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The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability.
- 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.
- Subjects :
- Animals
Cells, Cultured
Dose-Response Relationship, Radiation
Electric Stimulation methods
Embryo, Mammalian
Fibroblast Growth Factors genetics
Gene Expression Regulation genetics
Green Fluorescent Proteins biosynthesis
Hippocampus cytology
Humans
Immunoprecipitation methods
Ion Channel Gating physiology
Membrane Potentials drug effects
Membrane Potentials genetics
Membrane Potentials radiation effects
Neurons drug effects
Patch-Clamp Techniques methods
Rats
Sodium Channel Blockers pharmacology
Sodium Channels chemistry
Sodium Channels genetics
Tetrodotoxin pharmacology
Fibroblast Growth Factors physiology
Mutation physiology
Neurons physiology
Phenylalanine genetics
Serine genetics
Sodium Channels physiology
Subjects
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