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The Journal of Neuroscience, December 15, 2002, 22(24):10699-10709
Functional and Biochemical Analysis of a Sodium Channel  1
Subunit Mutation Responsible for Generalized Epilepsy with Febrile
Seizures Plus Type 1
Laurence S.
Meadows1, 2, *,
Jyoti
Malhotra2, *,
Andrew
Loukas1,
Veena
Thyagarajan2,
Kristin A.
Kazen-Gillespie2,
Matthew C.
Koopman2,
Steven
Kriegler2,
Lori L.
Isom2, and
David S.
Ragsdale1
1 Department of Neurology and Neurosurgery, Montreal
Neurological Institute, McGill University, Montreal, Quebec H3A 2B4,
Canada, and 2 Department of Pharmacology, University of
Michigan, Ann Arbor, Michigan 48109-0632
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
immunoglobin domain of the auxiliary  1 subunit of the voltage-gated
sodium channel. The mutation disrupts 1 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 1
mutation results in seizures. First, using electrophysiological
recordings from mammalian cell lines, coexpressing sodium channel  subunits and either wild-type 1 or C121W1, we show that loss of
1 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
1. In contrast, neither wild-type 1 nor C121W1 significantly
affected sodium current time course or the voltage dependence of
channel activation. We also show, using a Drosophila S2
cell adhesion assay, that the C121W mutation disrupts 1-1
homophilic cell adhesion, suggesting that the mutation may alter the
ability of 1 to mediate protein-protein interactions critical for
sodium channel localization. Finally, we demonstrate that neither
functional modulation nor cell adhesion mediated by wild-type 1 is
occluded by coexpression of C121W1, arguing against the idea that
the mutant 1 acts as a dominant-negative subunit. Together,
these data suggest that C121W1 causes subtle effects on channel
function and subcellular distribution that bias neurons toward
hyperexcitabity and epileptogenesis.
Key words:
voltage-gated sodium channel; 1 subunit; epilepsy; channelopathy; patch clamp; cell adhesion; Drosophila S2
cells
*
L.S.M. and J.M. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/222410699-11$05.00/0
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