Enhanced inactivation and acceleration of activation of the sodium channelassociated with epilepsy in man

Generalized epilepsy with febrile seizures-plus (GEFS(+)) is a benign Mende lian syndrome characterized by childhood-onset febrile and afebrile seizure s. Three point mutations within two voltage-gated sodium channel genes have been identified so far: in GEFS(+) type 1 a mutation in the beta (1)-subun it gene SCN1B, and in GEFS(+) type 2 two mutations within the neuronal alph a -subunit gene SCN1A. Functional expression of the SCN1B and one of the SC N1A mutations revealed defects in fast channel inactivation which are in li ne with previous findings on myotonia causing mutations in SCN4A, the skele tal muscle sodium channel alpha -subunit gene, all showing an impaired fast inactivation. We now studied the second GEFS+ mutation (T875M in SCN1A), u sing the highly homologous SCN4A gene (mutation T685M). Unexpectedly, the e xperiments revealed a pronounced enhancement of both fast and slow inactiva tion and a defect of channel activation for T685M compared to wild-type cha nnels. Steady-state fast and slow inactivation curves were shifted in the h yperpolarizing direction, entry into slow inactivation was threefold accele rated, recovery from slow inactivation was slowed by threefold and the time course of activation was slightly but significantly accelerated. in contra st to other disease-causing mutations in SCN1A, SCN1B and SCN4A, the only m echanism that could explain hyperexcitability of the cell membrane would be the acceleration of activation. Because the enhancement of slow inactivati on was the most obvious alteration in gating found for T685M, this might be the disease-causing mechanism for that mutation. In this case, the occurre nce of epileptic seizures could be explained by a decrease of excitability of inhibitory neurons.