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1.A.1.10.5
Voltage-sensitive Na+ channel, type 9, α-subunit, Nav1.7 or SCN9A (orthologous to 1.A.1.10.1). Loss of function, resulting from point mutations, results in a channelopathy called Congenital Insensitivity to Pain (CIP) (He et al. 2018), that causes the congenital inability to experience pain (Cregg et al., 2010; Kleopa, 2011). An S241T mutation causes inherited erythromelalgia IEM; erythermalgia, an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth (due to altered gating) (Lampert et al., 2006; Drenth and Waxman, 2007). Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain (Dib-Hajj et al., 2007). Blocked by 1-benzazepin-2-one (Kd = 1.6 nM) (Williams et al., 2007). Mutations in the Nav1.7 Na channel α-subunit give rise to familial pain syndromes called chronic non-paoxysmal neuropathic pain (Catterall et al., 2008; Fischer and Waxman, 2010; Dabby et al. 2011 ). It interacts with the sodium channel beta3 (Scn3b), rather than the beta1 subunit, as well as the collapsing-response mediator protein (Crmp2) through which the analgesic drug lacosamide regulates Nav1.7 current (Kanellopoulos et al. 2018). The R1488 variant is totally inactive (He et al. 2018). Nav1.7 is inhibited by knottins (see TC# 8.B.19.2) (Agwa et al. 2018). Nav1.7 interacts with the following proteins: syn3b (TC# 8.a.17.1.2; the β3 subunit), Crmp2, Syt2 (Q8N9I0) and Tmed10 (P49755), and it also regulates opioid receptor efficacy (Kanellopoulos et al. 2018). Mutations in TRPA1 and Nav1.7 to  insensitivity to pain-promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019). Nav1.7 is associated with endometrial cancer (Liu et al. 2019) and fever-associated seizures or epilepsy (FASE) (Ding et al. 2019). Nav1.7 and Nav1.8 peripheral nerve sodium channels are modulated by protein kinases A and C (Vijayaragavan et al. 2004).

Accession Number:Q15858
Protein Name:Sodium channel protein type 9 subunit alpha
Length:1988
Molecular Weight:226342.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:22
Location1 / Topology2 / Orientation3: Membrane1 / Multi-pass membrane protein2
Substrate sodium(1+)

Cross database links:

RefSeq: NP_002968.1   
Entrez Gene ID: 6335   
Pfam: PF00520    PF06512   
OMIM: 133020  phenotype
167400  phenotype
243000  phenotype
603415  gene
KEGG: hsa:6335   

Gene Ontology

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

References (12)

[1] “Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.”  Klugbauer N.et.al.   7720699
[2] “An SCN9A channelopathy causes congenital inability to experience pain.”  Cox J.J.et.al.   17167479
[3] “Expression of alternatively spliced sodium channel alpha-subunit genes: unique splicing patterns are observed in dorsal root ganglia.”  Raymond C.K.et.al.   15302875
[4] “Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.”  Yang Y.et.al.   14985375
[5] “A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia.”  Sangameswaran L.et.al.   9169448
[6] “Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A.”  Jo T.et.al.   15178348
[7] “Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra.”  Yu L.-R.et.al.   17924679
[8] “Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy.”  Cummins T.R.et.al.   15385606
[9] “Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha subunit Nav1.7.”  Michiels J.J.et.al.   16216943
[10] “Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons.”  Dib-Hajj S.D.et.al.   15958509
[11] “SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.”  Fertleman C.R.et.al.   17145499
[12] “A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons.”  Rush A.M.et.al.   16702558
Structure:
5EK0   6J8G   6J8H   6J8I   6J8J   6N4Q   6N4R   6NT3   6NT4   6VXO   [...more]

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Predict TMSs (Predict number of transmembrane segments)
Window Size: Angle:  
FASTA formatted sequence 
1:	MAMLPPPGPQ SFVHFTKQSL ALIEQRIAER KSKEPKEEKK DDDEEAPKPS SDLEAGKQLP 
61:	FIYGDIPPGM VSEPLEDLDP YYADKKTFIV LNKGKTIFRF NATPALYMLS PFSPLRRISI 
121:	KILVHSLFSM LIMCTILTNC IFMTMNNPPD WTKNVEYTFT GIYTFESLVK ILARGFCVGE 
181:	FTFLRDPWNW LDFVVIVFAY LTEFVNLGNV SALRTFRVLR ALKTISVIPG LKTIVGALIQ 
241:	SVKKLSDVMI LTVFCLSVFA LIGLQLFMGN LKHKCFRNSL ENNETLESIM NTLESEEDFR 
301:	KYFYYLEGSK DALLCGFSTD SGQCPEGYTC VKIGRNPDYG YTSFDTFSWA FLALFRLMTQ 
361:	DYWENLYQQT LRAAGKTYMI FFVVVIFLGS FYLINLILAV VAMAYEEQNQ ANIEEAKQKE 
421:	LEFQQMLDRL KKEQEEAEAI AAAAAEYTSI RRSRIMGLSE SSSETSKLSS KSAKERRNRR 
481:	KKKNQKKLSS GEEKGDAEKL SKSESEDSIR RKSFHLGVEG HRRAHEKRLS TPNQSPLSIR 
541:	GSLFSARRSS RTSLFSFKGR GRDIGSETEF ADDEHSIFGD NESRRGSLFV PHRPQERRSS 
601:	NISQASRSPP MLPVNGKMHS AVDCNGVVSL VDGRSALMLP NGQLLPEVII DKATSDDSGT 
661:	TNQIHKKRRC SSYLLSEDML NDPNLRQRAM SRASILTNTV EELEESRQKC PPWWYRFAHK 
721:	FLIWNCSPYW IKFKKCIYFI VMDPFVDLAI TICIVLNTLF MAMEHHPMTE EFKNVLAIGN 
781:	LVFTGIFAAE MVLKLIAMDP YEYFQVGWNI FDSLIVTLSL VELFLADVEG LSVLRSFRLL 
841:	RVFKLAKSWP TLNMLIKIIG NSVGALGNLT LVLAIIVFIF AVVGMQLFGK SYKECVCKIN 
901:	DDCTLPRWHM NDFFHSFLIV FRVLCGEWIE TMWDCMEVAG QAMCLIVYMM VMVIGNLVVL 
961:	NLFLALLLSS FSSDNLTAIE EDPDANNLQI AVTRIKKGIN YVKQTLREFI LKAFSKKPKI 
1021:	SREIRQAEDL NTKKENYISN HTLAEMSKGH NFLKEKDKIS GFGSSVDKHL MEDSDGQSFI 
1081:	HNPSLTVTVP IAPGESDLEN MNAEELSSDS DSEYSKVRLN RSSSSECSTV DNPLPGEGEE 
1141:	AEAEPMNSDE PEACFTDGCV RRFSCCQVNI ESGKGKIWWN IRKTCYKIVE HSWFESFIVL 
1201:	MILLSSGALA FEDIYIERKK TIKIILEYAD KIFTYIFILE MLLKWIAYGY KTYFTNAWCW 
1261:	LDFLIVDVSL VTLVANTLGY SDLGPIKSLR TLRALRPLRA LSRFEGMRVV VNALIGAIPS 
1321:	IMNVLLVCLI FWLIFSIMGV NLFAGKFYEC INTTDGSRFP ASQVPNRSEC FALMNVSQNV 
1381:	RWKNLKVNFD NVGLGYLSLL QVATFKGWTI IMYAAVDSVN VDKQPKYEYS LYMYIYFVVF 
1441:	IIFGSFFTLN LFIGVIIDNF NQQKKKLGGQ DIFMTEEQKK YYNAMKKLGS KKPQKPIPRP 
1501:	GNKIQGCIFD LVTNQAFDIS IMVLICLNMV TMMVEKEGQS QHMTEVLYWI NVVFIILFTG 
1561:	ECVLKLISLR HYYFTVGWNI FDFVVVIISI VGMFLADLIE TYFVSPTLFR VIRLARIGRI 
1621:	LRLVKGAKGI RTLLFALMMS LPALFNIGLL LFLVMFIYAI FGMSNFAYVK KEDGINDMFN 
1681:	FETFGNSMIC LFQITTSAGW DGLLAPILNS KPPDCDPKKV HPGSSVEGDC GNPSVGIFYF 
1741:	VSYIIISFLV VVNMYIAVIL ENFSVATEES TEPLSEDDFE MFYEVWEKFD PDATQFIEFS 
1801:	KLSDFAAALD PPLLIAKPNK VQLIAMDLPM VSGDRIHCLD ILFAFTKRVL GESGEMDSLR 
1861:	SQMEERFMSA NPSKVSYEPI TTTLKRKQED VSATVIQRAY RRYRLRQNVK NISSIYIKDG 
1921:	DRDDDLLNKK DMAFDNVNEN SSPEKTDATS STTSPPSYDS VTKPDKEKYE QDRTEKEDKG 
1981:	KDSKESKK