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Nav1.8

Family: Voltage-gated sodium channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Activators
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 1956 3p22-p21 SCN10A sodium channel, voltage-gated, type X, alpha subunit 29
Mouse 24 1 1957 9 F4 Scn10a sodium channel, voltage-gated, type X, alpha
Rat 24 1 1957 8q32 Scn10a sodium channel, voltage-gated, type X, alpha subunit
Previous and Unofficial Names
PN3
SNS
Nav1.8
hPN3
sodium channel, voltage-gated, type X, alpha polypeptide
Na(V)1.8
peripheral nerve sodium channel 3
sensory neuron sodium channel
sodium channel protein type 10 subunit alpha
sodium channel protein type X subunit alpha
sodium channel type X alpha polypeptide
sodium channel voltage-gated type X alpha polypeptide
sodium channel, voltage-gated, type 10, alpha polypeptide
sodium channel, voltage-gated, type X, alpha
voltage-gated sodium channel subunit alpha Nav1.8
Database Links
ChEMBL Target 18080 (Hs), 101093 (Mm), 12545 (Rn)
DrugBank Target 198 (Hs)
Ensembl ENSG00000185313 (Hs), ENSMUSG00000034533 (Mm), ENSRNOG00000032473 (Rn)
Entrez Gene 6336 (Hs), 20264 (Mm), 29571 (Rn)
GeneCards SCN10A (Hs)
GenitoUrinary Development Molecular Anatomy Project Scn10a (Mm)
HomoloGene 21300 (Hs)
Human Protein Reference Database 09188 (Hs)
InterPro Q9Y5Y9 (Hs), Q6QIY3 (Mm), Q62968 (Rn)
KEGG Gene hsa:6336 (Hs), mmu:20264 (Mm), rno:29571 (Rn)
OMIM 604427 (Hs)
PharmGKB Gene PA35000 (Hs)
PhosphoSitePlus Q9Y5Y9 (Hs), Q6QIY3 (Mm)
Protein Ontology (PRO) PRO:000002096 (Hs)
RefSeq Nucleotide NM_006514 (Hs), NM_009134 (Mm), NM_017247 (Rn)
RefSeq Protein NP_006505 (Hs), NP_033160 (Mm), NP_058943 (Rn)
TreeFam ENSG00000185313 (Hs), ENSMUSG00000034533 (Mm), ENSRNOG00000032473 (Rn)
UniGene Hs. 250443 (Hs)
UniProt Q9Y5Y9 (Hs), Q6QIY3 (Mm), Q62968 (Rn)
Wikipedia Nav1.8
Voltage-gated sodium channels
Search for 3D structures on the PDB
Search by keyword: Voltage-gated sodium channels Nav1.8 Search by accession number: Q62968, Q6QIY3, Q9Y5Y9
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
β1, β2, β3 29
Other Associated Proteins
Name References
CAP-1 19
AnnexinI/p11 21
Associated Protein Comments
AnnexinI/p11 facilitates insertion of channels into the cell membrane [21] and CAP-1 regulates uptake from the cell membrane [19].
Ion Selectivity and Conductance Comments
From the original measurements of the slow, TTX-resistant sodium current in dorsal root ganglion neurons (which we know now is due to Nav1.8), we can conclude that this channel is selective for Na over K and Ca (Na+ > K+>> Ca2+) like all other sodium channels. There are no comparable measurements on cloned channels that have been published. [15] “Selectivity measurements were made on Nav1.8 channels conducting the slow TTX-resistant sodium current of dorsal root ganglion neurons.”
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -15.7 0.36 – 0.54 9 DRG neurons Rat
Inactivation  -30.9 4.7 – 13.5 9
Comments  τ varies for both activation and inactivation depending on the voltage at which it is measured.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  10.3 - 29 Xenopus laevis oocyte Rat
Inactivation  -52.9 – -30.0 - 1,29
Comments  The values above are for Nav1.8 expressed alone. V0.5,act for Nav1.8 expressed with β subunits is between 1.6 and 11.5mV and for V0.5,inact is between -46.6 and -58.4mV.
Activators
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
veratridine Rn - - 5x10-7 - 5x10-5 -90.0 14
batrachotoxin Hs - - 5x10-6 - 1x10-5 -90.0 7
View species-specific activator tables
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
A-803467 Rn 8.1 pIC50 - - 18
tetrodotoxin Rn 4.2 pIC50 - -60.0 1
lidocaine Rn 4.0 pIC50 - -100.0 17
Pore Blocker Comments
Lignocaine produces 41% block at 1mM [1].
Tissue Distribution
>90% of nociceptors and 40% of myelinated A-fibres including low-threshold mechanoreceptors
Species:  Mouse
Technique:  Analysis in NaV1.8-Cre mice
References:  26
Small and medium diameter DRG neurons and their axons.
Species:  Rat
Technique:  Immunohistochemistry
References:  12
Functional Assays
Current clamp.
Species:  Rat
Tissue:  Dorsal root ganglion.
Response measured:  Contribution to action potential electrogenesis
References:  6,22
Voltage clamp recording.
Species:  Rat
Tissue:  Dorsal root ganglion.
Response measured:  voltage-clamp parameters within DRG neurons.
References:  2,9
Voltage clamp recording
Species:  Rat
Tissue:  Oocyte
Response measured:  Voltage clamp parameters in oocytes
References:  1
Physiological Functions
Nav1.8 contributes the majority of the inward current underlying the depolarizing phase of the action potential.
Species:  Rat
Tissue:  Dorsal root ganglion (DRG) neurons
References:  6,22
Nav1.8 supports repetitive firing in depolarized neurons.
Species:  Rat
Tissue:  DRG neurons
References:  22
Physiological Consequences of Altering Gene Expression
Nav1.8-null mice exhibit reduced pain responses.
Species:  Mouse
Tissue:  Nervous system.
Technique:  Knockout mouse
References:  3
NaV1.8 upregulation within cerebellar Purkinje neurons produces deficits in cerebellar function
Species:  Mouse
Tissue: 
Technique:  Transgenic mouse
References: 
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Scn10atm1Lex Scn10atm1Lex/Scn10atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:108029  MP:0005402 abnormal action potential PMID: 16857712 
Scn10atm1Jnw Scn10atm1Jnw/Scn10atm1Jnw
B6.129P2-Scn10a		 MGI:108029  MP:0002734 abnormal mechanical nociception PMID: 10448219 
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 
S100a10tm1Jnw|Scn10a+|Scn10atm2(cre)Jnw S100a10tm1Jnw/S100a10tm1Jnw,Scn10atm2(cre)Jnw/Scn10a+
involves: 129 * C57BL/6		 MGI:108029  MGI:1339468  MP:0001970 abnormal pain threshold PMID: 17035534 
Scn10atm1Lex Scn10atm1Lex/Scn10atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:108029  MP:0001970 abnormal pain threshold PMID: 19931571 
Scn10atm1Jnw Scn10atm1Jnw/Scn10atm1Jnw
B6.129P2-Scn10a		 MGI:108029  MP:0002733 abnormal thermal nociception PMID: 10448219 
S100a10tm1Jnw|Scn10a+|Scn10atm2(cre)Jnw S100a10tm1Jnw/S100a10tm1Jnw,Scn10atm2(cre)Jnw/Scn10a+
involves: 129 * C57BL/6		 MGI:108029  MGI:1339468  MP:0003177 allodynia PMID: 17035534 
S100a10tm1Jnw|Scn10a+|Scn10atm2(cre)Jnw S100a10tm1Jnw/S100a10tm1Jnw,Scn10atm2(cre)Jnw/Scn10a+
involves: 129 * C57BL/6		 MGI:108029  MGI:1339468  MP:0003469 decreased single cell response intensity PMID: 17035534 
Scn10atm1Lex Scn10atm1Lex/Scn10atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:108029  MP:0005407 hyperalgesia PMID: 19931571 
Scn10atm1Jnw Scn10atm1Jnw/Scn10atm1Jnw
B6.129P2-Scn10a		 MGI:108029  MP:0003043 hypoalgesia PMID: 10448219 
Scn10atm1Lex Scn10atm1Lex/Scn10atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:108029  MP:0002578 impaired ability to fire action potentials PMID: 16857712 
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 
Clinically-Relevant Mutations and Pathophysiology
Role:  Removal of TTX resistance.
References:  27
Click column headers to sort
Type Species Molecular location Description Reference
Missense Rat S356F 27
Disease:  Small Fiber Neuropathy
References:  13
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human A1304T 13
Missense Human L554P 13
Disease:  Multiple sclerosis
Role:  Nav mRNA and protein are upregulated within cerebellar Purkinje neurons in both humans and mouse models of multiple sclerosis, where they may produce abnormal patterns of firing which may be contributing to ataxia.
References:  5,23-24
Mutations not determined
Disease:  Functional dyspepsia
Role:  Multiple polymorphisms reported to be associated with functional dyspepsia
References:  4
Mutations not determined
Clinically-Relevant Mutations and Pathophysiology Comments
Rapid recovery from inactivation is conferred by a three amino acid insert in D IV S3-S4 [11]
Gene Expression and Pathophysiology
Nav1.8 is upregulated in models of inflammatory pain and by inflammatory mediators.
Tissue or cell type:  DRG neurons.
Pathophysiology:  Inflammatory pain.
Species:  Rat
Technique:  In situ hybridization and electrophysiology.
References:  8,16,25,28
Nav1.8 protein is translocated to the axon following peripheral nerve injury.
Tissue or cell type:  DRG neurons
Pathophysiology:  Peripheral nerve injury.
Species:  Rat
Technique:  Immunohistochemistry
References:  20,30
Nav1.8 expression decreases following axotomy.
Tissue or cell type:  DRG neurons.
Pathophysiology:  Peripheral nerve injury.
Species:  Rat
Technique:  RT-PCR
References:  10
Nav1.8 mRNA and protein are upregulated within cerebellar Purkinje neurons.
Tissue or cell type:  Cerebellar Purkinje neurons.
Pathophysiology:  Chronic relapsing experimental allergic encephalomyelitis (modelling multiple sclerosis).
Species:  Mouse
Technique:  In situ hybridization and immunocytochemistry.
References:  5
Nav1.8 mRNA and protein are upregulated within cerebellar Purkinje neurons.
Tissue or cell type:  Cerebellar Purkinje neurons.
Pathophysiology:  Multiple sclerosis.
Species:  Human
Technique:  In situ hybridization and immunocytochemistry.
References:  5

REFERENCES

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1. Akopian, AN; Sivilotti, L; Wood, JN. (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 379 (6562): 257-62. [PMID:8538791]

2. Akopian, AN; Sivilotti, L; Wood, JN. (1996) A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature, 379 (6562): 257-62. [PMID:11007885]

3. Akopian, AN; Souslova, V; England, S; Okuse, K; Ogata, N; Ure, J; Smith, A; Kerr, BJ; McMahon, SB; Boyce, S; Hill, R; Stanfa, LC; Dickenson, AH; Wood, JN. (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat. Neurosci., 2 (6): 541-8. [PMID:10448219]

4. Arisawa, T; Tahara, T; Shiroeda, H; Minato, T; Matsue, Y; Saito, T; Fukuyama, T; Otsuka, T; Fukumura, A; Nakamura, M; et al.. (2012) Genetic polymorphisms of SCN10A are associated with functional dyspepsia in Japanese subjects. J. Gastroenterol.,  [Epub ahead of print]. [PMID:22618805]

5. Black, JA; Dib-Hajj, S; Baker, D; Newcombe, J; Cuzner, ML; Waxman, SG. (2000) Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A., 97 (21): 11598-602. [PMID:11027357]

6. Blair, NT; Bean, BP. (2002) Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci., 22 (23): 10277-90. [PMID:12451128]

7. Bosmans, F; Maertens, C; Verdonck, F; Tytgat, J. (2004) The poison Dart frog's batrachotoxin modulates Nav1.8. FEBS Lett., 577 (1-2): 245-8. [PMID:15527793]

8. Cardenas, CG; Del Mar, LP; Cooper, BY; Scroggs, RS. (1997) 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. J. Neurosci., 17 (19): 7181-9. [PMID:9295364]

9. Cummins, TR; Waxman, SG. (1997) Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J. Neurosci., 17 (10): 3503-14. [PMID:9133375]

10. Dib-Hajj, S; Black, JA; Felts, P; Waxman, SG. (1996) Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc. Natl. Acad. Sci. U.S.A., 93 (25): 14950-4. [PMID:8962162]

11. Dib-Hajj, SD; Ishikawa, K; Cummins, TR; Waxman, SG. (1997) Insertion of a SNS-specific tetrapeptide in S3-S4 linker of D4 accelerates recovery from inactivation of skeletal muscle voltage-gated Na channel mu1 in HEK293 cells. FEBS Lett., 416 (1): 11-4. [PMID:9369222]

12. Djouhri, L; Fang, X; Okuse, K; Wood, JN; Berry, CM; Lawson, SN. (2003) The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J. Physiol. (Lond.), 550 (Pt 3): 739-52. [PMID:12794175]

13. Faber, CG; Lauria, G; Merkies, IS; Cheng, X; Han, C; Ahn, HS; Persson, AK; Hoeijmakers, JG; Gerrits, MM; Pierro, T; et al.. (2012) Gain-of-function Nav1.8 mutations in painful neuropathy. Proc. Natl. Acad. Sci. U.S.A., 109 (47): 19444-9. [PMID:23115331]

14. Farrag, KJ; Bhattacharjee, A; Docherty, RJ. (2008) A comparison of the effects of veratridine on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in isolated rat dorsal root ganglion neurons. Pflugers Arch., 455 (5): 929-38. [PMID:17962978]

15. Fedulova, SA; Kostyuk, PG; Veselovsky, NS. (1991) Ionic mechanisms of electrical excitability in rat sensory neurons during postnatal ontogenesis. Neuroscience, 41 (1): 303-9. [PMID:1647504]

16. Gold, MS; Levine, JD; Correa, AM. (1998) Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons in vitro. J. Neurosci., 18 (24): 10345-55. [PMID:9852572]

17. How, SW; Cheng, AL. (1992) Present status of cancer treatment in Taiwan. Gan To Kagaku Ryoho, 19 (8 Suppl): 1136-8. [PMID:1514825]

18. Jarvis, MF; Honore, P; Shieh, CC; Chapman, M; Joshi, S; Zhang, XF; Kort, M; Carroll, W; Marron, B; Atkinson, R; et al.. (2007) A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U.S.A., 104 (20): 8520-5. [PMID:17483457]

19. Liu C, Cummins TR, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD. (2005) CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Na(v)1.8. Mol Cell Neurosci., 28 (4): 636-649. [PMID:15797711]

20. Novakovic, SD; Tzoumaka, E; McGivern, JG; Haraguchi, M; Sangameswaran, L; Gogas, KR; Eglen, RM; Hunter, JC. (1998) Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic conditions. J. Neurosci., 18 (6): 2174-87. [PMID:9482802]

21. Okuse, K; Malik-Hall, M; Baker, MD; Poon, WY; Kong, H; Chao, MV; Wood, JN. (2002) Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature, 417 (6889): 653-6. [PMID:12050667]

22. Renganathan, M; Cummins, TR; Waxman, SG. (2001) Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. J. Neurophysiol., 86 (2): 629-40. [PMID:11495938]

23. Renganathan, M; Gelderblom, M; Black, JA; Waxman, SG. (2003) Expression of Nav1.8 sodium channels perturbs the firing patterns of cerebellar Purkinje cells. Brain Res., 959 (2): 235-42. [PMID:12493611]

24. Saab, CY; Craner, MJ; Kataoka, Y; Waxman, SG. (2004) Abnormal Purkinje cell activity in vivo in experimental allergic encephalomyelitis. Exp Brain Res, 158 (1): 1-8. [PMID:15118796]

25. Saab, CY; Cummins, TR; Waxman, SG. (2003) GTP gamma S increases Nav1.8 current in small-diameter dorsal root ganglia neurons. Exp Brain Res, 152 (4): 415-9. [PMID:12898089]

26. Shields, SD; Ahn, HS; Yang, Y; Han, C; Seal, RP; Wood, JN; Waxman, SG; Dib-Hajj, SD. (2012) Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain, 153 (10): 2017-30. [PMID:22703890]

27. Sivilotti, L; Okuse, K; Akopian, AN; Moss, S; Wood, JN. (1997) A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS. FEBS Lett., 409 (1): 49-52. [PMID:9199502]

28. Tanaka, M; Cummins, TR; Ishikawa, K; Dib-Hajj, SD; Black, JA; Waxman, SG. (1998) SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport, 9 (6): 967-72. [PMID:9601651]

29. Vijayaragavan, K; Powell, AJ; Kinghorn, IJ; Chahine, M. (2004) Role of auxiliary beta1-, beta2-, and beta3-subunits and their interaction with Na(v)1.8 voltage-gated sodium channel. Biochem. Biophys. Res. Commun., 319 (2): 531-40. [PMID:15178439]

30. Yiangou, Y; Birch, R; Sangameswaran, L; Eglen, R; Anand, P. (2000) SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett., 467 (2-3): 249-52. [PMID:10675548]

To cite this database page, please use the following:

William A. Catterall, Alan L. Goldin, Stephen G. Waxman.
Voltage-gated sodium channels: Nav1.8. Last modified on 04/01/2013. Accessed on 21/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=585.


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