Sodium channel in Epilepsy (WP5598)

Homo sapiens

This pathway illustrates the mechanistic information of sodium channel subtypes. The interactions exclusively focus on neuron electrical regulation. The information provides a roadmap for sodium channel dominanted epilepsygenesis.

For a description of pathway objects, see the WikiPathways Legend.

Authors

Yuanyuan Duan and Egon Willighagen

Activity

last edited

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Cited In

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Organisms

Homo sapiens

Communities

Annotations

Participants

Label Type Compact URI Comment
DNA Metabolite chebi:16991
Triciribine Metabolite wikidata:Q25326616
Ca²⁺ Metabolite chebi:29108
infliximab Metabolite wikidata:Q415264
4,9-Anhydrotetrodotoxin Metabolite pubchem.substance:107878
2-bromopalmitate Metabolite chebi:118417
-COOH Metabolite chebi:46883
cannabidiol Metabolite chebi:69478
GSK inhibitors Metabolite chebi:91092
camrelizumab Metabolite wikidata:Q60785565
SCN4A GeneProduct ensembl:ENSG00000007314
SCN3A GeneProduct ensembl:ENSG00000153253
SCN10A GeneProduct ensembl:ENSG00000185313
SCN8A GeneProduct ensembl:ENSG00000196876
SCN7A GeneProduct ensembl:ENSG00000136546
SCN2A GeneProduct ensembl:ENSG00000136531
SCN5A GeneProduct ensembl:ENSG00000183873
RNF121 GeneProduct ensembl:ENSG00000137522
SCN1B GeneProduct ensembl:ENSG00000105711
SCN9A GeneProduct ensembl:ENSG00000169432
SCN1A GeneProduct ensembl:ENSG00000144285
SCN11A GeneProduct ensembl:ENSG00000168356
SCN2B GeneProduct ensembl:ENSG00000149575
SCN3B GeneProduct ensembl:ENSG00000166257
SCN4B GeneProduct ensembl:ENSG00000177098
FGF13 GeneProduct ensembl:ENSG00000129682
BACE1 GeneProduct ensembl:ENSG00000186318
AKT1 GeneProduct ensembl:ENSG00000142208
NFASC GeneProduct ensembl:ENSG00000163531
RACK1 GeneProduct ensembl:ENSG00000204628
PSEN1 GeneProduct ensembl:ENSG00000080815
SCN1A GeneProduct ensembl:ENSG00000144285 PMID:31928904
CALM1 GeneProduct ensembl:ENSG00000198668
SCN1A mRNA GeneProduct ensembl:ENSG00000144285
MAPK8IP2 GeneProduct ensembl:ENSG00000008735
PDCD10 GeneProduct ensembl:ENSG00000114209
PTPRN GeneProduct ensembl:ENSG00000054356
GSK3B GeneProduct ensembl:ENSG00000082701
FGF14 GeneProduct ensembl:ENSG00000102466
CAMK2A GeneProduct ensembl:ENSG00000070808
JAK2 GeneProduct ensembl:ENSG00000096968
NEDD4 GeneProduct ensembl:ENSG00000069869
NEDD4L GeneProduct ensembl:ENSG00000049759
FYN GeneProduct ensembl:ENSG00000010810
FGF12 GeneProduct ensembl:ENSG00000114279
TNF GeneProduct ensembl:ENSG00000232810
WEE1 GeneProduct ensembl:ENSG00000166483
PRRT2 GeneProduct ensembl:ENSG00000167371
SCN3A GeneProduct ensembl:ENSG00000153253 More GoF[https://www.helbiglab.io/blog/scn3a-a-sodium-channel-in-epilepsy-and-brain-malformations]
SCNM1 GeneProduct ensembl:ENSG00000163156
Nav1.6 GeneProduct ensembl:ENSG00000196876
Nav1.1 Protein uniprot:P35498
Nav1.2 Protein uniprot:Q99250
Nav1.3 Protein uniprot:Q9NY46
Nav1.4 Protein uniprot:P35499
Nav1.5 Protein uniprot:Q14524
Nav1.7 Protein uniprot:Q01118
Nav1.8 Protein uniprot:Q9Y5Y9
Nav1.9 Protein uniprot:Q9UI33
Nax Protein uniprot:Q01118

References

  1. Motions of calmodulin characterized using both Bragg and diffuse X-ray scattering. Wall ME, Clarage JB, Phillips GN. Structure. 1997 Dec 15;5(12):1599–612. PubMed Europe PMC Scholia
  2. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, et al. Nat Genet. 1998 Aug;19(4):366–70. PubMed Europe PMC Scholia
  3. Nomenclature of voltage-gated sodium channels. Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, et al. Neuron. 2000 Nov;28(2):365–8. PubMed Europe PMC Scholia
  4. Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Wallace RH, Scheffer IE, Barnett S, Richards M, Dibbens L, Desai RR, et al. Am J Hum Genet. 2001 Apr;68(4):859–65. PubMed Europe PMC Scholia
  5. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus--and prevalence of variants in patients with epilepsy. Escayg A, Heils A, MacDonald BT, Haug K, Sander T, Meisler MH. Am J Hum Genet. 2001 Apr;68(4):866–73. PubMed Europe PMC Scholia
  6. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. Am J Hum Genet. 2001 Jun;68(6):1327–32. PubMed Europe PMC Scholia
  7. Fibroblast growth factor homologous factors are intracellular signaling proteins. Schoorlemmer J, Goldfarb M. Curr Biol. 2001 May 15;11(10):793–7. PubMed Europe PMC Scholia
  8. Sodium channel beta1 and beta3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain. Ratcliffe CF, Westenbroek RE, Curtis R, Catterall WA. J Cell Biol. 2001 Jul 23;154(2):427–34. PubMed Europe PMC Scholia
  9. Sodium-channel defects in benign familial neonatal-infantile seizures. Heron SE, Crossland KM, Andermann E, Phillips HA, Hall AJ, Bleasel A, et al. Lancet. 2002 Sep 14;360(9336):851–2. PubMed Europe PMC Scholia
  10. A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for beta subunit interaction. Spampanato J, Kearney JA, de Haan G, McEwen DP, Escayg A, Aradi I, et al. J Neurosci. 2004 Nov 3;24(44):10022–34. PubMed Europe PMC Scholia
  11. Molecular determinants of voltage-gated sodium channel regulation by the Nedd4/Nedd4-like proteins. Rougier JS, van Bemmelen MX, Bruce MC, Jespersen T, Gavillet B, Apothéloz F, et al. Am J Physiol Cell Physiol. 2005 Mar;288(3):C692-701. PubMed Europe PMC Scholia
  12. The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na(v1.6) voltage-dependent sodium channel. Rosker C, Lohberger B, Hofer D, Steinecker B, Quasthoff S, Schreibmayer W. Am J Physiol Cell Physiol. 2007 Aug;293(2):C783-9. PubMed Europe PMC Scholia
  13. Evidence for a direct role of the disease modifier SCNM1 in splicing. Howell VM, Jones JM, Bergren SK, Li L, Billi AC, Avenarius MR, et al. Hum Mol Genet. 2007 Oct 15;16(20):2506–16. PubMed Europe PMC Scholia
  14. Regulation of Na(v)1.2 channels by brain-derived neurotrophic factor, TrkB, and associated Fyn kinase. Ahn M, Beacham D, Westenbroek RE, Scheuer T, Catterall WA. J Neurosci. 2007 Oct 24;27(43):11533–42. PubMed Europe PMC Scholia
  15. Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. Goetz R, Dover K, Laezza F, Shtraizent N, Huang X, Tchetchik D, et al. J Biol Chem. 2009 Jun 26;284(26):17883–96. PubMed Europe PMC Scholia
  16. Identification of novel interaction sites that determine specificity between fibroblast growth factor homologous factors and voltage-gated sodium channels. Wang C, Wang C, Hoch EG, Pitt GS. J Biol Chem. 2011 Jul 8;286(27):24253–63. PubMed Europe PMC Scholia
  17. Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel. Gaudioso C, Carlier E, Youssouf F, Clare JJ, Debanne D, Alcaraz G. Biochem Biophys Res Commun. 2011 Jul 29;411(2):329–34. PubMed Europe PMC Scholia
  18. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Veeramah KR, O’Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, et al. Am J Hum Genet. 2012 Mar 9;90(3):502–10. PubMed Europe PMC Scholia
  19. Identification of the cysteine residue responsible for disulfide linkage of Na+ channel α and β2 subunits. Chen C, Calhoun JD, Zhang Y, Lopez-Santiago L, Zhou N, Davis TH, et al. J Biol Chem. 2012 Nov 9;287(46):39061–9. PubMed Europe PMC Scholia
  20. The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). Shavkunov AS, Wildburger NC, Nenov MN, James TF, Buzhdygan TP, Panova-Elektronova NI, et al. J Biol Chem. 2013 Jul 5;288(27):19370–85. PubMed Europe PMC Scholia
  21. Structural basis for the modulation of the neuronal voltage-gated sodium channel NaV1.6 by calmodulin. Reddy Chichili VP, Xiao Y, Seetharaman J, Cummins TR, Sivaraman J. Sci Rep. 2013;3:2435. PubMed Europe PMC Scholia
  22. Crystallographic insights into sodium-channel modulation by the β4 subunit. Gilchrist J, Das S, Van Petegem F, Bosmans F. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E5016-24. PubMed Europe PMC Scholia
  23. Transcription of the human sodium channel SCN1A gene is repressed by a scaffolding protein RACK1. Dong ZF, Tang LJ, Deng GF, Zeng T, Liu SJ, Wan RP, et al. Mol Neurobiol. 2014 Oct;50(2):438–48. PubMed Europe PMC Scholia
  24. Reciprocal changes in phosphorylation and methylation of mammalian brain sodium channels in response to seizures. Baek JH, Rubinstein M, Scheuer T, Trimmer JS. J Biol Chem. 2014 May 30;289(22):15363–73. PubMed Europe PMC Scholia
  25. The Nav1.2 channel is regulated by GSK3. James TF, Nenov MN, Wildburger NC, Lichti CF, Luisi J, Vergara F, et al. Biochim Biophys Acta. 2015 Apr;1850(4):832–44. PubMed Europe PMC Scholia
  26. GSK3 inhibitors stabilize Wee1 and reduce cerebellar granule cell progenitor proliferation. Penas C, Mishra JK, Wood SD, Schürer SC, Roush WR, Ayad NG. Cell Cycle. 2015;14(3):417–24. PubMed Europe PMC Scholia
  27. RING finger protein 121 facilitates the degradation and membrane localization of voltage-gated sodium channels. Ogino K, Low SE, Yamada K, Saint-Amant L, Zhou W, Muto A, et al. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2859–64. PubMed Europe PMC Scholia
  28. Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy. Wagnon JL, Meisler MH. Front Neurol. 2015 May 15;6:104. PubMed Europe PMC Scholia
  29. Clinical and genetic analysis of a family with two rare reflex epilepsies. Kasteleijn-Nolst Trenité DGA, Volkers L, Strengman E, Schippers HM, Perquin W, de Haan GJ, et al. Seizure. 2015 Jul;29:90–6. PubMed Europe PMC Scholia
  30. Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LHG, et al. Ann Neurol. 2016 Mar;79(3):428–36. PubMed Europe PMC Scholia
  31. Fgf13 Identified as a Novel Cause of GEFS. Wong JC, Escayg A. Epilepsy Curr. 2016;16(2):112–3. PubMed Europe PMC Scholia
  32. Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol. Patel RR, Barbosa C, Brustovetsky T, Brustovetsky N, Cummins TR. Brain. 2016 Aug;139(Pt 8):2164–81. PubMed Europe PMC Scholia
  33. De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis. Butler KM, da Silva C, Shafir Y, Weisfeld-Adams JD, Alexander JJ, Hegde M, et al. Epilepsy Res. 2017 Jan;129:17–25. PubMed Europe PMC Scholia
  34. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. Küry S, van Woerden GM, Besnard T, Proietti Onori M, Latypova X, Towne MC, et al. Am J Hum Genet. 2017 Nov 2;101(5):768–88. PubMed Europe PMC Scholia
  35. Mutations in SCN3A cause early infantile epileptic encephalopathy. Zaman T, Helbig I, Božović IB, DeBrosse SD, Bergqvist AC, Wallis K, et al. Ann Neurol. 2018 Apr;83(4):703–17. PubMed Europe PMC Scholia
  36. Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders. Du J, Simmons S, Brunklaus A, Adiconis X, Hession CC, Fu Z, et al. Eur J Paediatr Neurol. 2020 Jan;24:129–33. PubMed Europe PMC Scholia
  37. S-Palmitoylation of the sodium channel Nav1.6 regulates its activity and neuronal excitability. Pan Y, Xiao Y, Pei Z, Cummins TR. J Biol Chem. 2020 May 1;295(18):6151–64. PubMed Europe PMC Scholia
  38. JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation. Wadsworth PA, Singh AK, Nguyen N, Dvorak NM, Tapia CM, Russell WK, et al. Biochim Biophys Acta Mol Cell Res. 2020 Oct;1867(10):118786. PubMed Europe PMC Scholia
  39. CaMKII enhances voltage-gated sodium channel Nav1.6 activity and neuronal excitability. Zybura AS, Baucum AJ 2nd, Rush AM, Cummins TR, Hudmon A. J Biol Chem. 2020 Aug 14;295(33):11845–65. PubMed Europe PMC Scholia
  40. Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling. Bouza AA, Edokobi N, Hodges SL, Pinsky AM, Offord J, Piao L, et al. JCI Insight. 2021 Feb 8;6(3):e141776. PubMed Europe PMC Scholia
  41. Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1. Arribas-Blázquez M, Piniella D, Olivos-Oré LA, Bartolomé-Martín D, Leite C, Giménez C, et al. Neuropharmacology. 2021 Oct 1;197:108745. PubMed Europe PMC Scholia
  42. Pharmacological Inhibition of Wee1 Kinase Selectively Modulates the Voltage-Gated Na+ Channel 1.2 Macromolecular Complex. Dvorak NM, Tapia CM, Baumgartner TJ, Singh J, Laezza F, Singh AK. Cells. 2021 Nov 10;10(11):3103. PubMed Europe PMC Scholia
  43. CaMKII Inhibition Attenuates Distinct Gain-of-Function Effects Produced by Mutant Nav1.6 Channels and Reduces Neuronal Excitability. Zybura AS, Sahoo FK, Hudmon A, Cummins TR. Cells. 2022 Jul 4;11(13):2108. PubMed Europe PMC Scholia
  44. Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series. Seiffert S, Pendziwiat M, Bierhals T, Goel H, Schwarz N, van der Ven A, et al. EBioMedicine. 2022 Sep;83:104234. PubMed Europe PMC Scholia
  45. A Push-Pull Mechanism Between PRRT2 and β4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels. Valente P, Marte A, Franchi F, Sterlini B, Casagrande S, Corradi A, et al. Mol Neurobiol. 2023 Mar;60(3):1281–96. PubMed Europe PMC Scholia
  46. The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels. Franchi F, Marte A, Corradi B, Sterlini B, Alberini G, Romei A, et al. J Biol Chem. 2023 May;299(5):104632. PubMed Europe PMC Scholia
  47. Role of the voltage‑gated sodium channel Nav1.6 in glioma and candidate drugs screening. Ai Y, Zhang X, Hu X, Gao J, Liu J, Ou S, et al. Int J Mol Med. 2023 Jun;51(6):46. PubMed Europe PMC Scholia
  48. Anti-PD-1 treatment protects against seizure by suppressing sodium channel function. Yang Y, Chen Z, Zhou J, Jiang S, Wang G, Wan L, et al. CNS Neurosci Ther. 2024 Apr;30(4):e14504. PubMed Europe PMC Scholia
  49. A Novel Ubiquitin Ligase Adaptor PTPRN Suppresses Seizure Susceptibility through Endocytosis of NaV1.2 Sodium Channels. Wang Y, Yang H, Li N, Wang L, Guo C, Ma W, et al. Adv Sci (Weinh). 2024 Aug;11(29):e2400560. PubMed Europe PMC Scholia
  50. Exosomal TNF-α mediates voltage-gated Na+ channel 1.6 overexpression and contributes to brain tumor-induced neuronal hyperexcitability. Sanchez Trivino CA, Spelat R, Spada F, D’Angelo C, Manini I, Rolle IG, et al. J Clin Invest. 2024 Aug 1;134(18):e166271. PubMed Europe PMC Scholia