title: Voltage-gated Na+ channel β1B: a secreted cell adhesion molecule involved in human epilepsy.
abstract: Scn1b-null mice have a severe neurological and cardiac phenotype. Human mutations in SCN1B result in epilepsy and cardiac arrhythmia. SCN1B is expressed as two developmentally regulated splice variants, β1 and β1B, that are each expressed in brain and heart in rodents and humans. Here, we studied the structure and function of β1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to β1B. We show that wild-type β1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of β1B with voltage-gated Na+ channels Na(v)1.1 or Na(v)1.3 is not detectable by immunoprecipitation and β1B does not affect Na(v)1.3 cell surface expression as measured by [(3)H]saxitoxin binding. However, β1B coexpression results in subtle alteration of Na(v)1.3 currents in transfected cells, suggesting that β1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of β1B, generating a functional null allele. In contrast, two other SCN1B mutations associated with epilepsy, p.C121W and p.R85H, are expressed at the cell surface. We propose that β1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.
authors: Department of Pharmacology and Program in Neuroscience, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors: Gustavo A
authors: GA
authors: Patino
authors: William J
authors: WJ
authors: Brackenbury
authors: Yangyang
authors: Y
authors: Bao
authors: Luis F
authors: LF
authors: Lopez-Santiago
authors: Heather A
authors: HA
authors: O'Malley
authors: Chunling
authors: C
authors: Chen
authors: Jeffrey D
authors: JD
authors: Calhoun
authors: Ron G
authors: RG
authors: Lafrenière
authors: Patrick
authors: P
authors: Cossette
authors: Guy A
authors: GA
authors: Rouleau
authors: Lori L
authors: LL
authors: Isom
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000235:genetics; D019921:Biotinylation / Q000379:methods; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum; D006224:Cricetinae; D003412:Cricetulus; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D062552:NAV1.3 Voltage-Gated Sodium Channel; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012530:Saxitoxin / Q000493:pharmacokinetics; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
chemical_list: D015815:Cell Adhesion Molecules; D062552:NAV1.3 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D012333:RNA, Messenger; C470379:SCN1B protein, human; C524974:Scn1b protein, mouse; C515216:Scn3a protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D014316:Tritium; D012530:Saxitoxin; D001120:Arginine; D005998:Glycine