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Nav1.2

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
Gating Inhibitors
Pore Blockers
Tissue Distribution
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
References
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 1,33
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
NachII
RII/RIIA
RNSCPIIR
SCN
SCN2A
ScpII
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 18072 (Hs), 10559 (Rn)
DrugBank Target 3802 (Hs)
Ensembl ENSG00000136531 (Hs), ENSMUSG00000075318 (Mm), ENSRNOG00000005018 (Rn)
Entrez Gene 6326 (Hs), 110876 (Mm), 24766 (Rn)
GeneCards SCN2A (Hs)
GenitoUrinary Development Molecular Anatomy Project Scn2a1 (Mm)
HomoloGene 75001 (Hs)
Human Protein Reference Database 03133 (Hs)
InterPro Q99250 (Hs), P04775 (Rn)
KEGG Gene hsa:6326 (Hs), mmu:110876 (Mm), rno:24766 (Rn)
OMIM 182390 (Hs)
Orphanet Gene ORPHA118500 (Hs)
PharmGKB Gene PA162402515 (Hs), PA35004 (Hs)
PhosphoSitePlus Q99250 (Hs), Q62204 (Mm), P04775 (Rn)
Protein Ontology (PRO) PRO:000002098 (Hs)
RefSeq Nucleotide NM_001040142 (Hs), NM_001040143 (Hs), NM_001099298 (Mm), NM_012647 (Rn)
RefSeq Protein NP_001035232 (Hs), NP_001035233 (Hs), NP_001092768 (Mm), NP_036779 (Rn)
TreeFam ENSG00000136531 (Hs), ENSMUSG00000075318 (Mm), ENSRNOG00000005018 (Rn)
UniGene Hs. 93485 (Hs)
UniProt Q99250 (Hs), P04775 (Rn)
Wikipedia Nav1.2
Voltage-gated sodium channels
Search for 3D structures on the PDB
Search by keyword: Voltage-gated sodium channels Nav1.2 Search by accession number: P04775, Q99250
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
β2 10-11,14,31
β1 10-11,13,28
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 [19,21,34].
Ion Selectivity and Conductance
Species:  Rat
Rank order:  Na+ [- pS]
References:  27
Species:  Rat
Single channel conductance (pS):  19
References:  27
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. Affinity Units Concentration range (M) Holding voltage (mV) Reference
β-scorpion toxin Css IV Rn 9.7 pKd - Physiological 7
batrachotoxin Rn 9.1 pKd - Physiological 16
aconitine Rn 5.9 pKd - Physiological 6
veratridine Rn 5.2 pKd - Physiological 6
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. Affinity Units Concentration range (M) Holding voltage (mV) Reference
α-scorpion toxin Rn 8.7 pKd - Physiological 25
ATX-II Hs 8.1 pEC50 - -80.0 20
Bc-III Hs 5.8 pEC50 - -80.0 20
AFT-II Hs 5.7 pEC50 - -80.0 20
View species-specific gating inhibitor 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
tetrodotoxin Rn 8.0 pKd - -120.0 5
saxitoxin Rn 8.8 pIC50 - -120.0 5
etidocaine Rn 6.0 pIC50 - -120.0 22
lidocaine Rn 5.0 pIC50 - -120.0 23
phenytoin Hs 4.9 pIC50 - -62.0 24
phenytoin Rn 4.7 pIC50 - -120.0 23
lamotrigine Rn 4.5 pIC50 - -50.0 17,32
View species-specific pore blocker tables
Pore 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:  30
Spinal cord, localised in unmyelinated axons and motor neurons.
Species:  Rat
Technique:  Immunohistochemistry
References:  4,9,15,29
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:  29
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

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:  Benign Familial Neonatal-Infantile Seizures (BFNIS)
OMIM:  607745
Orphanet:  140927, 306
Role:  Mutations in Nav1.2 affect the initiation and conduction of excess action potentials.
Drugs:  Anti-epileptic drugs including phenytoin, lamotrigine and clonazepam.
References:  3,12,33
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human L1563V 12,33
Missense Human L1330F 12
Missense Human R1319Q 3
Missense Human L1003I 3
Missense Human V892I 3
Missense Human R223Q 3
Disease:  Epileptic encephalopathy, early infantile, 11; EIEE11
OMIM:  613721
References: 
Mutations not determined
Disease:  Generalized epilepsy with febrile seizures-plus context
Orphanet:  36387
References: 
Mutations not determined
Biologically Significant Variants
Isoform 2
Nucleotide accession:  NM_001040143 
Protein accession:  NP_001035233 
Amino acids:  2005
Type:  Splice variant
Species:  Human
References:  1,33
Isoform 1
Nucleotide accession:  NM_001040142 
Protein accession:  NP_001035232 
Amino acids:  2005
Type:  Splice variant
Species:  Human
References:  1,33
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 [26,33].

REFERENCES

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1. Ahmed, CM; Ware, DH; Lee, SC; Patten, CD; Ferrer-Montiel, AV; Schinder, AF; McPherson, JD; Wagner-McPherson, CB; Wasmuth, JJ; Evans, GA. (1992) Primary structure, chromosomal localization, and functional expression of a voltage-gated sodium channel from human brain. Proc. Natl. Acad. Sci. U.S.A., 89 (17): 8220-4. [PMID:1325650]

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. Neuron, 1 (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. Neuron, 30 (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. Nature, 434 (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. Neuron, 21 (4): 919-31. [PMID:9808476]

8. Clare, JJ; Tate, SN; Nobbs, M; Romanos, MA. (2000) Voltage-gated sodium channels as therapeutic targets. Drug Discov. Today, 5 (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. Lancet, 360 (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. Science, 256 (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. Cell, 83 (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. Neuron, 30 (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. Neuropharmacology, 44 (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. Science, 265 (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. 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]

28. 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]

29. Westenbroek, RE; Merrick, DK; Catterall, WA. (1989) Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron, 3 (6): 695-704. [PMID:2561976]

30. 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]

31. 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]

32. 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]

33. 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]

34. 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 13/08/2012. Accessed on 19/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=579.


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