C121W: A thermosensitive sodium channel mutation

A mutation in the β1 subunit of the voltage-gated sodium (NaV) channel, β1(CW), causes genetic epilepsy with febrile seizures plus (GEFS+), wherein elevated body temperature increases neuronal excitability. This study investigated the putative mechanism underlying seizure generation in β1(CW) caused by elevated temperature. Whole-cell voltage clamp experiments were performed on CHO cells expressing the α subunit of neuronal isoform NaV1.2, either alone, with β1, or with β1(CW) at 22°C and 34°C . Results suggest that wild-type β1 is protective against increased channel excitability induced by elevated temperature, and that this protection is lost in the absence of β1 or with the expression of β1(CW). At 34°C, β1(CW) increased channel excitability compared to wild-type β1 by decreasing use-dependent inactivation, increasing persistent current and window current, and delaying the onset of, and accelerating the recovery from, fast-inactivation. These results help explain how the β1(CW) mutation contributes to the febrile seizure phenotype by increasing channel excitability specifically at elevated temperature.