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Nav1.9

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Target not currently curated in GtoImmuPdb

Target id: 586

Nomenclature: Nav1.9

Family: Voltage-gated sodium channels (NaV)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 1791 3p22.2 SCN11A sodium voltage-gated channel alpha subunit 11 5
Mouse 24 1 1765 9 71.33 cM Scn11a sodium channel, voltage-gated, type XI, alpha 6
Rat 24 1 1765 8q32 Scn11a sodium voltage-gated channel alpha subunit 11 4
Previous and Unofficial Names Click here for help
NaN | SNS2 | SCN12A | sensory neuron sodium channel 2 | sodium channel protein type 11 subunit alpha | NaT | NSS2 | sodium channel, voltage-gated, type XI, alpha subunit | sodium channel, voltage gated, type XI alpha subunit | sodium channel
Database Links Click here for help
Alphafold Q9UI33 (Hs), Q9R053 (Mm), O88457 (Rn)
ChEMBL Target CHEMBL5167 (Hs), CHEMBL4523482 (Mm), CHEMBL2629 (Rn)
DrugBank Target Q9UI33 (Hs)
Ensembl Gene ENSG00000168356 (Hs), ENSMUSG00000034115 (Mm), ENSRNOG00000032884 (Rn)
Entrez Gene 11280 (Hs), 24046 (Mm), 29701 (Rn)
Human Protein Atlas ENSG00000168356 (Hs)
KEGG Gene hsa:11280 (Hs), mmu:24046 (Mm), rno:29701 (Rn)
OMIM 604385 (Hs)
Orphanet ORPHA328924 (Hs)
Pharos Q9UI33 (Hs)
RefSeq Nucleotide NM_014139 (Hs), NM_011887 (Mm), NM_019265 (Rn)
RefSeq Protein NP_054858 (Hs), NP_036017 (Mm), NP_062138 (Rn)
UniProtKB Q9UI33 (Hs), Q9R053 (Mm), O88457 (Rn)
Wikipedia SCN11A (Hs)
Functional Characteristics Click here for help
Activation V0.5 = -32 mV. Slow inactivation (16 ms)
Ion Selectivity and Conductance Comments
Ion selectivity ranks as follows: Na+>K+>>Ca2+for Nav1.9, as for other sodium channels[2896,77].
Voltage Dependence Click here for help
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -48.0 – -46.0 - 3 DRG neurons Mouse
Inactivation  -45.0 – -43.0 39.0 – 47.0 3
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -45.0 - 5 DRG neurons Human
Inactivation  - -
Comments  Values for human derived in presence of flouride.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -32.0 2.0 15 Neurons (myenteric plexus) Rat
Inactivation  -31.0 12.0 – 101.0 15
Comments  Values for myenteric plexus derived in absence of fluoride. Values shift to the left by approximately 20mV in the presence of fluoride. Ultraslow inactivation (V1/2 = -56mV) turns off 50% of channels at -60mV [15].
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -54.0 – -47.0 2.9 – 4.1 3,11 DRG neurons Rat
Inactivation  -54.0 – -44.0 43.0 – 843.0 3,11
Comments  This channel has prominent ultraslow inactivation; τrecovery =16s at -120 mV; 97% of channels are ultraslow inactivated at -60mV [3].

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Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
tetrodotoxin Small molecule or natural product Click here for species-specific activity table Rn Pore blocker 4.4 pIC50 - -120.0 3
⤷ pIC50 4.4 (IC50 3.9x10-5 M) [3]
Holding voltage: -120.0 mV
Tissue Distribution Click here for help
Preferential distribution in myenteric plexus neurons.
Species:  Rat
Technique:  RT-PCR
References:  15
Preferential distribution in c-type DRG neruons, trigeminal neurons and their axons.
Species:  Rat
Technique:  Immunohistochemistry
References:  4-5,7-8
Functional Assays Click here for help
Patch-clamp electrophysiology demonstrates a TTX-resistant, persistent sodium current with broad overlap between activation and steady-state inactivation.
Species:  Rat
Tissue:  DRG neurons
Response measured: 
References:  3
There is limited expression of NaV1.9 in heterologous systems that is caused by the C-terminal structure of NaV1.9. The authors describe a chimera of NaV1.9 harboring the C-terminus of NaV1.4 which yields functional expression (although with accelerated activation and inactivation) not only in neuronal cells but also in non-excitable cells, such as HEK 293T or Xenopus oocytes. Since the entire transmembrane domain is preserved, it is suited for studying pharmacological properties of the channel and the functional impact of disease-causing mutations.
Species:  None
Tissue: 
Response measured: 
References:  9
Expression of wild-type and mutant NaV1.9 mutant channels in superior cervical ganglion neurons, which do not produce endogenous NaV1.8 or NaV1.9 currents, provides a novel platform where NaV1.9 is expressed at relatively high (nA) levels that facilitate voltage-clamp analysis.
Species:  None
Tissue: 
Response measured: 
References:  10
Physiological Functions Click here for help
Nav1.9 contributes a depolarising influence at resting potential, and amplifies and prolongs slow subthreshold depolarisations and increases excitability.
Species:  Rat
Tissue:  DRG neurons
References:  2,11
Physiological Consequences of Altering Gene Expression Click here for help
Nav1.9 is upregulated by GTP and inflammatory mediators such as PGE2.
Species:  Mouse
Tissue:  DRG neurons
Technique:  Voltage-clamp electrophysiology
References:  2,16
Studies in null mutants suggest that Nav1.9 plays a role in inflammatory pain responses. Nav1.9 null mice show decreased inflammation-induced pain hypersensitivity.
Species:  Mouse
Tissue:  Peripheral nociceptive neurons
Technique:  Knockout.
References:  1,14
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Scn11atm1Lex Scn11atm1Lex/Scn11atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:1345149  MP:0002734 abnormal mechanical nociception PMID: 19931571 
Scn11atm1Mdba Scn11atm1Mdba/Scn11atm1Mdba
involves: C57BL/6		 MGI:1345149  MP:0002272 abnormal nervous system electrophysiology PMID: 18096591 
Scn11atm1Dgen Scn11atm1Dgen/Scn11atm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:1345149  MP:0002736 abnormal nociception after inflammation PMID: 15964986 
Scn11a+|Scn11atm1Dgen Scn11atm1Dgen/Scn11a+
involves: 129P2/OlaHsd * C57BL/6		 MGI:1345149  MP:0002736 abnormal nociception after inflammation PMID: 15964986 
Scn11atm1Wlf Scn11atm1Wlf/Scn11atm1Wlf
B6.Cg-Scn11a		 MGI:1345149  MP:0002736 abnormal nociception after inflammation PMID: 17167076 
Scn11atm1Lex Scn11atm1Lex/Scn11atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:1345149  MP:0002736 abnormal nociception after inflammation PMID: 19931571 
Scn11atm1Lex Scn11atm1Lex/Scn11atm1Lex
involves: 129S5/SvEvBrd * C57BL/6		 MGI:1345149  MP:0001970 abnormal pain threshold PMID: 19931571 
Scn11atm1Wlf Scn11atm1Wlf/Scn11atm1Wlf
B6.Cg-Scn11a		 MGI:1345149  MP:0003463 abnormal single cell response PMID: 17167076 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Episodic pain syndrome, familial, 3; FEPS3
Description: Autosomal dominant, episodic distal limb pain felt as extremely cold, accompanied by sweating, triggered by fatigue, relieved by anti-inflammatory medications.
Synonyms: Familial episodic pain syndrome [Orphanet: ORPHA391384]
Familial episodic pain syndrome with predominantly lower limb involvement [Orphanet: ORPHA391392]
OMIM: 615552
Orphanet: ORPHA391384, ORPHA391392
Role:  The I381T mutation shifts activation 6.9mV negative, and slows deactivation. The mutation shifts inactivation in depolarizing direction by 13.3mV. Increased overlap between activation and inactivation increases predicted window current. DRG neurons expressing the mutant channel display depolarized (5.5mV) resting potential, decreased current threshold, increased frequency of firing, and spontaneous activity.
References:  12
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R225C c.673C>T Mutation associated with increased current density. DRG neurons expressing mutant channel display increased firing frequency and spontaneous firing. 17
Missense Human I381T c.1142T>C Mutation associated with painful peripheral neuropathy. Mutation hyperpolarizes activation by 6.9 mV, depolarizes inactivation by 13.3 mV, and slows deactivation. Mutant channels produce hyperexcitability and spontaneous firing in DRG neurons. 12
Missense Human A808G c.2423C>G Mutation associated with increased current density. DRG neurons expressing mutant channel display increased firing frequency and spontaneous firing. 17
Missense Human L1158P c.3473T>C Mutation associated with painful small-fiber neuropathy. Mutation hyperpolarizes activation by 6.7 mV and slows deactivation. Mutant channels produce hyperexcitability in DRG neurons. 12
Disease:  Neuropathy, hereditary sensory and autonomic, type VII; HSAN7
Synonyms: Hereditary sensory and autonomic neuropathy [Disease Ontology: DOID:11533]
Hereditary sensory and autonomic neuropathy type 7 [Orphanet: ORPHA391397]
Disease Ontology: DOID:11533
OMIM: 615548
Orphanet: ORPHA391397
Role:  The L811P mutation hyperpolarises activation by -26mV, and slows deactivation in knock-in mice. The human mutation expressed in a ND7/23 cell line hyperpolarises activation by -28mV, slows deactivation, and depolarizes V1/2 for inactivation by 2.5mV.
References:  13
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human L811P c.2432T>C Mutation associated with loss of pain perception and self-mutilation 13
Disease:  Sodium channelopathy-related small fiber neuropathy
Orphanet: ORPHA306577
Role:  The G699R mutation hyperpolarizes activation by 10.1mV. The mutation depolarizes inactivation by 6.3mV. As expected from increased overlap between activation and inactivation (predicted window current) the mutant channels produce a current with two-fold larger non-inactivating current. DRG neurons expressing mutant channels display depolarized (4.3)mV) resting potential, lower action potential threshold, and increased frequency firing.
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human G699R c.2095G>A Mutation hyperpolarizes activation by 10.1 mV, depolarizes inactivation by 6.3 mV, and slows deactivation. Mutant channels produce hyperexcitability in DRG neurons. 10

References

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1. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP, Egerton J, Stean T, Morisset V, Grose D, Gunthorpe MJ, Chessell IP, Tate S, Green PJ, Woolf CJ. (2006) The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci, 26 (50): 12852-60. [PMID:17167076]

2. Baker MD, Chandra SY, Ding Y, Waxman SG, Wood JN. (2003) GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones. J Physiol (Lond.), 548 (Pt 2): 373-82. [PMID:12651922]

3. Cummins TR, Dib-Hajj SD, Black JA, Akopian AN, Wood JN, Waxman SG. (1999) A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J Neurosci, 19 (24): RC43. [PMID:10594087]

4. Dib-Hajj SD, Tyrrell L, Black JA, Waxman SG. (1998) NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. Proc Natl Acad Sci USA, 95 (15): 8963-8. [PMID:9671787]

5. Dib-Hajj SD, Tyrrell L, Cummins TR, Black JA, Wood PM, Waxman SG. (1999) Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons. FEBS Lett, 462 (1-2): 117-20. [PMID:10580103]

6. Dib-Hajj SD, Tyrrell L, Escayg A, Wood PM, Meisler MH, Waxman SG. (1999) Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN. Genomics, 59 (3): 309-18. [PMID:10444332]

7. Fang X, Djouhri L, Black JA, Dib-Hajj SD, Waxman SG, Lawson SN. (2002) The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons. J Neurosci, 22 (17): 7425-33. [PMID:12196564]

8. Fjell J, Hjelmström P, Hormuzdiar W, Milenkovic M, Aglieco F, Tyrrell L, Dib-Hajj S, Waxman SG, Black JA. (2000) Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors. Neuroreport, 11 (1): 199-202. [PMID:10683857]

9. Goral RO, Leipold E, Nematian-Ardestani E, Heinemann SH. (2015) Heterologous expression of NaV1.9 chimeras in various cell systems. Pflugers Arch, 467 (12): 2423-35. [PMID:25916202]

10. Han C, Yang Y, de Greef BT, Hoeijmakers JG, Gerrits MM, Verhamme C, Qu J, Lauria G, Merkies IS, Faber CG et al.. (2015) The Domain II S4-S5 Linker in Nav1.9: A Missense Mutation Enhances Activation, Impairs Fast Inactivation, and Produces Human Painful Neuropathy. Neuromolecular Med, 17 (2): 158-69. [PMID:25791876]

11. Herzog RI, Cummins TR, Waxman SG. (2001) Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. J Neurophysiol, 86 (3): 1351-64. [PMID:11535682]

12. Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JG, Gerrits MM, Tyrrell L, Lauria G, Faber CG, Dib-Hajj SD et al.. (2014) Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain, 137 (Pt 6): 1627-42. [PMID:24776970]

13. Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, Ebbinghaus M, Goral RO, Stödberg T, Hennings JC et al.. (2013) A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet, 45 (11): 1399-404. [PMID:24036948]

14. Priest BT, Murphy BA, Lindia JA, Diaz C, Abbadie C, Ritter AM, Liberator P, Iyer LM, Kash SF, Kohler MG, Kaczorowski GJ, MacIntyre DE, Martin WJ. (2005) Contribution of the tetrodotoxin-resistant voltage-gated sodium channel NaV1.9 to sensory transmission and nociceptive behavior. Proc Natl Acad Sci USA, 102 (26): 9382-7. [PMID:15964986]

15. Rugiero F, Mistry M, Sage D, Black JA, Waxman SG, Crest M, Clerc N, Delmas P, Gola M. (2003) Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. J Neurosci, 23 (7): 2715-25. [PMID:12684457]

16. Rush AM, Waxman SG. (2004) PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins. Brain Res, 1023 (2): 264-71. [PMID:15374752]

17. Zhang XY, Wen J, Yang W, Wang C, Gao L, Zheng LH, Wang T, Ran K, Li Y, Li X et al.. (2013) Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet, 93 (5): 957-66. [PMID:24207120]

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