A thermosensitive mutation alters the effects of lacosamide on slow inactivation in neuronal voltage-gated sodium channels, NaV1.2

Epilepsy is a disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels (Na-Vs). The C121W mutation of the beta 1 subunit, in particular, gives rise to the thermosensitive generalized epilepsy with febrile seizures plus (GEFS+) phenotype. Lacosamide is used to treat epileptic seizures and is distinct from other anti-seizure drugs by targeting Na-V slow-inactivation. We studied the effects of a physiologically relevant concentration of lacosamide on the biophysical properties of Na(V)1.2 channels associated with either WT-beta 1 or the mutant C121W-beta 1 subunit. Biophysical parameters were measured at both normal (22 degrees C) and elevated (34 degrees C) temperatures to elicit the differential temperature-sensitivity of C121W. Lacosamide was more effective in Na(V)1.2 associated with the WT-beta 1 than with C121W-beta 1 at either temperature. There is also a more potent effect by lacosamide on slow inactivation at elevated temperatures. Our data suggest a modulatory role is imparted by the beta 1 subunit in the interaction between the drug and the channel.