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The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability.

Authors :
Laezza F
Gerber BR
Lou JY
Kozel MA
Hartman H
Craig AM
Ornitz DM
Nerbonne JM
Source :
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2007 Oct 31; Vol. 27 (44), pp. 12033-44.
Publication Year :
2007

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 (alpha) 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) alpha 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 alpha subunits. Rather, FGF14(F145S) associates with wild-type FGF14 and disrupts the interaction between wild-type FGF14 and Na(v) alpha 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 alpha subunits and altering neuronal excitability.

Details

Language :
English
ISSN :
1529-2401
Volume :
27
Issue :
44
Database :
MEDLINE
Journal :
The Journal of neuroscience : the official journal of the Society for Neuroscience
Publication Type :
Academic Journal
Accession number :
17978045
Full Text :
https://doi.org/10.1523/JNEUROSCI.2282-07.2007