The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability

Fernanda Laezza, Benjamin R. Gerber, Jun Yang Lou, Marie A. Kozel, Hali Hartman, Ann Marie Craig, David M. Ornitz, Jeanne M. Nerbonne

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)12033-12044
Number of pages12
JournalJournal of Neuroscience
Volume27
Issue number44
DOIs
StatePublished - Oct 31 2007
Externally publishedYes

Fingerprint

Mutation
Spinocerebellar Ataxias
Receptor Protein-Tyrosine Kinases
Missense Mutation
Mutant Proteins
fibroblast growth factor 14
Phenotype
Neurons
Proteins

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. / Laezza, Fernanda; Gerber, Benjamin R.; Lou, Jun Yang; Kozel, Marie A.; Hartman, Hali; Craig, Ann Marie; Ornitz, David M.; Nerbonne, Jeanne M.

In: Journal of Neuroscience, Vol. 27, No. 44, 31.10.2007, p. 12033-12044.

Research output: Contribution to journalArticle

Laezza, Fernanda ; Gerber, Benjamin R. ; Lou, Jun Yang ; Kozel, Marie A. ; Hartman, Hali ; Craig, Ann Marie ; Ornitz, David M. ; Nerbonne, Jeanne M. / The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 44. pp. 12033-12044.
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