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J Biol Chem. 2013 Jul 5;288(27):19370-85. doi: 10.1074/jbc.M112.445924. Epub 2013 May 2.

The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3).

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  • 1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, USA.

Abstract

The FGF14 protein controls biophysical properties and subcellular distribution of neuronal voltage-gated Na(+) (Nav) channels through direct binding to the channel C terminus. To gain insights into the dynamic regulation of this protein/protein interaction complex, we employed the split luciferase complementation assay to screen a small molecule library of kinase inhibitors against the FGF14·Nav1.6 channel complex and identified inhibitors of GSK3 as hits. Through a combination of a luminescence-based counter-screening, co-immunoprecipitation, patch clamp electrophysiology, and quantitative confocal immunofluorescence, we demonstrate that inhibition of GSK3 reduces the assembly of the FGF14·Nav channel complex, modifies FGF14-dependent regulation of Na(+) currents, and induces dissociation and subcellular redistribution of the native FGF14·Nav channel complex in hippocampal neurons. These results further emphasize the role of FGF14 as a critical component of the Nav channel macromolecular complex, providing evidence for a novel GSK3-dependent signaling pathway that might control excitability through specific protein/protein interactions.

KEYWORDS:

Excitability; FGF14; GSK3; Ion Channels; Neurons; Phosphorylation; Protein/Protein Interactions; Sodium Channels

PMID:
23640885
[PubMed - indexed for MEDLINE]
PMCID:
PMC3707642
Free PMC Article
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