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The Journal of Neuroscience, October 31, 2007, 27(44):12033-12044; doi:10.1523/JNEUROSCI.2282-07.2007

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Cellular/Molecular
The FGF14^F145S Mutation Disrupts the Interaction of FGF14 with Voltage-Gated Na⁺ Channels and Impairs Neuronal Excitability

Fernanda Laezza,^1,2 Benjamin R. Gerber,¹ Jun-Yang Lou,¹ Marie A. Kozel,¹ Hali Hartman,³ Ann Marie Craig,² David M. Ornitz,¹ and Jeanne M. Nerbonne¹

Departments of ¹Molecular Biology and Pharmacology and ²Anatomy and Neurobiology, Washington University Medical School, St. Louis, Missouri 63110, and ³Institute of Molecular Cardiology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

Correspondence should be addressed to Dr. Jeanne M. Nerbonne, Department of Molecular Biology and Pharmacology, Box 8103, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110. Email: jnerbonne{at}wustl.edu

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 () subunits of voltage-gated Na⁺ (Na_v) channels. The neurological phenotypes seen in Fgf14^–/– mice and the identification of an FGF14 missense mutation (FGF14^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^F145S reduces Na_v subunit expression at the axon initial segment, attenuates Na_v channel currents, and reduces the excitability of hippocampal neurons. In addition, and in contrast with wild-type FGF14, FGF14^F145S does not interact directly with Na_v channel subunits. Rather, FGF14^F145S associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na_v subunits, suggesting that the mutant FGF14^F145S protein acts as a dominant negative, interfering with the interaction between wild-type FGF14 and Na_v channel subunits and altering neuronal excitability.

Key words: FHFs; Na_v channels; action potentials; repetitive firing; axon initial segment; subunit

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Received May 18, 2007; revised Sept. 10, 2007; accepted Sept. 16, 2007.

Correspondence should be addressed to Dr. Jeanne M. Nerbonne, Department of Molecular Biology and Pharmacology, Box 8103, Washington University Medical School, 660 South Euclid Avenue, St. Louis, MO 63110. Email: jnerbonne{at}wustl.edu

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