Modulation of sodium current in mammalian cells by an epilepsy-correlated beta 1-subunit mutation.
The syndrome of generalized epilepsy with febrile seizure plus (GEFS+) is associated with a single point mutation on the gene SCN1B that results in a substitution of the cysteine 121 with a tryptophane in the sodium channel beta 1-subunit protein. We have studied, in the HEK cells permanently transfected with the skeletal muscle sodium channel alpha-subunit (SkM1), the effects of a transient transfection of the wild type (WT) or C121W mutant beta 1-subunit. Coexpression of the WT beta 1 produces two effects on the sodium currents expressed in mammalian cells: the increase in the density of sodium channels, and the modulation of the inactivation of the sodium currents, inducing a hastening of the recovery from the inactivation. This modulation is less severe as observed when sodium channels are expressed in frog oocytes. We have observed that mutant C121W lacks this modulatory property, but maintains its property to increase the current density. Our observation suggests a possible involvement of this lack of modulation in the development of the GEFS+, providing the first hypothesis based on the observation of the functional properties of the beta 1-subunit C121W mutant in mammalian cells, which certainly represents a more physiological preparation, instead of in Xenopus oocytes, where the modulatory properties of the beta 1-subunit are artificially amplified.
Tammaro
Paolo
P
Istituto di Cibernetica e Biofisica, CNR, Via De Marini, 6, I-16149, Genoa, Italy.
Conti
Franco
F
Moran
Oscar
O
D000818:Animals; D002460:Cell Line; D004553:Electric Conductivity; D004827:Epilepsy / Q000235:genetics; D006801:Humans; D007700:Kinetics; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D021122:Protein Subunits; D003294:Seizures, Febrile / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D013577:Syndrome; D014162:Transfection; D014407:Tumor Cells, Cultured
D021122:Protein Subunits; D015222:Sodium Channels; D012964:Sodium