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Protein

Sodium channel protein type 9 subunit alpha

Gene

SCN9A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na+ ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na+ channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784).10 Publications

GO - Molecular functioni

  • sodium ion binding Source: Ensembl
  • voltage-gated sodium channel activity Source: UniProtKB

GO - Biological processi

  • behavioral response to pain Source: Ensembl
  • inflammatory response Source: Ensembl
  • membrane depolarization during action potential Source: GO_Central
  • neuronal action potential Source: GO_Central
  • post-embryonic development Source: Ensembl
  • response to toxic substance Source: Ensembl
  • sensory perception of pain Source: UniProtKB
  • sodium ion transmembrane transport Source: UniProtKB
  • sodium ion transport Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Ion channel, Sodium channel, Voltage-gated channel

Keywords - Biological processi

Ion transport, Sodium transport, Transport

Keywords - Ligandi

Sodium

Enzyme and pathway databases

BioCyciZFISH:ENSG00000169432-MONOMER.
ReactomeiR-HSA-445095. Interaction between L1 and Ankyrins.
R-HSA-5576892. Phase 0 - rapid depolarisation.

Protein family/group databases

TCDBi1.A.1.10.5. the voltage-gated ion channel (vic) superfamily.

Names & Taxonomyi

Protein namesi
Recommended name:
Sodium channel protein type 9 subunit alphaCurated
Alternative name(s):
Neuroendocrine sodium channel1 Publication
Short name:
hNE-Na1 Publication
Peripheral sodium channel 1
Short name:
PN1By similarity
Sodium channel protein type IX subunit alpha
Voltage-gated sodium channel subunit alpha Nav1.7
Gene namesi
Name:SCN9AImported
Synonyms:NENA
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:10597. SCN9A.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 121CytoplasmicSequence analysisAdd BLAST121
Transmembranei122 – 145Helical; Name=S1 of repeat ISequence analysisAdd BLAST24
Topological domaini146 – 153ExtracellularSequence analysis8
Transmembranei154 – 173Helical; Name=S2 of repeat ISequence analysisAdd BLAST20
Topological domaini174 – 186CytoplasmicSequence analysisAdd BLAST13
Transmembranei187 – 205Helical; Name=S3 of repeat ISequence analysisAdd BLAST19
Topological domaini206 – 211ExtracellularSequence analysis6
Transmembranei212 – 231Helical; Voltage-sensor; Name=S4 of repeat ISequence analysisAdd BLAST20
Topological domaini232 – 247CytoplasmicSequence analysisAdd BLAST16
Transmembranei248 – 271Helical; Name=S5 of repeat ISequence analysisAdd BLAST24
Topological domaini272 – 378ExtracellularSequence analysisAdd BLAST107
Transmembranei379 – 404Helical; Name=S6 of repeat ISequence analysisAdd BLAST26
Topological domaini405 – 738CytoplasmicSequence analysisAdd BLAST334
Transmembranei739 – 763Helical; Name=S1 of repeat IISequence analysisAdd BLAST25
Topological domaini764 – 774ExtracellularSequence analysisAdd BLAST11
Transmembranei775 – 798Helical; Name=S2 of repeat IISequence analysisAdd BLAST24
Topological domaini799 – 806CytoplasmicSequence analysis8
Transmembranei807 – 826Helical; Name=S3 of repeat IISequence analysisAdd BLAST20
Topological domaini827 – 832ExtracellularSequence analysis6
Transmembranei833 – 852Helical; Voltage-sensor; Name=S4 of repeat IISequence analysisAdd BLAST20
Topological domaini853 – 868CytoplasmicSequence analysisAdd BLAST16
Transmembranei869 – 889Helical; Name=S5 of repeat IISequence analysisAdd BLAST21
Topological domaini890 – 942ExtracellularSequence analysisAdd BLAST53
Transmembranei943 – 968Helical; Name=S6 of repeat IISequence analysisAdd BLAST26
Topological domaini969 – 1187CytoplasmicSequence analysisAdd BLAST219
Transmembranei1188 – 1211Helical; Name=S1 of repeat IIISequence analysisAdd BLAST24
Topological domaini1212 – 1224ExtracellularSequence analysisAdd BLAST13
Transmembranei1225 – 1250Helical; Name=S2 of repeat IIISequence analysisAdd BLAST26
Topological domaini1251 – 1256CytoplasmicSequence analysis6
Transmembranei1257 – 1278Helical; Name=S3 of repeat IIISequence analysisAdd BLAST22
Topological domaini1279 – 1282ExtracellularSequence analysis4
Transmembranei1283 – 1304Helical; Voltage-sensor; Name=S4 of repeat IIISequence analysisAdd BLAST22
Topological domaini1305 – 1323CytoplasmicSequence analysisAdd BLAST19
Transmembranei1324 – 1351Helical; Name=S5 of repeat IIISequence analysisAdd BLAST28
Topological domaini1352 – 1430ExtracellularSequence analysisAdd BLAST79
Transmembranei1431 – 1457Helical; Name=S6 of repeat IIISequence analysisAdd BLAST27
Topological domaini1458 – 1510CytoplasmicSequence analysisAdd BLAST53
Transmembranei1511 – 1534Helical; Name=S1 of repeat IVSequence analysisAdd BLAST24
Topological domaini1535 – 1545ExtracellularSequence analysisAdd BLAST11
Transmembranei1546 – 1569Helical; Name=S2 of repeat IVSequence analysisAdd BLAST24
Topological domaini1570 – 1575CytoplasmicSequence analysis6
Transmembranei1576 – 1599Helical; Name=S3 of repeat IVSequence analysisAdd BLAST24
Topological domaini1600 – 1609ExtracellularSequence analysis10
Transmembranei1610 – 1631Helical; Voltage-sensor; Name=S4 of repeat IVSequence analysisAdd BLAST22
Topological domaini1632 – 1646CytoplasmicSequence analysisAdd BLAST15
Transmembranei1647 – 1669Helical; Name=S5 of repeat IVSequence analysisAdd BLAST23
Topological domaini1670 – 1735ExtracellularSequence analysisAdd BLAST66
Transmembranei1736 – 1760Helical; Name=S6 of repeat IVSequence analysisAdd BLAST25
Topological domaini1761 – 1988CytoplasmicSequence analysisAdd BLAST228

GO - Cellular componenti

  • cell projection Source: UniProtKB-SubCell
  • integral component of plasma membrane Source: UniProtKB
  • voltage-gated sodium channel complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Membrane

Pathology & Biotechi

Involvement in diseasei

Primary erythermalgia (PERYTHM)8 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands.
See also OMIM:133020
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06459510Q → R in PERYTHM; causes a hyperpolarizing shift of -5.3 mV for the midpoint of activation which is smaller than that seen in other mutations causing early-onset erythromelalgia mutations; also causes a faster rate of activation and slower deactivation compared to wild-type; expression of the mutant protein induced hyperexcitability in dorsal root ganglion neurons but the increase is smaller than that produced by Thr-859. 1 PublicationCorresponds to variant rs267607030dbSNPEnsembl.1
Natural variantiVAR_064598216F → S in PERYTHM; hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation and enhances the response to slow, small depolarizations. 2 PublicationsCorresponds to variant rs80356469dbSNPEnsembl.1
Natural variantiVAR_032014241S → T in PERYTHM. 1 PublicationCorresponds to variant rs80356470dbSNPEnsembl.1
Natural variantiVAR_064600395N → K in PERYTHM. 1 PublicationCorresponds to variant rs80356471dbSNPEnsembl.1
Natural variantiVAR_064601406E → K in PERYTHM. 1
Natural variantiVAR_019947859I → T in PERYTHM; sporadic; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 4 PublicationsCorresponds to variant rs80356474dbSNPEnsembl.1
Natural variantiVAR_064609869L → F in PERYTHM; causes a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation and an 18-fold increase in deactivation time compared to wild-type; the mean ramp current amplitude in response to slow depolarization is higher in the mutant channels. 2 PublicationsCorresponds to variant rs80356476dbSNPEnsembl.1
Natural variantiVAR_019948869L → H in PERYTHM; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 3 PublicationsCorresponds to variant rs80356475dbSNPEnsembl.1
Natural variantiVAR_0320191460F → V in PERYTHM; produces a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation. 1 PublicationCorresponds to variant rs80356478dbSNPEnsembl.1
Natural variantiVAR_0722801643A → E in PERYTHM and PEPD; hyperpolarizes voltage-dependence of channel activation; depolarizes the voltage-dependence of steady-state fast inactivation; slows channel deactivation; enhances persistent and resurgent current; enhances neuronal hyperexcitability in dorsal root ganglion neurons. 2 Publications1
Natural variantiVAR_0722811643A → T in PERYTHM; no effect on voltage-dependence of channel activation; depolarizes the voltage dependence of steady-state fast inactivation; accelerates channel deactivation; no increase in persistent and resurgent currents; enhances neuronal hyperexcitability in dorsal root ganglion neurons. 1 Publication1
Indifference to pain, congenital, autosomal recessive (CIP)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating.
See also OMIM:243000
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064610907R → Q in CIP; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication1
Natural variantiVAR_0646141381 – 1385Missing in CIP; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication5
Paroxysmal extreme pain disorder (PEPD)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing.
See also OMIM:167400
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0320151007R → C in PEPD. 1 PublicationCorresponds to variant rs121908910dbSNPEnsembl.1
Natural variantiVAR_0320161309V → D in PEPD. 1 PublicationCorresponds to variant rs121908911dbSNPEnsembl.1
Natural variantiVAR_0320171309V → F in PEPD. 1 PublicationCorresponds to variant rs121908912dbSNPEnsembl.1
Natural variantiVAR_0320181310V → F in PEPD. 1 PublicationCorresponds to variant rs121908913dbSNPEnsembl.1
Natural variantiVAR_0320201472I → T in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 PublicationCorresponds to variant rs121908914dbSNPEnsembl.1
Natural variantiVAR_0320211473F → V in PEPD. 1 Publication1
Natural variantiVAR_0320221475T → I in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 PublicationCorresponds to variant rs121908915dbSNPEnsembl.1
Natural variantiVAR_0722791623L → P in PEPD; depolarizes the voltage-dependence of channel activation and steady-state fast inactivation; increases ramp current. 1 Publication1
Natural variantiVAR_0320231638M → K in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication1
Natural variantiVAR_0722801643A → E in PERYTHM and PEPD; hyperpolarizes voltage-dependence of channel activation; depolarizes the voltage-dependence of steady-state fast inactivation; slows channel deactivation; enhances persistent and resurgent current; enhances neuronal hyperexcitability in dorsal root ganglion neurons. 2 Publications1
Generalized epilepsy with febrile seizures plus 7 (GEFS+7)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity.
See also OMIM:613863
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_064604641N → Y in GEFS+7. 1 PublicationCorresponds to variant rs121908918dbSNPEnsembl.1
Natural variantiVAR_064605666K → R in GEFS+7; also found in a patient with severe myoclonic epilepsy in infancy. 1 PublicationCorresponds to variant rs121908919dbSNPEnsembl.1
Febrile seizures, familial, 3B (FEB3B)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionSeizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy.
See also OMIM:613863
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06459662I → V in FEB3B. 1 PublicationCorresponds to variant rs121908920dbSNPEnsembl.1
Natural variantiVAR_064597149P → Q in FEB3B. 1 PublicationCorresponds to variant rs121908921dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1490S → A: Abolishes stimulation by agents that stimulate PKC activity. 1 Publication1
Mutagenesisi1490S → D or E: Increases current amplitude. 1 Publication1
Mutagenesisi1643A → D: Depolarizes the voltage-dependence of steady-state fast inactivation; enhances persistent current. 1 Publication1
Mutagenesisi1643A → K: No effect on voltage-dependence of steady-state fast inactivation. 1 Publication1
Mutagenesisi1643A → V: No effect on voltage-dependence of steady-state fast inactivation. 1 Publication1

Keywords - Diseasei

Disease mutation, Epilepsy

Organism-specific databases

DisGeNETi6335.
MalaCardsiSCN9A.
MIMi133020. phenotype.
167400. phenotype.
243000. phenotype.
613863. phenotype.
OpenTargetsiENSG00000169432.
Orphaneti88642. Channelopathy-associated congenital insensitivity to pain.
33069. Dravet syndrome.
1956. Erythromelalgia.
36387. Generalized epilepsy with febrile seizures-plus.
970. Hereditary sensory and autonomic neuropathy type 2.
46348. Paroxysmal extreme pain disorder.
90026. Primary erythermalgia.
306577. Sodium channelopathy-related small fiber neuropathy.
PharmGKBiPA35010.

Chemistry databases

ChEMBLiCHEMBL4296.
DrugBankiDB06218. Lacosamide.
DB00281. Lidocaine.
DB00243. Ranolazine.
DB06201. Rufinamide.
DB00313. Valproic Acid.
DB00909. Zonisamide.
GuidetoPHARMACOLOGYi584.

Polymorphism and mutation databases

BioMutaiSCN9A.
DMDMi327478559.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000485021 – 1988Sodium channel protein type 9 subunit alphaAdd BLAST1988

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi209N-linked (GlcNAc...)Sequence analysis1
Glycosylationi283N-linked (GlcNAc...)Sequence analysis1
Glycosylationi1352N-linked (GlcNAc...)Sequence analysis1
Glycosylationi1366N-linked (GlcNAc...)Sequence analysis1
Glycosylationi1375N-linked (GlcNAc...)Sequence analysis1
Modified residuei1490Phosphoserine; by PKC1 Publication1

Post-translational modificationi

Phosphorylation at Ser-1490 by PKC in a highly conserved cytoplasmic loop increases peak sodium currents.1 Publication
Ubiquitinated by NEDD4L; which may promote its endocytosis. Does not seem to be ubiquitinated by NEDD4.By similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ15858.
PaxDbiQ15858.
PeptideAtlasiQ15858.
PRIDEiQ15858.

PTM databases

iPTMnetiQ15858.
PhosphoSitePlusiQ15858.

Expressioni

Tissue specificityi

Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion.4 Publications

Gene expression databases

BgeeiENSG00000169432.
CleanExiHS_SCN9A.
ExpressionAtlasiQ15858. baseline and differential.
GenevisibleiQ15858. HS.

Organism-specific databases

HPAiCAB013679.
HPA061843.

Interactioni

Subunit structurei

The sodium channel complex consists of a large, channel-forming alpha subunit and 2-3 smaller, ancillary beta subunits (PubMed:7720699, PubMed:17167479, PubMed:25240195). Interacts with NEDD4 and NEDD4L (By similarity).By similarity3 Publications

Protein-protein interaction databases

IntActiQ15858. 2 interactors.
STRINGi9606.ENSP00000386306.

Chemistry databases

BindingDBiQ15858.

Structurei

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5EK0X-ray3.53A/B/C/D1527-1559[»]
A/B/C/D1581-1622[»]
ProteinModelPortaliQ15858.
SMRiQ15858.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati112 – 410ICuratedAdd BLAST299
Repeati726 – 989IICuratedAdd BLAST264
Repeati1180 – 1488IIICuratedAdd BLAST309
Repeati1497 – 1795IVCuratedAdd BLAST299
Domaini1889 – 1918IQAdd BLAST30

Domaini

The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1,S2,S3,S5,S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.1 Publication

Sequence similaritiesi

Contains 1 IQ domain.Curated

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2301. Eukaryota.
ENOG410XNP6. LUCA.
GeneTreeiENSGT00830000128242.
HOVERGENiHBG053100.
InParanoidiQ15858.
KOiK04841.
OMAiVSQNVRW.
OrthoDBiEOG091G00FK.
PhylomeDBiQ15858.
TreeFamiTF323985.

Family and domain databases

Gene3Di1.20.120.350. 4 hits.
InterProiIPR027359. Channel_four-helix_dom.
IPR005821. Ion_trans_dom.
IPR000048. IQ_motif_EF-hand-BS.
IPR001696. Na_channel_asu.
IPR010526. Na_trans_assoc.
IPR024583. Na_trans_cytopl.
IPR028803. SCN9A.
[Graphical view]
PANTHERiPTHR10037:SF221. PTHR10037:SF221. 2 hits.
PfamiPF00520. Ion_trans. 4 hits.
PF06512. Na_trans_assoc. 1 hit.
PF11933. Na_trans_cytopl. 1 hit.
[Graphical view]
PRINTSiPR00170. NACHANNEL.
SMARTiSM00015. IQ. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q15858-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS
60 70 80 90 100
SDLEAGKQLP FIYGDIPPGM VSEPLEDLDP YYADKKTFIV LNKGKTIFRF
110 120 130 140 150
NATPALYMLS PFSPLRRISI KILVHSLFSM LIMCTILTNC IFMTMNNPPD
160 170 180 190 200
WTKNVEYTFT GIYTFESLVK ILARGFCVGE FTFLRDPWNW LDFVVIVFAY
210 220 230 240 250
LTEFVNLGNV SALRTFRVLR ALKTISVIPG LKTIVGALIQ SVKKLSDVMI
260 270 280 290 300
LTVFCLSVFA LIGLQLFMGN LKHKCFRNSL ENNETLESIM NTLESEEDFR
310 320 330 340 350
KYFYYLEGSK DALLCGFSTD SGQCPEGYTC VKIGRNPDYG YTSFDTFSWA
360 370 380 390 400
FLALFRLMTQ DYWENLYQQT LRAAGKTYMI FFVVVIFLGS FYLINLILAV
410 420 430 440 450
VAMAYEEQNQ ANIEEAKQKE LEFQQMLDRL KKEQEEAEAI AAAAAEYTSI
460 470 480 490 500
RRSRIMGLSE SSSETSKLSS KSAKERRNRR KKKNQKKLSS GEEKGDAEKL
510 520 530 540 550
SKSESEDSIR RKSFHLGVEG HRRAHEKRLS TPNQSPLSIR GSLFSARRSS
560 570 580 590 600
RTSLFSFKGR GRDIGSETEF ADDEHSIFGD NESRRGSLFV PHRPQERRSS
610 620 630 640 650
NISQASRSPP MLPVNGKMHS AVDCNGVVSL VDGRSALMLP NGQLLPEVII
660 670 680 690 700
DKATSDDSGT TNQIHKKRRC SSYLLSEDML NDPNLRQRAM SRASILTNTV
710 720 730 740 750
EELEESRQKC PPWWYRFAHK FLIWNCSPYW IKFKKCIYFI VMDPFVDLAI
760 770 780 790 800
TICIVLNTLF MAMEHHPMTE EFKNVLAIGN LVFTGIFAAE MVLKLIAMDP
810 820 830 840 850
YEYFQVGWNI FDSLIVTLSL VELFLADVEG LSVLRSFRLL RVFKLAKSWP
860 870 880 890 900
TLNMLIKIIG NSVGALGNLT LVLAIIVFIF AVVGMQLFGK SYKECVCKIN
910 920 930 940 950
DDCTLPRWHM NDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVYMM
960 970 980 990 1000
VMVIGNLVVL NLFLALLLSS FSSDNLTAIE EDPDANNLQI AVTRIKKGIN
1010 1020 1030 1040 1050
YVKQTLREFI LKAFSKKPKI SREIRQAEDL NTKKENYISN HTLAEMSKGH
1060 1070 1080 1090 1100
NFLKEKDKIS GFGSSVDKHL MEDSDGQSFI HNPSLTVTVP IAPGESDLEN
1110 1120 1130 1140 1150
MNAEELSSDS DSEYSKVRLN RSSSSECSTV DNPLPGEGEE AEAEPMNSDE
1160 1170 1180 1190 1200
PEACFTDGCV WRFSCCQVNI ESGKGKIWWN IRKTCYKIVE HSWFESFIVL
1210 1220 1230 1240 1250
MILLSSGALA FEDIYIERKK TIKIILEYAD KIFTYIFILE MLLKWIAYGY
1260 1270 1280 1290 1300
KTYFTNAWCW LDFLIVDVSL VTLVANTLGY SDLGPIKSLR TLRALRPLRA
1310 1320 1330 1340 1350
LSRFEGMRVV VNALIGAIPS IMNVLLVCLI FWLIFSIMGV NLFAGKFYEC
1360 1370 1380 1390 1400
INTTDGSRFP ASQVPNRSEC FALMNVSQNV RWKNLKVNFD NVGLGYLSLL
1410 1420 1430 1440 1450
QVATFKGWTI IMYAAVDSVN VDKQPKYEYS LYMYIYFVVF IIFGSFFTLN
1460 1470 1480 1490 1500
LFIGVIIDNF NQQKKKLGGQ DIFMTEEQKK YYNAMKKLGS KKPQKPIPRP
1510 1520 1530 1540 1550
GNKIQGCIFD LVTNQAFDIS IMVLICLNMV TMMVEKEGQS QHMTEVLYWI
1560 1570 1580 1590 1600
NVVFIILFTG ECVLKLISLR HYYFTVGWNI FDFVVVIISI VGMFLADLIE
1610 1620 1630 1640 1650
TYFVSPTLFR VIRLARIGRI LRLVKGAKGI RTLLFALMMS LPALFNIGLL
1660 1670 1680 1690 1700
LFLVMFIYAI FGMSNFAYVK KEDGINDMFN FETFGNSMIC LFQITTSAGW
1710 1720 1730 1740 1750
DGLLAPILNS KPPDCDPKKV HPGSSVEGDC GNPSVGIFYF VSYIIISFLV
1760 1770 1780 1790 1800
VVNMYIAVIL ENFSVATEES TEPLSEDDFE MFYEVWEKFD PDATQFIEFS
1810 1820 1830 1840 1850
KLSDFAAALD PPLLIAKPNK VQLIAMDLPM VSGDRIHCLD ILFAFTKRVL
1860 1870 1880 1890 1900
GESGEMDSLR SQMEERFMSA NPSKVSYEPI TTTLKRKQED VSATVIQRAY
1910 1920 1930 1940 1950
RRYRLRQNVK NISSIYIKDG DRDDDLLNKK DMAFDNVNEN SSPEKTDATS
1960 1970 1980
STTSPPSYDS VTKPDKEKYE QDRTEKEDKG KDSKESKK
Length:1,988
Mass (Da):226,372
Last modified:April 5, 2011 - v3
Checksum:i1BAEB8F32EBF5438
GO
Isoform 2 (identifier: Q15858-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     200-229: YLTEFVNLGNVSALRTFRVLRALKTISVIP → YVTEFVDLGNVSALRTFRVLRALKTISVIP

Show »
Length:1,988
Mass (Da):226,359
Checksum:i8C9066AD56148C02
GO
Isoform 3 (identifier: Q15858-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     648-658: Missing.

Show »
Length:1,977
Mass (Da):225,227
Checksum:i8B2BD5CF665F11A8
GO
Isoform 4 (identifier: Q15858-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     200-229: YLTEFVNLGNVSALRTFRVLRALKTISVIP → YVTEFVDLGNVSALRTFRVLRALKTISVIP
     648-658: Missing.

Show »
Length:1,977
Mass (Da):225,214
Checksum:i1701A8F994ADBC06
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti267F → S in AAT85834 (PubMed:15302875).Curated1
Sequence conflicti301K → R in AAT85835 (PubMed:15302875).Curated1
Sequence conflicti309S → P in AAT85834 (PubMed:15302875).Curated1
Sequence conflicti420E → G in AAT85834 (PubMed:15302875).Curated1
Sequence conflicti430L → P in AAT85834 (PubMed:15302875).Curated1
Sequence conflicti501S → P in AAT85835 (PubMed:15302875).Curated1
Sequence conflicti610P → T in AAT85835 (PubMed:15302875).Curated1
Sequence conflicti642G → R in AAT85835 (PubMed:15302875).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06459510Q → R in PERYTHM; causes a hyperpolarizing shift of -5.3 mV for the midpoint of activation which is smaller than that seen in other mutations causing early-onset erythromelalgia mutations; also causes a faster rate of activation and slower deactivation compared to wild-type; expression of the mutant protein induced hyperexcitability in dorsal root ganglion neurons but the increase is smaller than that produced by Thr-859. 1 PublicationCorresponds to variant rs267607030dbSNPEnsembl.1
Natural variantiVAR_06459662I → V in FEB3B. 1 PublicationCorresponds to variant rs121908920dbSNPEnsembl.1
Natural variantiVAR_064597149P → Q in FEB3B. 1 PublicationCorresponds to variant rs121908921dbSNPEnsembl.1
Natural variantiVAR_064598216F → S in PERYTHM; hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation and enhances the response to slow, small depolarizations. 2 PublicationsCorresponds to variant rs80356469dbSNPEnsembl.1
Natural variantiVAR_064599228I → M.1 PublicationCorresponds to variant rs71428908dbSNPEnsembl.1
Natural variantiVAR_032014241S → T in PERYTHM. 1 PublicationCorresponds to variant rs80356470dbSNPEnsembl.1
Natural variantiVAR_064600395N → K in PERYTHM. 1 PublicationCorresponds to variant rs80356471dbSNPEnsembl.1
Natural variantiVAR_064601406E → K in PERYTHM. 1
Natural variantiVAR_064602490S → N.1 PublicationCorresponds to variant rs58022607dbSNPEnsembl.1
Natural variantiVAR_064603519E → K.1 PublicationCorresponds to variant rs187453572dbSNPEnsembl.1
Natural variantiVAR_064604641N → Y in GEFS+7. 1 PublicationCorresponds to variant rs121908918dbSNPEnsembl.1
Natural variantiVAR_064605666K → R in GEFS+7; also found in a patient with severe myoclonic epilepsy in infancy. 1 PublicationCorresponds to variant rs121908919dbSNPEnsembl.1
Natural variantiVAR_064606695I → M.1 PublicationCorresponds to variant rs199588089dbSNPEnsembl.1
Natural variantiVAR_064607710C → Y Found in a patient with severe myoclonic epilepsy in infancy. 1 PublicationCorresponds to variant rs201709980dbSNPEnsembl.1
Natural variantiVAR_064608750I → V.1 PublicationCorresponds to variant rs182650126dbSNPEnsembl.1
Natural variantiVAR_019947859I → T in PERYTHM; sporadic; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 4 PublicationsCorresponds to variant rs80356474dbSNPEnsembl.1
Natural variantiVAR_064609869L → F in PERYTHM; causes a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation and an 18-fold increase in deactivation time compared to wild-type; the mean ramp current amplitude in response to slow depolarization is higher in the mutant channels. 2 PublicationsCorresponds to variant rs80356476dbSNPEnsembl.1
Natural variantiVAR_019948869L → H in PERYTHM; activated at more negative potentials; slower inactivation kinetics than wild-type channels. 3 PublicationsCorresponds to variant rs80356475dbSNPEnsembl.1
Natural variantiVAR_064610907R → Q in CIP; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication1
Natural variantiVAR_030444932M → L.Corresponds to variant rs12478318dbSNPEnsembl.1
Natural variantiVAR_055646943M → L.Corresponds to variant rs12478318dbSNPEnsembl.1
Natural variantiVAR_0320151007R → C in PEPD. 1 PublicationCorresponds to variant rs121908910dbSNPEnsembl.1
Natural variantiVAR_0646111134L → F.1 PublicationCorresponds to variant rs200160858dbSNPEnsembl.1
Natural variantiVAR_0199491161W → R.3 PublicationsCorresponds to variant rs6746030dbSNPEnsembl.1
Natural variantiVAR_0646121171E → Q Found in a patient with severe myoclonic epilepsy in infancy. 1 Publication1
Natural variantiVAR_0646131278L → V.1 PublicationCorresponds to variant rs180922748dbSNPEnsembl.1
Natural variantiVAR_0320161309V → D in PEPD. 1 PublicationCorresponds to variant rs121908911dbSNPEnsembl.1
Natural variantiVAR_0320171309V → F in PEPD. 1 PublicationCorresponds to variant rs121908912dbSNPEnsembl.1
Natural variantiVAR_0320181310V → F in PEPD. 1 PublicationCorresponds to variant rs121908913dbSNPEnsembl.1
Natural variantiVAR_0646141381 – 1385Missing in CIP; significant reduction in membrane localization of the mutant protein compared to the wild-type; complete loss of function of the sodium channel. 1 Publication5
Natural variantiVAR_0320191460F → V in PERYTHM; produces a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation. 1 PublicationCorresponds to variant rs80356478dbSNPEnsembl.1
Natural variantiVAR_0320201472I → T in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 PublicationCorresponds to variant rs121908914dbSNPEnsembl.1
Natural variantiVAR_0320211473F → V in PEPD. 1 Publication1
Natural variantiVAR_0320221475T → I in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 PublicationCorresponds to variant rs121908915dbSNPEnsembl.1
Natural variantiVAR_0722791623L → P in PEPD; depolarizes the voltage-dependence of channel activation and steady-state fast inactivation; increases ramp current. 1 Publication1
Natural variantiVAR_0320231638M → K in PEPD; reduction in fast inactivation leading to persistent sodium current. 1 Publication1
Natural variantiVAR_0722801643A → E in PERYTHM and PEPD; hyperpolarizes voltage-dependence of channel activation; depolarizes the voltage-dependence of steady-state fast inactivation; slows channel deactivation; enhances persistent and resurgent current; enhances neuronal hyperexcitability in dorsal root ganglion neurons. 2 Publications1
Natural variantiVAR_0722811643A → T in PERYTHM; no effect on voltage-dependence of channel activation; depolarizes the voltage dependence of steady-state fast inactivation; accelerates channel deactivation; no increase in persistent and resurgent currents; enhances neuronal hyperexcitability in dorsal root ganglion neurons. 1 Publication1
Natural variantiVAR_0199501919D → G.Corresponds to variant rs3750904dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_012028200 – 229YLTEF…ISVIP → YVTEFVDLGNVSALRTFRVL RALKTISVIP in isoform 2 and isoform 4. 1 PublicationAdd BLAST30
Alternative sequenceiVSP_012029648 – 658Missing in isoform 3 and isoform 4. 3 PublicationsAdd BLAST11

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82835 mRNA. Translation: CAA58042.1.
DQ857292 mRNA. Translation: ABI51981.1.
AC074101 Genomic DNA. No translation available.
AC107082 Genomic DNA. No translation available.
AC108146 Genomic DNA. No translation available.
AY682084 mRNA. Translation: AAT85833.1.
AY682085 mRNA. Translation: AAT85834.1.
AY682086 mRNA. Translation: AAT85835.1.
AJ310882 mRNA. Translation: CAC84550.1.
AJ310883 mRNA. Translation: CAC84551.1.
AJ310897 mRNA. Translation: CAC84537.1.
AJ580918 Genomic DNA. Translation: CAE45644.1.
AJ580919 Genomic DNA. Translation: CAE45645.1.
CCDSiCCDS46441.1. [Q15858-3]
PIRiS54771.
RefSeqiNP_002968.1. NM_002977.3.
XP_005246814.1. XM_005246757.2. [Q15858-1]
XP_011509918.1. XM_011511616.2. [Q15858-1]
XP_011509919.1. XM_011511617.2. [Q15858-2]
XP_011509920.1. XM_011511618.2. [Q15858-4]
UniGeneiHs.439145.

Genome annotation databases

EnsembliENST00000303354; ENSP00000304748; ENSG00000169432. [Q15858-1]
ENST00000409435; ENSP00000386330; ENSG00000169432. [Q15858-1]
ENST00000409672; ENSP00000386306; ENSG00000169432. [Q15858-3]
GeneIDi6335.
KEGGihsa:6335.
UCSCiuc002udr.2. human. [Q15858-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Wikipedia

SCN9A entry

Protein Spotlight

Silent pain - Issue 102 of February 2009

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X82835 mRNA. Translation: CAA58042.1.
DQ857292 mRNA. Translation: ABI51981.1.
AC074101 Genomic DNA. No translation available.
AC107082 Genomic DNA. No translation available.
AC108146 Genomic DNA. No translation available.
AY682084 mRNA. Translation: AAT85833.1.
AY682085 mRNA. Translation: AAT85834.1.
AY682086 mRNA. Translation: AAT85835.1.
AJ310882 mRNA. Translation: CAC84550.1.
AJ310883 mRNA. Translation: CAC84551.1.
AJ310897 mRNA. Translation: CAC84537.1.
AJ580918 Genomic DNA. Translation: CAE45644.1.
AJ580919 Genomic DNA. Translation: CAE45645.1.
CCDSiCCDS46441.1. [Q15858-3]
PIRiS54771.
RefSeqiNP_002968.1. NM_002977.3.
XP_005246814.1. XM_005246757.2. [Q15858-1]
XP_011509918.1. XM_011511616.2. [Q15858-1]
XP_011509919.1. XM_011511617.2. [Q15858-2]
XP_011509920.1. XM_011511618.2. [Q15858-4]
UniGeneiHs.439145.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5EK0X-ray3.53A/B/C/D1527-1559[»]
A/B/C/D1581-1622[»]
ProteinModelPortaliQ15858.
SMRiQ15858.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ15858. 2 interactors.
STRINGi9606.ENSP00000386306.

Chemistry databases

BindingDBiQ15858.
ChEMBLiCHEMBL4296.
DrugBankiDB06218. Lacosamide.
DB00281. Lidocaine.
DB00243. Ranolazine.
DB06201. Rufinamide.
DB00313. Valproic Acid.
DB00909. Zonisamide.
GuidetoPHARMACOLOGYi584.

Protein family/group databases

TCDBi1.A.1.10.5. the voltage-gated ion channel (vic) superfamily.

PTM databases

iPTMnetiQ15858.
PhosphoSitePlusiQ15858.

Polymorphism and mutation databases

BioMutaiSCN9A.
DMDMi327478559.

Proteomic databases

EPDiQ15858.
PaxDbiQ15858.
PeptideAtlasiQ15858.
PRIDEiQ15858.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000303354; ENSP00000304748; ENSG00000169432. [Q15858-1]
ENST00000409435; ENSP00000386330; ENSG00000169432. [Q15858-1]
ENST00000409672; ENSP00000386306; ENSG00000169432. [Q15858-3]
GeneIDi6335.
KEGGihsa:6335.
UCSCiuc002udr.2. human. [Q15858-1]

Organism-specific databases

CTDi6335.
DisGeNETi6335.
GeneCardsiSCN9A.
GeneReviewsiSCN9A.
HGNCiHGNC:10597. SCN9A.
HPAiCAB013679.
HPA061843.
MalaCardsiSCN9A.
MIMi133020. phenotype.
167400. phenotype.
243000. phenotype.
603415. gene.
613863. phenotype.
neXtProtiNX_Q15858.
OpenTargetsiENSG00000169432.
Orphaneti88642. Channelopathy-associated congenital insensitivity to pain.
33069. Dravet syndrome.
1956. Erythromelalgia.
36387. Generalized epilepsy with febrile seizures-plus.
970. Hereditary sensory and autonomic neuropathy type 2.
46348. Paroxysmal extreme pain disorder.
90026. Primary erythermalgia.
306577. Sodium channelopathy-related small fiber neuropathy.
PharmGKBiPA35010.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2301. Eukaryota.
ENOG410XNP6. LUCA.
GeneTreeiENSGT00830000128242.
HOVERGENiHBG053100.
InParanoidiQ15858.
KOiK04841.
OMAiVSQNVRW.
OrthoDBiEOG091G00FK.
PhylomeDBiQ15858.
TreeFamiTF323985.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000169432-MONOMER.
ReactomeiR-HSA-445095. Interaction between L1 and Ankyrins.
R-HSA-5576892. Phase 0 - rapid depolarisation.

Miscellaneous databases

GeneWikiiNav1.7.
GenomeRNAii6335.
PROiQ15858.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000169432.
CleanExiHS_SCN9A.
ExpressionAtlasiQ15858. baseline and differential.
GenevisibleiQ15858. HS.

Family and domain databases

Gene3Di1.20.120.350. 4 hits.
InterProiIPR027359. Channel_four-helix_dom.
IPR005821. Ion_trans_dom.
IPR000048. IQ_motif_EF-hand-BS.
IPR001696. Na_channel_asu.
IPR010526. Na_trans_assoc.
IPR024583. Na_trans_cytopl.
IPR028803. SCN9A.
[Graphical view]
PANTHERiPTHR10037:SF221. PTHR10037:SF221. 2 hits.
PfamiPF00520. Ion_trans. 4 hits.
PF06512. Na_trans_assoc. 1 hit.
PF11933. Na_trans_cytopl. 1 hit.
[Graphical view]
PRINTSiPR00170. NACHANNEL.
SMARTiSM00015. IQ. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSCN9A_HUMAN
AccessioniPrimary (citable) accession number: Q15858
Secondary accession number(s): A1BUH5
, Q6B4R9, Q6B4S0, Q6B4S1, Q70HX1, Q70HX2, Q8WTU1, Q8WWN4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 23, 2004
Last sequence update: April 5, 2011
Last modified: November 2, 2016
This is version 157 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.