Nav1.3

Target id: 580

Nomenclature: Nav1.3

Family: Voltage-gated sodium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Nav1.3 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 1 2000 2q23-24 SCN3A sodium voltage-gated channel alpha subunit 3
Mouse 24 1 1947 2 C1.3 Scn3a sodium channel, voltage-gated, type III, alpha
Rat 24 1 1951 3q21 Scn3a sodium voltage-gated channel alpha subunit 3
Previous and Unofficial Names
Scn3a | Brain type III | sodium channel, voltage-gated, type III, alpha subunit | sodium channel, voltage gated, type III alpha subunit
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
β3 14,18
β1 14
Other Associated Proteins
Name References
Not determined
Functional Characteristics
Activation V0.5 = -24 mV. Fast inactivation (0.8 ms)
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -24.0 - 6 HEK 293 cells Human
Inactivation  -69.9 - 6
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -29.1 - 4 DRG neurons Rat
Inactivation  -72.2 10.0 – 156.0 4
Comments  The range of τ in these neurons is measured at voltages between -20 and -70 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -25.5 - 4 HEK 293 cells. Rat
Inactivation  -64.9 35.0 – 149.0 4
Comments  The range of τ in these neurons is measured at voltages between -40 and -70 mV.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -12.1 - 14 CHO cells. Human
Inactivation  -47.5 - 14
Comments  The values given are for Nav1.3 alone. Voltage dependence was also measured for Nav1.3 co-expressed with the auxilliary subunits β1-3.

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
batrachotoxin Hs - - - - -
veratridine Hs - - - - -
Activator Comments
β-scorpion toxins are known activators for the rat receptor [11].
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
AFT-II Hs Slows inactivation 6.3 pEC50 - -80.0 15
pEC50 6.3 [15]
Holding voltage: -80.0 mV
ATX-II Hs Slows inactivation 6.1 pEC50 - -80.0 15
pEC50 6.1 [15]
Holding voltage: -80.0 mV
Bc-III Hs Slows inactivation 5.8 pEC50 - -80.0 15
pEC50 5.8 [15]
Holding voltage: -80.0 mV
Gating Inhibitor Comments
α-scorpion toxins have been reported as affective gating inhibitors for the rat NaV1.3 receptor [11].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
tetrodotoxin Hs Pore blocker 8.4 pIC50 - - 3
pIC50 8.4 (IC50 4x10-9 M) [3]
lacosamide Rn Antagonist 3.4 pIC50 - - 19
pIC50 3.4 (IC50 4.15x10-4 M) [19]
saxitoxin Hs Pore blocker - - - -
View species-specific channel blocker tables
Tissue Distribution
Spinal cord, thalamus, amygdala, cerebellum, adult and fetal whole brain and heart
Species:  Human
Technique:  RT-PCR
References:  20
Hypomyelinated mouse axons
Species:  Mouse
Technique:  Immunohistochemistry
References:  22
Cardiac myocytes.
Species:  Mouse
Technique:  Immunocytochemistry
References:  13
Development: Expression increases from before E10, to reach a maximum at birth, decreasing during the first two weeks postnatal to the low adult levels.
Adult: Cerebral cortex, hippocampus, corpus striatum, midbrain > colliculi, medulla-pons > retina, spinal cord.
Species:  Rat
Technique:  In situ hybridisation
References:  1
Functional Assays
Whole-cell patch clamp electrophysiology
Species:  Rat
Tissue:  Dorsal root ganglion neurons
Response measured:  Activation, inactivation, kinetics, repriming
References:  4
Physiological Functions
Rapid repriming (recovery from inactivation), supporting repetitive firing patterns.
Species:  Rat
Tissue:  DRG neurons
References:  4-5
Ramp currents elicited between -70 and -30mV in HEK293 cells, or -50 and -30mV in axotomised DRG neurons may amplify depolarisations below action potential threshold.
Species:  Rat
Tissue:  DRG neurons
References:  4-5
Persistent current through these channels may contribute to spontaneous and/or repetitive firing.
Species:  Rat
Tissue:  DRG neurons, HEK293 cells.
References:  5,12
Physiological Consequences of Altering Gene Expression
Neuropathic pain is ameliorated by shRNA knock-down
Species:  Rat
Tissue:  DRG neuron
Technique:  shRNA knockdown
References:  16
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Scn3aGt(OST52130)Lex Scn3aGt(OST52130)Lex/Scn3aGt(OST52130)Lex
involves: 129S5/SvEvBrd * C57BL/6J
MGI:98249  MP:0001265 decreased body size
Scn3a+|Scn3aGt(OST52130)Lex Scn3aGt(OST52130)Lex/Scn3a+
involves: 129S5/SvEvBrd * C57BL/6J
MGI:98249  MP:0005292 improved glucose tolerance
Scn3aGt(OST52130)Lex Scn3aGt(OST52130)Lex/Scn3aGt(OST52130)Lex
involves: 129S5/SvEvBrd * C57BL/6J
MGI:98249  MP:0005202 lethargy
Scn3aGt(OST52130)Lex Scn3aGt(OST52130)Lex/Scn3aGt(OST52130)Lex
involves: 129S5/SvEvBrd * C57BL/6J
MGI:98249  MP:0002082 postnatal lethality
Clinically-Relevant Mutations and Pathophysiology
Disease:  Epilepsy
Role: 
References:  6,10
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human K354Q 6,10
Gene Expression and Pathophysiology
Nav1.3 is upregulated following peripheral nerve injury.
Tissue or cell type:  Dorsal root ganglion and dorsal horn neurons
Pathophysiology:  Upregulation may promote hyperexcitability
Species:  Rat
Technique:  Experimentally induced nerve injury.
References:  2,5,8,21
Nav1.3 is upregulated following spinal cord injury.
Tissue or cell type:  Dorsal horn, thalamus
Pathophysiology:  Upregulation may promote hyper-responsiveness along the pain pathway
Species:  Rat
Technique:  Spinal cord contusion injury
References:  7,9
General Comments
Contactin associates with Nav1.3 in native tissues and increases channel density at the cell surface [17].

References

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1. Beckh S, Noda M, Lübbert H, Numa S. (1989) Differential regulation of three sodium channel messenger RNAs in the rat central nervous system during development. EMBO J.8 (12): 3611-6. [PMID:2555170]

2. Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ, Waxman SG. (1999) Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J. Neurophysiol.82 (5): 2776-85. [PMID:10561444]

3. Chen YH, Dale TJ, Romanos MA, Whitaker WR, Xie XM, Clare JJ. (2000) Cloning, distribution and functional analysis of the type III sodium channel from human brain. Eur. J. Neurosci.12 (12): 4281-9. [PMID:11122339]

4. Cummins TR, Aglieco F, Renganathan M, Herzog RI, Dib-Hajj SD, Waxman SG. (2001) Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. J. Neurosci.21 (16): 5952-61. [PMID:11487618]

5. 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]

6. Estacion M, Gasser A, Dib-Hajj SD, Waxman SG. (2010) A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons. Exp. Neurol.224 (2): 362-8. [PMID:20420834]

7. Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG. (2003) Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J. Neurosci.23 (26): 8881-92. [PMID:14523090]

8. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. (2004) Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J. Neurosci.24 (20): 4832-9. [PMID:15152043]

9. Hains BC, Saab CY, Waxman SG. (2005) Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. Brain128 (Pt 10): 2359-71. [PMID:16109750]

10. Holland KD, Kearney JA, Glauser TA, Buck G, Keddache M, Blankston JR, Glaaser IW, Kass RS, Meisler MH. (2008) Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci. Lett.433 (1): 65-70. [PMID:18242854]

11. Joho RH, Moorman JR, VanDongen AM, Kirsch GE, Silberberg H, Schuster G, Brown AM. (1990) Toxin and kinetic profile of rat brain type III sodium channels expressed in Xenopus oocytes. Brain Res. Mol. Brain Res.7 (2): 105-13. [PMID:2160038]

12. Lampert A, Hains BC, Waxman SG. (2006) Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Exp. Brain Res.174 (4): 660-6. [PMID:16718433]

13. Maier SK, Westenbroek RE, Schenkman KA, Feigl EO, Scheuer T, Catterall WA. (2002) An unexpected role for brain-type sodium channels in coupling of cell surface depolarization to contraction in the heart. Proc. Natl. Acad. Sci. U.S.A.99 (6): 4073-8. [PMID:11891345]

14. Meadows LS, Chen YH, Powell AJ, Clare JJ, Ragsdale DS. (2002) Functional modulation of human brain Nav1.3 sodium channels, expressed in mammalian cells, by auxiliary beta 1, beta 2 and beta 3 subunits. Neuroscience114 (3): 745-53. [PMID:12220575]

15. Oliveira JS, Redaelli E, Zaharenko AJ, Cassulini RR, Konno K, Pimenta DC, Freitas JC, Clare JJ, Wanke E. (2004) Binding specificity of sea anemone toxins to Nav 1.1-1.6 sodium channels: unexpected contributions from differences in the IV/S3-S4 outer loop. J. Biol. Chem.279 (32): 33323-35. [PMID:15169781]

16. Samad OA, Tan AM, Cheng X, Foster E, Dib-Hajj SD, Waxman SG. (2013) Virus-mediated shRNA Knockdown of Na(v)1.3 in Rat Dorsal Root Ganglion Attenuates Nerve Injury-induced Neuropathic Pain. Mol. Ther.21 (1): 49-56. [PMID:22910296]

17. Shah BS, Rush AM, Liu S, Tyrrell L, Black JA, Dib-Hajj SD, Waxman SG. (2004) Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. J. Neurosci.24 (33): 7387-99. [PMID:15317864]

18. Shah BS, Stevens EB, Pinnock RD, Dixon AK, Lee K. (2001) Developmental expression of the novel voltage-gated sodium channel auxiliary subunit beta3, in rat CNS. J. Physiol. (Lond.)534 (Pt 3): 763-76. [PMID:11483707]

19. Sheets PL, Heers C, Stoehr T, Cummins TR. (2008) Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J. Pharmacol. Exp. Ther.326 (1): 89-99. [PMID:18378801]

20. Thimmapaya R, Neelands T, Niforatos W, Davis-Taber RA, Choi W, Putman CB, Kroeger PE, Packer J, Gopalakrishnan M, Faltynek CR, Surowy CS, Scott VE. (2005) Distribution and functional characterization of human Nav1.3 splice variants. Eur. J. Neurosci.22 (1): 1-9. [PMID:16029190]

21. Waxman SG, Kocsis JD, Black JA. (1994) Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J. Neurophysiol.72 (1): 466-70. [PMID:7965028]

22. Westenbroek RE, Noebels JL, Catterall WA. (1992) Elevated expression of type II Na+ channels in hypomyelinated axons of shiverer mouse brain. J. Neurosci.12 (6): 2259-67. [PMID:1318958]

Contributors

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How to cite this page

William A. Catterall, Alan L. Goldin, Stephen G. Waxman.
Voltage-gated sodium channels: Nav1.3. Last modified on 30/06/2015. Accessed on 21/09/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=580.