Beschreibung:
<jats:p> Functional and Biochemical Analysis of a Sodium Channel β1-Subunit Mutation Responsible for Generalized Epilepsy with Febrile Seizures Plus Type 1 </jats:p><jats:p> Meadows LS, Malhotra J, Loukas A, Thyagarajan V, Kazen-Gillespie KA, Koopman MC, Kriegler S, Isom LL, Ragsdale DS </jats:p><jats:p> J Neurosci 2002;22(24):10699–10709 </jats:p><jats:p> Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobulin domain of the auxiliary β<jats:sub>1</jats:sub> subunit of the voltage-gated sodium channel. The mutation disrupts β<jats:sub>1</jats:sub> function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this β<jats:sub>1</jats:sub> mutation results in seizures. First, with electrophysiological recordings from mammalian cell lines, coexpressing sodium channel asubunits and either wild-type β<jats:sub>1</jats:sub> or C121Wβ<jats:sub>1</jats:sub>, we show that loss of β<jats:sub>1</jats:sub> functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type β<jats:sub>1</jats:sub>. In contrast, neither wild-type β<jats:sub>1</jats:sub> nor C121Wβ<jats:sub>1</jats:sub> significantly affected sodium current time course or the voltage dependence of channel activation. We also show, by using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts β<jats:sub>1</jats:sub>-β<jats:sub>1</jats:sub> homophilic cell adhesion, suggesting that the mutation may alter the ability of β<jats:sub>1</jats:sub> to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type β<jats:sub>1</jats:sub> is occluded by coexpression of C121Wβ<jats:sub>1</jats:sub>, arguing against the idea that the mutant β<jats:sub>1</jats:sub> acts as a dominant-negative subunit. Together, these data suggest that C121Wβ<jats:sub>1</jats:sub> causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitability and epileptogenesis. </jats:p>