FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels

Fernanda Laezza, Angelika Lampert, Marie A. Kozel, Benjamin R. Gerber, Anthony M. Rush, Jeanne M. Nerbonne, Stephen G. Waxman, Sulayman D. Dib-Hajj, David M. Ornitz

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Abstract

The Intracellular Fibroblast Growth Factor (iFGF) subfamily includes four members (FGFs 11-14) of the structurally related FGF superfamily. Previous studies showed that the iFGFs interact directly with the pore-forming (α) subunits of voltage-gated sodium (Nav) channels and regulate the functional properties of sodium channel currents. Sequence heterogeneity among the iFGFs is thought to confer specificity to this regulation. Here, we demonstrate that the two N-terminal alternatively spliced FGF14 variants, FGF14-1a and FGF14-1b, differentially regulate currents produced by Nav1.2 and Nav1.6 channels. FGF14-1b, but not FGF14-1a, attenuates both Nav1.2 and Nav1.6 current densities. In contrast, co-expression of an FGF14 mutant, lacking the N-terminus, increased Nav1.6 current densities. In neurons, both FGF14-1a and FGF14-1b localized at the axonal initial segment, and deletion of the N-terminus abolished this localization. Thus, the FGF14 N-terminus is required for targeting and functional regulation of Nav channels, suggesting an important function for FGF14 alternative splicing in regulating neuronal excitability.

Original languageEnglish (US)
Pages (from-to)90-101
Number of pages12
JournalMolecular and Cellular Neuroscience
Volume42
Issue number2
DOIs
StatePublished - Sep 2009
Externally publishedYes

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Voltage-Gated Sodium Channels
Fibroblast Growth Factors
Sodium Channels
Alternative Splicing
Neurons
fibroblast growth factor 14

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. / Laezza, Fernanda; Lampert, Angelika; Kozel, Marie A.; Gerber, Benjamin R.; Rush, Anthony M.; Nerbonne, Jeanne M.; Waxman, Stephen G.; Dib-Hajj, Sulayman D.; Ornitz, David M.

In: Molecular and Cellular Neuroscience, Vol. 42, No. 2, 09.2009, p. 90-101.

Research output: Contribution to journalArticle

Laezza, F, Lampert, A, Kozel, MA, Gerber, BR, Rush, AM, Nerbonne, JM, Waxman, SG, Dib-Hajj, SD & Ornitz, DM 2009, 'FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels', Molecular and Cellular Neuroscience, vol. 42, no. 2, pp. 90-101. https://doi.org/10.1016/j.mcn.2009.05.007
Laezza, Fernanda ; Lampert, Angelika ; Kozel, Marie A. ; Gerber, Benjamin R. ; Rush, Anthony M. ; Nerbonne, Jeanne M. ; Waxman, Stephen G. ; Dib-Hajj, Sulayman D. ; Ornitz, David M. / FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. In: Molecular and Cellular Neuroscience. 2009 ; Vol. 42, No. 2. pp. 90-101.
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