
LRLVKGAKGI RTLLFALMMS LPALFNIGLL LFLVMFIYAI FGMSNFAYVK KEDGINDMFN
FETFGNSMIC LFQITTSAGW DGLLAPILNS KPPDCDPKKV HPGSSVEGDC GNPSVGIFYF
VSYIIISFLV VVNMYIAVIL ENFSVATEES TEPLSEDDFE MFYEVWEKFD PDATQFIEFS
KLSDFAAALD PPLLIAKPNK VQLIAMDLPM VSGDRIHCLD ILFAFTKRVL GESGEMDSLR
SQMEERFMSA NPSKVSYEPI TTTLKRKQED VSATVIQRAY RRYRLRQNVK NISSIYIKDG
DRDDDLLNKK DMAFDNVNEN SSPEKTDATS STTSPPSYDS VTKPDKEKYE QDRTEKEDKG
KDSKESKK
