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Nav1.7

Family: Voltage-gated sodium channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Gating Inhibitors
Pore Blockers
Tissue Distribution
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 1977 2q24 SCN9A sodium channel, voltage-gated, type IX, alpha subunit 43
Mouse 24 1 1975 2 C1.3 Scn9a sodium channel, voltage-gated, type IX, alpha 2,44
Rat 24 1 1984 3q21 Scn9a sodium channel, voltage-gated, type IX, alpha 54,59
Previous and Unofficial Names
PN1
hNE-Na
Nas
Nav1.7
NaS
NE-NA
NENA
ETHA
sodium channel, voltage-gated, type IX, alpha polypeptide
Scn2a
peripheral sodium channel 1
sodium channel protein type 9 subunit alpha
sodium channel protein type IX subunit alpha
sodium channel type IX alpha polypeptide
sodium channel voltage-gated type IX alpha polypeptide
sodium channel, voltage-gated, type 9, alpha polypeptide
sodium channel, voltage-gated, type IX, alpha
voltage-gated sodium channel subunit alpha Nav1.7
Database Links
ChEMBL Target 18061 (Hs)
DrugBank Target 1995 (Hs)
Ensembl ENSG00000169432 (Hs), ENSMUSG00000075316 (Mm), ENSRNOG00000006639 (Rn)
Entrez Gene 6335 (Hs), 20274 (Mm), 78956 (Rn)
GeneCards SCN9A (Hs)
GenitoUrinary Development Molecular Anatomy Project Scn9a (Mm)
HomoloGene 2237 (Hs)
Human Protein Reference Database 04565 (Hs)
InterPro Q15858 (Hs), Q62205 (Mm), O08562 (Rn)
KEGG Gene hsa:6335 (Hs), mmu:20274 (Mm), rno:78956 (Rn)
OMIM 603415 (Hs)
Orphanet Gene ORPHA118525 (Hs)
PharmGKB Gene PA35010 (Hs)
PhosphoSitePlus Q15858 (Hs), Q62205 (Mm), O08562 (Rn)
Protein Ontology (PRO) PRO:000002104 (Hs)
RefSeq Nucleotide NM_002977 (Hs), NM_018852 (Mm), NM_133289 (Rn)
RefSeq Protein NP_002968 (Hs), NP_061340 (Mm), NP_579823 (Rn)
TreeFam ENSG00000169432 (Hs), ENSMUSG00000075316 (Mm), ENSRNOG00000006639 (Rn)
UniGene Hs. 699185 (Hs)
UniProt Q15858 (Hs), Q62205 (Mm), O08562 (Rn)
Wikipedia Nav1.7
Voltage-gated sodium channels
Search for 3D structures on the PDB
Search by keyword: Voltage-gated sodium channels Nav1.7 Search by accession number: Q62205, Q15858, O08562
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
β2 26,40
β1 28,39,48
Other Associated Proteins
Name References
Not determined
Ion Selectivity and Conductance
Species:  Rat
Rank order:  Na+ [- pS]
References:  53
Species:  Rat
Single channel conductance (pS):  19.5
References:  53
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -24.6 - 17 HEK 293 cells. Human
Inactivation  -73.6 1.0 17
Comments  This is a human channel with a TTX resistant mutation (Y362S).
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -27.3 0.1 9 Nav1.8 null mouse DRG neurons. Human
Inactivation  -71.3 1.0 9
Comments  Human channel with a TTX resistant mutation (Y362S), kinetics measured at 10mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -25.6 – -27.9 (median: -26.0) - 9,60 Xenopus laevis oocyte Rat
Inactivation  -61.9 – -68.4 (median: -67.0) 1.0 – 429.0 9,60
Gating inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
N-Me-aminopyrimidinone 9 Hs 7.1 pIC50 - - 51
Gating Inhibitor Comments
Scorpion toxins are known inhibitors of Nav1.7 for example the α-scorpion toxins (Odonthobuthus doriae) [47] and other scopion toxins (Lqh-2 and Lqh-3) [5].
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
XEN907 Hs 8.52 pIC50 - - 14
tetrodotoxin Rn 8.4 pIC50 - -100.0 54
tetrodotoxin Hs 7.6 pIC50 - -100.0 43
pyrrolopyrimidine 48 Hs 6.96 pIC50 - - 4
lidocaine Rn 3.3 pIC50 - -100.0 9
Cd2+ Hs 3.0 pIC50 - -100.0 43
View species-specific pore blocker tables
Tissue Distribution
All types of DRG neurons, sympathetic neurons, Schwann cells and neuroendocrine cells.
Species:  Rat
Technique:  In situ hybridisation
References:  29
All types of DRG neurons, sympathetic neurons, Schwann cells and neuroendorcrine cells.
Species:  Rat
Technique:  Northern Blot
References:  43
All types of DRG neurons, sympathetic neurons, Schwann cells and neuroendocrine cells.
Species:  Rat
Technique:  RT-PCR
References:  54
Physiological Consequences of Altering Gene Expression
Epilepsy
Species:  Mouse
Tissue: 
Technique:  Knock-in of N641Y
References:  56
Minett et al. suggest that NaV1.7 in sympathetic ganglion neurons is essential for neuropathic pain
Species:  Mouse
Tissue:  DRG-neuron, sympathetic ganglion neurons
Technique:  Cell type-specific knockout
References:  50
NaV1.7 is essential for heat pain after burning injuries
Species:  Mouse
Tissue:  DRG neurons
Technique:  Knockout
References:  55
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Scn9atm1.1Naas Scn9atm1.1Naas/Scn9atm1.1Naas
B6.129-Scn9a		 MGI:107636  MP:0001499 abnormal kindling response PMID: 19763161 
Scn10a+|Scn10atm2(cre)Jnw|Scn9atm1Jnw Scn10atm2(cre)Jnw/Scn10a+,Scn9atm1Jnw/Scn9atm1Jnw
involves: 129		 MGI:107636  MGI:108029  MP:0002736 abnormal nociception after inflammation PMID: 15314237 
Scn10a+|Scn10atm2(cre)Jnw|Scn9atm1Jnw Scn10atm2(cre)Jnw/Scn10a+,Scn9atm1Jnw/Scn9atm1Jnw
involves: 129		 MGI:107636  MGI:108029  MP:0001970 abnormal pain threshold PMID: 15314237 
Scn9atm1.1Naas Scn9atm1.1Naas/Scn9atm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J		 MGI:107636  MP:0001650 abnormal seizure response to electrical stimulation PMID: 19763161 
Scn9a+|Scn9atm1Dgen Scn9atm1Dgen/Scn9a+
involves: 129P2/OlaHsd * C57BL/6		 MGI:107636  MP:0009141 increased prepulse inhibition
Scn10a+|Scn10atm2(cre)Jnw|Scn9atm1Jnw Scn10atm2(cre)Jnw/Scn10a+,Scn9atm1Jnw/Scn9atm1Jnw
involves: 129		 MGI:107636  MGI:108029  MP:0001973 increased thermal nociceptive threshold PMID: 15314237 
Scn9atm1.1Naas Scn9atm1.1Naas/Scn9atm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J		 MGI:107636  MP:0002193 minimal clonic seizures PMID: 19763161 
Scn9atm1.1Jnw Scn9atm1.1Jnw/Scn9atm1.1Jnw
involves: 129		 MGI:107636  MP:0002058 neonatal lethality PMID: 15314237 
Scn9atm1Dgen Scn9atm1Dgen/Scn9atm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:107636  MP:0002081 perinatal lethality
Clinically-Relevant Mutations and Pathophysiology
Disease:  Febrile seizures
OMIM:  613863
References: 
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human N461Y 56
Disease:  Small-Fiber Peripheral Neuropathy
OMIM:  133020
Orphanet:  118525
References: 
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human D623N 27
Missense Human I720K 27
Missense Human M932L/V991L 27
Missense Human M1532I 27
Missense Human I739V 34
Missense Human I228M 24
Missense Human R185H 35
Disease:  Acromesomelia (small hands and feet) and painful neuropathy
References: 
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human G856D 38
Disease:  Human SNP that increases sensitivity to pain
OMIM:  243000
References: 
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human R1150W 25,52
Disease:  Erythermalgia
OMIM:  133020
Orphanet:  90026
Role:  Nav1.7 mutations cause burning pain and flushing of the extremities.
References:  12,15,18,20,49,61-62
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human F1449V 20
Missense Human A863P 37
Missense Human L858F 21,36
Missense Human P610T 21
Missense Human N395K 21
Missense Human F216S 12,21
Missense Human S241T 46,49
Missense Human I848T 17,21
Missense Human G823R 45
Missense Human Del-955 6
Missense Human L858H 17
Missense Human A1632E 23
Missense Human M1136V 7
Missense Human Q10R 33
Missense Human V400M 31
Missense Human V872G 13
Missense Human G616R 11
Missense Human P1308L 8
Missense Human S241P 22
Missense Human I234T 1
Disease:  Congenital inability to experience pain
OMIM:  243000
Orphanet:  88642
Role:  Mutations in Nav lead to an insensitivity to pain (without peripheral nerve pathology).
References:  16,32
Click column headers to sort
Type Species Molecular location Description Reference
Compound mutation Human C1719R & IVS17+3delA 57
Truncation Human W897X 16
Truncation Human K767X 16
Truncation Human S459X 16
Truncation Human Y328X 32
Truncation Human R277X 32
Disease:  Paroxysmal Extreme Pain Disorder (PEPD)
OMIM:  167400
Orphanet:  46348
Role:  Mutations in Nav1.7 lead to periods of rectal, ocular, or submandibular pain with flushing.
References:  3,10,30
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human T1464I 30
Missense Human F1462V 30
Missense Human V1298D 30
Missense Human R996C 30
Missense Human M1627K 19,30
Missense Human I1461T 30,41-42
Missense Human V1299F 30,58
Missense Human V1298F 8,30
Missense Human G1607R 10
Disease:  Epilepsy, generalized, with febrile seizures plus, type 7; GEFSP7
OMIM:  613863
Orphanet:  36387
References: 
Mutations not determined

REFERENCES

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1. Ahn, HS; Dib-Hajj, SD; Cox, JJ; Tyrrell, L; Elmslie, FV; Clarke, AA; Drenth, JP; Woods, CG; Waxman, SG. (2010) A new Nav1.7 sodium channel mutation I234T in a child with severe pain. Eur J Pain, 14 (9): 944-50. [PMID:20385509]

2. Beckers, MC; Ernst, E; Belcher, S; Howe, J; Levenson, R; Gros, P. (1996) A new sodium channel alpha-subunit gene (Scn9a) from Schwann cells maps to the Scn1a, Scn2a, Scn3a cluster of mouse chromosome 2. Genomics, 36 (1): 202-5. [PMID:8812438]

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5. Chen, H; Lu, S; Leipold, E; Gordon, D; Hansel, A; Heinemann, SH. (2002) Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3. Eur. J. Neurosci., 16 (4): 767-70. [PMID:12270053]

6. Cheng, X; Dib-Hajj, SD; Tyrrell, L; Te Morsche, RH; Drenth, JP; Waxman, SG. (2011) Deletion mutation of sodium channel Na(V)1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability. Brain, 134 (Pt 7): 1972-86. [PMID:21705421]

7. Cheng, X; Dib-Hajj, SD; Tyrrell, L; Waxman, SG. (2008) Mutation I136V alters electrophysiological properties of the Na(v)1.7 channel in a family with onset of erythromelalgia in the second decade. Mol Pain, 4: 1. [PMID:18171466]

8. Cheng, X; Dib-Hajj, SD; Tyrrell, L; Wright, DA; Fischer, TZ; Waxman, SG. (2010) Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders. Mol Pain, 6: 24. [PMID:20429905]

9. Chevrier, P; Vijayaragavan, K; Chahine, M. (2004) Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br. J. Pharmacol., 142 (3): 576-84. [PMID:15148257]

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12. Choi, JS; Dib-Hajj, SD; Waxman, SG. (2006) Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy. Neurology, 67 (9): 1563-7. [PMID:16988069]

13. Choi, JS; Zhang, L; Dib-Hajj, SD; Han, C; Tyrrell, L; Lin, Z; Wang, X; Yang, Y; Waxman, SG. (2009) Mexiletine-responsive erythromelalgia due to a new Na(v)1.7 mutation showing use-dependent current fall-off. Exp. Neurol., 216 (2): 383-9. [PMID:19162012]

14. Chowdhury, S; Chafeev, M; Liu, S; Sun, J; Raina, V; Chui, R; Young, W; Kwan, R; Fu, J; Cadieux, JA. (2011) Discovery of XEN907, a spirooxindole blocker of NaV1.7 for the treatment of pain. Bioorg. Med. Chem. Lett., 21 (12): 3676-81. [PMID:21570288]

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17. Cummins, TR; Dib-Hajj, SD; Waxman, SG. (2004) Electrophysiological properties of mutant Nav1.7 sodium channels in a painful inherited neuropathy. J. Neurosci., 24 (38): 8232-6. [PMID:15385606]

18. Dib-Hajj, SD; Cummins, TR; Black, JA; Waxman, SG. (2010) Sodium channels in normal and pathological pain. Annu. Rev. Neurosci., 33: 325-47. [PMID:20367448]

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20. Dib-Hajj, SD; Rush, AM; Cummins, TR; Hisama, FM; Novella, S; Tyrrell, L; Marshall, L; Waxman, SG. (2005) Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain, 128 (Pt 8): 1847-54. [PMID:15958509]

21. Drenth, JP; te Morsche, RH; Guillet, G; Taieb, A; Kirby, RL; Jansen, JB. (2005) SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J. Invest. Dermatol., 124 (6): 1333-8. [PMID:15955112]

22. Estacion, M; Choi, JS; Eastman, EM; Lin, Z; Li, Y; Tyrrell, L; Yang, Y; Dib-Hajj, SD; Waxman, SG. (2010) Can robots patch-clamp as well as humans? Characterization of a novel sodium channel mutation. J. Physiol. (Lond.), 588 (Pt 11): 1915-27. [PMID:20123784]

23. Estacion, M; Dib-Hajj, SD; Benke, PJ; Te Morsche, RH; Eastman, EM; Macala, LJ; Drenth, JP; Waxman, SG. (2008) NaV1.7 gain-of-function mutations as a continuum: A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci., 28 (43): 11079-88. [PMID:18945915]

24. Estacion, M; Han, C; Choi, JS; Hoeijmakers, JG; Lauria, G; Drenth, JP; Gerrits, MM; Dib-Hajj, SD; Faber, CG; Merkies, IS; et al.. (2011) Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7. Mol Pain, 7: 92. [PMID:22136189]

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31. Fischer, TZ; Gilmore, ES; Estacion, M; Eastman, E; Taylor, S; Melanson, M; Dib-Hajj, SD; Waxman, SG. (2009) A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia. Ann. Neurol., 65 (6): 733-41. [PMID:19557861]

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33. Han, C; Dib-Hajj, SD; Lin, Z; Li, Y; Eastman, EM; Tyrrell, L; Cao, X; Yang, Y; Waxman, SG. (2009) Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain, 132 (Pt 7): 1711-22. [PMID:19369487]

34. Han, C; Hoeijmakers, JG; Ahn, HS; Zhao, P; Shah, P; Lauria, G; Gerrits, MM; te Morsche, RH; Dib-Hajj, SD; Drenth, JP; et al.. (2012) Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. Neurology, 78 (21): 1635-43. [PMID:22539570]

35. Han, C; Hoeijmakers, JG; Liu, S; Gerrits, MM; te Morsche, RH; Lauria, G; Dib-Hajj, SD; Drenth, JP; Faber, CG; Merkies, IS; et al.. (2012) Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy. Brain, 135 (Pt 9): 2613-28. [PMID:22826602]

36. Han, C; Rush, AM; Dib-Hajj, SD; Li, S; Xu, Z; Wang, Y; Tyrrell, L; Wang, X; Yang, Y; Waxman, SG. (2006) Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann. Neurol., 59 (3): 553-8. [PMID:16392115]

37. Harty, TP; Dib-Hajj, SD; Tyrrell, L; Blackman, R; Hisama, FM; Rose, JB; Waxman, SG. (2006) Na(V)1.7 mutant A863P in erythromelalgia: effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons. J. Neurosci., 26 (48): 12566-75. [PMID:17135418]

38. Hoeijmakers, JG; Han, C; Merkies, IS; Macala, LJ; Lauria, G; Gerrits, MM; Dib-Hajj, SD; Faber, CG; Waxman, SG. (2012) Small nerve fibres, small hands and small feet: a new syndrome of pain, dysautonomia and acromesomelia in a kindred with a novel NaV1.7 mutation. Brain, 135 (Pt 2): 345-58. [PMID:22286749]

39. Isom, LL; De Jongh, KS; Patton, DE; Reber, BF; Offord, J; Charbonneau, H; Walsh, K; Goldin, AL; Catterall, WA. (1992) Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science, 256 (5058): 839-42. [PMID:1375395]

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41. Jarecki, BW; Sheets, PL; Jackson, JO; Cummins, TR. (2008) Paroxysmal extreme pain disorder mutations within the D3/S4-S5 linker of Nav1.7 cause moderate destabilization of fast inactivation. J. Physiol. (Lond.), 586 (Pt 17): 4137-53. [PMID:18599537]

42. Jarecki, BW; Sheets, PL; Xiao, Y; Jackson, JO; Cummins, TR. (2009) Alternative splicing of Na(V)1.7 exon 5 increases the impact of the painful PEPD mutant channel I1461T. Channels (Austin), 3 (4): 259-67. [PMID:19633428]

43. Klugbauer, N; Lacinova, L; Flockerzi, V; Hofmann, F. (1995) Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J., 14 (6): 1084-90. [PMID:7720699]

44. Kozak, CA; Sangameswaran, L. (1996) Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse. Mamm. Genome, 7 (10): 787-8. [PMID:8854872]

45. Lampert, A; Dib-Hajj, SD; Eastman, EM; Tyrrell, L; Lin, Z; Yang, Y; Waxman, SG. (2009) Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials. Biochem. Biophys. Res. Commun., 390 (2): 319-24. [PMID:19800314]

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To cite this database page, please use the following:

William A. Catterall, Alan L. Goldin, Stephen G. Waxman.
Voltage-gated sodium channels: Nav1.7. Last modified on 04/01/2013. Accessed on 23/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=584.


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