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 (α) subunits of voltage-gated Na + (Nav) channels. The neurological phenotypes seen in Fgf14-/- mice and the identification of an FGF14 missense mutation (FGF14F145S) 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 FGF14F145S reduces Nav α subunit expression at the axon initial segment, attenuates Nav channel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14F145S does not interact directly with Nav channel α subunits. Rather, FGF14F145S associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Nav α subunits, suggesting that the mutant FGF14F145S protein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Nav channel α subunits and altering neuronal excitability.

Original languageEnglish
Pages (from-to)12033-12044
Number of pages12
JournalJournal of Neuroscience
Issue number44
StatePublished - Oct 31 2007


  • Action potentials
  • Axon initial segment
  • FHFs
  • Na channels
  • Repetitive firing
  • α subunit


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