Voltage-gated Na + channel β1B: A secreted cell adhesion molecule involved in human epilepsy

Gustavo A. Patino, William J. Brackenbury, Yangyang Bao, Luis F. Lopez-Santiago, Heather A. O'Malley, Chunling Chen, Jeffrey D. Calhoun, Ron G. Lafrenière, Patrick Cossette, Guy A. Rouleau, Lori L. Isom

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Scn1b-null mice have a severe neurological and cardiac phenotype.Humanmutations inSCN1Bresult 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 Nav1.1 or Nav1.3 is not detectable by immunoprecipitation and β1B does not affect Nav1.3 cell surface expression as measured by [ 3H]saxitoxin binding. However, β1B coexpression results in subtle alteration of Na v1.3 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.Wepropose that β1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.

Original languageEnglish (US)
Pages (from-to)14577-14591
Number of pages15
JournalJournal of Neuroscience
Volume31
Issue number41
DOIs
StatePublished - Oct 12 2011
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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