Nomenclature: Nav1.2

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. 

Contents

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 24 0 2005 2q22-23 SCN2A sodium channel, voltage-gated, type II, alpha subunit 1,34
Mouse 24 0 2006 2 C1.3 Scn2a1 sodium channel, voltage-gated, type II, alpha 1
Rat 24 0 2005 3q24 Scn2a1 sodium channel, voltage-gated, type II, alpha 1 2,26
Previous and Unofficial Names
Brain-II
Rat-2
Type-II
Nav1.2
Brain type II
SCN2A1
SCN2A2
HBSCII
HBSCI
sodium channel, voltage-gated, type II, alpha 2 polypeptide
sodium channel, voltage-gated, type II, alpha 1 polypeptide
ScpII
RII/RIIA
RNSCPIIR
SCN
SCN2A
NachII
RIIA sodium channel protein
Sodium channel voltage-gated type II alpha polypeptide
Sodium channel, voltage-gated, type II, alpha polypeptide
alternative product
sodium channel protein brain II subunit alpha
sodium channel protein type 2 subunit alpha
sodium channel protein type II subunit alpha
sodium channel protein, brain II subunit alpha
sodium channel, voltage-gated, type 2, alpha 1 polypeptide
sodium channel, voltage-gated, type 2, alpha 1 subunit
sodium channel, voltage-gated, type II, alpha 1
voltage-gated sodium channel subunit alpha Nav1.2
A230052E19Rik
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
β2 10-11,14,32
β1 10-11,13,29
Other Associated Proteins
Name References
Not determined
Associated Protein Comments
β-3 and β-4 subunits also associate with Nav1.2 channels when co-expressed but there are no direct biochemical data on purified sodium channels at present [19,21,35].
Functional Characteristics
Fast inactivation (0.8 ms)
Ion Selectivity and Conductance
Species:  Rat
Rank order:  Na+ [- pS]
References:  28
Species:  Rat
Single channel conductance (pS):  19
References:  28
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  5.9 - 18 HEK 293 cells transiently transfected with Nav1.2. Rat
Inactivation  43.9 - 18
Comments  τact < 0.4ms at Vact; τinact = 0.8ms at 0mV.

Measurements obtained with an intracellular solution containing Cs-aspartate as the primary solute.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -24.0 - 8 CHO cells stably transfected with Nav1.2. Human
Inactivation  -63.0 - 8
Comments  Measurements obtained using cesium fluoride as the major intracellular solute.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -24.3 - 21 HEK 293 cells transiently transfected with Nav1.2. Rat
Inactivation  -63.4 - 21
Comments  Measurements obtained using N-methyl-D-glucamine chloride as the major intracellular solute.
Voltage Dependence Comments
The values given for activation and inactivation parameters are for α-subunits expressed alone in mammalian cells. Co-expression of β-subunits shifts the voltage dependence [21], as does the use of intracellular solutions with other major anions (see table).
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
β-scorpion toxin Css IV Rn Partial agonist 9.7 pKd - Physiological 7
pKd 9.7 [7]
Holding voltage: Physiological
batrachotoxin Rn Agonist 9.1 pKd - Physiological 16
pKd 9.1 (Kd 7.94x10-10 M) [16]
Holding voltage: Physiological
aconitine Rn Agonist 5.9 pKd - Physiological 6
pKd 5.9 [6]
Holding voltage: Physiological
veratridine Rn Partial agonist 5.2 pKd - Physiological 6
pKd 5.2 (Kd 6.31x10-6 M) [6]
Holding voltage: Physiological
Activator Comments
Veratridine and aconitine have been studied on sodium channels in synaptosomes, which are predominantly Nav1.2. Binding affinity for batrachotoxin is greatly enhanced by the presence of co-activators in binding experiments and by depolarising prepulses in voltage-clamp experiments because of high affinity binding to the open/activated state.
Gating inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
α-scorpion toxin Rn - 8.7 pKd - Physiological 25
pKd 8.7 [25]
Holding voltage: Physiological
ATX-II Hs Antagonist 8.1 pEC50 - -80.0 20
pEC50 8.1 [20]
Holding voltage: -80.0 mV
Bc-III Hs Antagonist 5.8 pEC50 - -80.0 20
pEC50 5.8 [20]
Holding voltage: -80.0 mV
AFT-II Hs Antagonist 5.7 pEC50 - -80.0 20
pEC50 5.7 [20]
Holding voltage: -80.0 mV
View species-specific gating inhibitor tables
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 - - - 1x10-8 -
Conc range: 1x10-8 M
tetrodotoxin Rn - 8.0 pKd - -120.0 5
pKd 8.0 [5]
Holding voltage: -120.0 mV
saxitoxin Rn - 8.8 pIC50 - -120.0 5
pIC50 8.8 (IC50 1.7x10-9 M) [5]
Holding voltage: -120.0 mV
etidocaine Rn - 6.0 pIC50 - -120.0 22
pIC50 6.0 [22]
Holding voltage: -120.0 mV
lidocaine Rn - 5.0 pIC50 - -120.0 23
pIC50 5.0 [23]
Holding voltage: -120.0 mV
phenytoin Hs - 4.9 pIC50 - -62.0 24
pIC50 4.9 [24]
Holding voltage: -62.0 mV
phenytoin Rn - 4.7 pIC50 - -120.0 23
pIC50 4.7 [23]
Holding voltage: -120.0 mV
lamotrigine Rn - 4.5 pIC50 - -50.0 17,33
pIC50 4.5 [17,33]
Holding voltage: -50.0 mV
View species-specific channel blocker tables
Channel Blocker Comments
pIC50 values for lidocaine, etidocaine, lamotrigine and phenytoin reflect the KDD values for the resting state of sodium channels are 10 to 100-fold higher, that is lower afinity.
Tissue Distribution
Brain, localised at highest density in unmyelinated axons and in developing pre-myelinated axons, and also present in neuronal cell bodies and dendrites.
Species:  Human
Technique:  Immunohistochemistry
References:  31
Spinal cord, localised in unmyelinated axons and motor neurons.
Species:  Rat
Technique:  Immunohistochemistry
References:  4,9,15,30
Brain, localised at highest density in unmyelinated axons and in developing pre-myelinated axons, and also present in neuronal cell bodies and dendrites.
Species:  Rat
Technique:  Immunohistochemistry
References:  30
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0005277 abnormal brainstem morphology PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0001588 abnormal hemoglobin PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0002272 abnormal nervous system electrophysiology PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0009546 absent gastric milk in neonates PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0001575 cyanosis PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0005039 hypoxia PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0002082 postnatal lethality PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0001954 respiratory distress PMID: 10827969 
Scn2a1tm1Mml Scn2a1tm1Mml/Scn2a1tm1Mml
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J
MGI:98248  MP:0001263 weight loss PMID: 10827969 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Epileptic encephalopathy, early infantile, 11; EIEE11
OMIM:  613721
Orphanet:  1934
References: 
Mutations not determined
Disease:  Benign Familial Neonatal-Infantile Seizures (BFNIS)
OMIM:  607745
Orphanet:  140927, 306
Role: 
Drugs: 
References:  3,12,34
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human L1563V 12,34
Missense Human L1330F 12
Missense Human R1319Q 3
Missense Human L1003I 3
Missense Human V892I 3
Missense Human R223Q 3
Disease:  Generalized epilepsy with febrile seizures-plus context
Orphanet:  36387
References: 
Mutations not determined
Disease:  West syndrome
Orphanet:  3451
References: 
Mutations not determined
Disease:  Dravet syndrome
Orphanet:  33069
References:  27
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human R1312T Nucleotide transversion 3935G>C causes amino acid substitution arginine -> threonine. 27
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  Isoform 2
Amino acids:  2005
Nucleotide accession: 
Protein accession: 
References:  1,34
Type:  Splice variant
Species:  Human
Description:  Isoform 1
Amino acids:  2005
Nucleotide accession: 
Protein accession: 
References:  1,34
Biologically Significant Variant Comments
The D209/N209 difference in the sequence for these two variants leads to a shift in the voltage dependence of Nav and altered response to epilepsy mutations [26,34].

REFERENCES

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2. Auld VJ, Goldin AL, Krafte DS, Marshall J, Dunn JM, Catterall WA, Lester HA, Davidson N, Dunn RJ. (1988) A rat brain Na+ channel alpha subunit with novel gating properties. Neuron1 (6): 449-61. [PMID:2856097]

3. Berkovic SF, Heron SE, Giordano L, Marini C, Guerrini R, Kaplan RE, Gambardella A, Steinlein OK, Grinton BE, Dean JT, Bordo L, Hodgson BL, Yamamoto T, Mulley JC, Zara F, Scheffer IE. (2004) Benign familial neonatal-infantile seizures: characterization of a new sodium channelopathy. Ann. Neurol.55 (4): 550-7. [PMID:15048894]

4. Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, Matthews G. (2001) Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron30 (1): 91-104. [PMID:11343647]

5. Bricelj VM, Connell L, Konoki K, Macquarrie SP, Scheuer T, Catterall WA, Trainer VL. (2005) Sodium channel mutation leading to saxitoxin resistance in clams increases risk of PSP. Nature434 (7034): 763-7. [PMID:15815630]

6. Catterall WA, Morrow CS, Daly JW, Brown GB. (1981) Binding of batrachotoxinin A 20-alpha-benzoate to a receptor site associated with sodium channels in synaptic nerve ending particles. J. Biol. Chem.256 (17): 8922-7. [PMID:6114956]

7. Cestèle S, Qu Y, Rogers JC, Rochat H, Scheuer T, Catterall WA. (1998) Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3-S4 loop in domain II. Neuron21 (4): 919-31. [PMID:9808476]

8. Clare JJ, Tate SN, Nobbs M, Romanos MA. (2000) Voltage-gated sodium channels as therapeutic targets. Drug Discov. Today5 (11): 506-520. [PMID:11084387]

9. Gong B, Rhodes KJ, Bekele-Arcuri Z, Trimmer JS. (1999) Type I and type II Na(+) channel alpha-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain. J. Comp. Neurol.412 (2): 342-52. [PMID:10441760]

10. Hartshorne RP, Catterall WA. (1984) The sodium channel from rat brain. Purification and subunit composition. J. Biol. Chem.259 (3): 1667-75. [PMID:6319405]

11. Hartshorne RP, Messner DJ, Coppersmith JC, Catterall WA. (1982) The saxitoxin receptor of the sodium channel from rat brain. Evidence for two nonidentical beta subunits. J. Biol. Chem.257 (23): 13888-91. [PMID:6292214]

12. Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, Shevell M, Mercho S, Seni MH, Guiot MC, Mulley JC, Berkovic SF, Scheffer IE. (2002) Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet360 (9336): 851-2. [PMID:12243921]

13. 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. Science256 (5058): 839-42. [PMID:1375395]

14. Isom LL, Ragsdale DS, De Jongh KS, Westenbroek RE, Reber BF, Scheuer T, Catterall WA. (1995) Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell83 (3): 433-42. [PMID:8521473]

15. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA. (2001) Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron30 (1): 105-19. [PMID:11343648]

16. Linford NJ, Cantrell AR, Qu Y, Scheuer T, Catterall WA. (1998) Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel. Proc. Natl. Acad. Sci. U.S.A.95 (23): 13947-52. [PMID:9811906]

17. Liu G, Yarov-Yarovoy V, Nobbs M, Clare JJ, Scheuer T, Catterall WA. (2003) Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels. Neuropharmacology44 (3): 413-22. [PMID:12604088]

18. Mantegazza M, Yu FH, Catterall WA, Scheuer T. (2001) Role of the C-terminal domain in inactivation of brain and cardiac sodium channels. Proc. Natl. Acad. Sci. U.S.A.98 (26): 15348-53. [PMID:11742069]

19. Morgan K, Stevens EB, Shah B, Cox PJ, Dixon AK, Lee K, Pinnock RD, Hughes J, Richardson PJ, Mizuguchi K, Jackson AP. (2000) beta 3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc. Natl. Acad. Sci. U.S.A.97 (5): 2308-13. [PMID:10688874]

20. 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]

21. Qu Y, Curtis R, Lawson D, Gilbride K, Ge P, DiStefano PS, Silos-Santiago I, Catterall WA, Scheuer T. (2001) Differential modulation of sodium channel gating and persistent sodium currents by the beta1, beta2, and beta3 subunits. Mol. Cell. Neurosci.18 (5): 570-80. [PMID:11922146]

22. Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. (1994) Molecular determinants of state-dependent block of Na+ channels by local anesthetics. Science265 (5179): 1724-8. [PMID:8085162]

23. Ragsdale DS, McPhee JC, Scheuer T, Catterall WA. (1996) Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels. Proc. Natl. Acad. Sci. U.S.A.93 (17): 9270-5. [PMID:8799190]

24. Ragsdale DS, Scheuer T, Catterall WA. (1991) Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. Mol. Pharmacol.40 (5): 756-65. [PMID:1658608]

25. Rogers JC, Qu Y, Tanada TN, Scheuer T, Catterall WA. (1996) Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit. J. Biol. Chem.271 (27): 15950-62. [PMID:8663157]

26. Sarao R, Gupta SK, Auld VJ, Dunn RJ. (1991) Developmentally regulated alternative RNA splicing of rat brain sodium channel mRNAs. Nucleic Acids Res.19 (20): 5673-9. [PMID:1658739]

27. Shi X, Yasumoto S, Nakagawa E, Fukasawa T, Uchiya S, Hirose S. (2009) Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Dev.31 (10): 758-62. [PMID:19783390]

28. Stühmer W, Methfessel C, Sakmann B, Noda M, Numa S. (1987) Patch clamp characterization of sodium channels expressed from rat brain cDNA. Eur. Biophys. J.14 (3): 131-8. [PMID:2435540]

29. Sutkowski EM, Catterall WA. (1990) Beta 1 subunits of sodium channels. Studies with subunit-specific antibodies. J. Biol. Chem.265 (21): 12393-9. [PMID:2165060]

30. Westenbroek RE, Merrick DK, Catterall WA. (1989) Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron3 (6): 695-704. [PMID:2561976]

31. Whitaker WR, Clare JJ, Powell AJ, Chen YH, Faull RL, Emson PC. (2000) Distribution of voltage-gated sodium channel alpha-subunit and beta-subunit mRNAs in human hippocampal formation, cortex, and cerebellum. J. Comp. Neurol.422 (1): 123-39. [PMID:10842222]

32. Wollner DA, Messner DJ, Catterall WA. (1987) Beta 2 subunits of sodium channels from vertebrate brain. Studies with subunit-specific antibodies. J. Biol. Chem.262 (30): 14709-15. [PMID:2444590]

33. Xie X, Lancaster B, Peakman T, Garthwaite J. (1995) Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na+ channels and with native Na+ channels in rat hippocampal neurones. Pflugers Arch.430 (3): 437-46. [PMID:7491269]

34. Xu R, Thomas EA, Jenkins M, Gazina EV, Chiu C, Heron SE, Mulley JC, Scheffer IE, Berkovic SF, Petrou S. (2007) A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel. Mol. Cell. Neurosci.35 (2): 292-301. [PMID:17467289]

35. Yu FH, Westenbroek RE, Silos-Santiago I, McCormick KA, Lawson D, Ge P, Ferriera H, Lilly J, DiStefano PS, Catterall WA, Scheuer T, Curtis R. (2003) Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J. Neurosci.23 (20): 7577-85. [PMID:12930796]

To cite this database page, please use the following:

William A. Catterall, Alan L. Goldin, Stephen G. Waxman.
Voltage-gated sodium channels: Nav1.2. Last modified on 18/03/2014. Accessed on 02/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=579.

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