The FGF14 super(F145S) Mutation Disrupts the Interaction of FGF14 with Voltage-Gated Na super(+) Channels and Impairs Neuronal Excitability

Fibroblast growth factor 14 (FGF14) belongs to the intracellular FGF homologous factor subfamily of FGF proteins (iFGFs) that are not secreted and do not activate tyrosine kinase receptors. The iFGFs, however, have been shown to interact with the pore-forming ( alpha ) subunits of voltage-gated Na super(+) (Na sub(v)) channels. The neurological phenotypes seen in Fgf14 super(-/-) mice and the identification of an FGF14 missense mutation (FGF14 super(F145S)) in a Dutch family presenting with cognitive impairment and spinocerebellar ataxia suggest links between FGF14 and neuronal functioning. Here, we demonstrate that the expression of FGF14 super(F145S) reduces Na sub(v) alpha subunit expression at the axon initial segment, attenuates Na sub(v) channel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14 super(F145S) does not interact directly with Na sub(v) channel alpha subunits. Rather, FGF14 super(F145S) associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na sub(v) alpha subunits, suggesting that the mutant FGF14 super(F145S) protein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Na sub(v) channel alpha subunits and altering neuronal excitability.