Voltage-gated Na+ channel beta1B: a secreted cell adhesion molecule involved in human epilepsy.
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Patino GA, Brackenbury WJ, Bao Y, Lopez-Santiago LF, O'Malley HA, Chen C, Calhoun JD, Lafreniere RG, Cossette P, Rouleau GA, Isom LL
Voltage-gated Na+ channel beta1B: a secreted cell adhesion molecule involved in human epilepsy.
J Neurosci. 2011 Oct 12;31(41):14577-91. doi: 10.1523/JNEUROSCI.0361-11.2011.
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- 21994374 [ View in PubMed]
- 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, beta1 and beta1B, that are each expressed in brain and heart in rodents and humans. Here, we studied the structure and function of beta1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to beta1B. We show that wild-type beta1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of beta1B with voltage-gated Na+ channels Na(v)1.1 or Na(v)1.3 is not detectable by immunoprecipitation and beta1B does not affect Na(v)1.3 cell surface expression as measured by [(3)H]saxitoxin binding. However, beta1B coexpression results in subtle alteration of Na(v)1.3 currents in transfected cells, suggesting that beta1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of beta1B, 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 beta1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.