Voltage-Gated Na+ Channel beta 1B: A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

TY - JOUR

T1 - Voltage-Gated Na+ Channel beta 1B

T2 - A Secreted Cell Adhesion Molecule Involved in Human Epilepsy

AU - Patino, Gustavo A.

AU - Brackenbury, William J.

AU - Bao, Yangyang

AU - Lopez-Santiago, Luis F.

AU - O'Malley, Heather A.

AU - Chen, Chunling

AU - Calhoun, Jeffrey D.

AU - Lafreniere, Ron G.

AU - Cossette, Patrick

AU - Rouleau, Guy A.

AU - Isom, Lori L.

PY - 2011/10/12

Y1 - 2011/10/12

N2 - 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, beta 1 and beta 1B, that are each expressed in brain and heart in rodents and humans. Here, we studied the structure and function of beta 1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to beta 1B. We show that wild-type beta 1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of beta 1B with voltage-gated Na+ channels Na(v)1.1 or Na(v)1.3 is not detectable by immunoprecipitation and beta 1B does not affect Na(v)1.3 cell surface expression as measured by [H-3] saxitoxin binding. However, beta 1B coexpression results in subtle alteration of Na(v)1.3 currents in transfected cells, suggesting that beta 1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of beta 1B, 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 beta 1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.

AB - 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, beta 1 and beta 1B, that are each expressed in brain and heart in rodents and humans. Here, we studied the structure and function of beta 1B and investigated a novel human SCN1B epilepsy-related mutation (p.G257R) unique to beta 1B. We show that wild-type beta 1B is not a transmembrane protein, but a soluble protein expressed predominantly during embryonic development that promotes neurite outgrowth. Association of beta 1B with voltage-gated Na+ channels Na(v)1.1 or Na(v)1.3 is not detectable by immunoprecipitation and beta 1B does not affect Na(v)1.3 cell surface expression as measured by [H-3] saxitoxin binding. However, beta 1B coexpression results in subtle alteration of Na(v)1.3 currents in transfected cells, suggesting that beta 1B may modulate Na+ current in brain. Similar to the previously characterized p.R125C mutation, p.G257R results in intracellular retention of beta 1B, 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 beta 1B p.G257R may contribute to epilepsy through a mechanism that includes intracellular retention resulting in aberrant neuronal pathfinding.

KW - FEBRILE SEIZURES PLUS

KW - SUBUNIT-MEDIATED MODULATION

KW - SODIUM-CHANNEL

KW - GENERALIZED EPILEPSY

KW - FUNCTIONAL EXPRESSION

KW - NEURITE OUTGROWTH

KW - RAT-BRAIN

KW - MESSENGER-RNA

KW - MUTATIONS

KW - ANKYRIN

UR - http://www.scopus.com/inward/record.url?scp=80054049693&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.0361-11.2011

DO - 10.1523/JNEUROSCI.0361-11.2011

M3 - Article

C2 - 21994374

SN - 0270-6474

VL - 31

SP - 14577

EP - 14591

JO - Journal of neuroscience

JF - Journal of neuroscience

IS - 41

ER -