Differential Regulation of Nav1.1 and SCN1A Disease Mutant Sodium Current Properties by Fibroblast Growth Factor Homologous Factors

Fibroblast growth factor homologous factors (FHFs) regulate the activity of several different voltage-gated sodium channels (Na_vs). However, more work is needed to determine how specific FHF isoforms and variants affect the properties of different Na_v isoforms. In addition, it is not known if FHFs can differentially modulate the properties of Na_v variants associated with disease. Here, we investigated the effects of FHF2A and FHF2B on Nav1.1 properties as well as on a familial hemiplegic migraine 3 (FHM3) causing mutation in this channel, F1774S. We found that FHF2A, but not 2B, induced prominent long-term inactivation (LTI) in the wild-type (WT) Nav1.1. Interestingly, FHF2A induced LTI in the F1774S FHM3 mutant channel to a greater extent than in the WT. Furthermore, persistent currents caused by the F1774S mutation were attenuated by the co-expression of FHF2A, leading to a possible rescue of the mutant channel phenotype. By contrast, the P1894L mutation, which is associated with epilepsy and mild intellectual disability, greatly attenuated the LTI induced by FHF2A. Overall, our data show for the first time that FHF2A might be a significant modulator of Nav1.1 that can differentially modulate the impact of Nav1.1 disease-associated mutations.