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

Alexander S. Shavkunov, Norelle C. Wildburger, Miroslav N. Nenov, Thomas F. James, Tetyana P. Buzhdygan, Neli I. Panova-Elektronova, Thomas A. Green, Ronald L. Veselenak, Nigel Bourne, Fernanda Laezza

Research output: Contribution to journalArticle

55 Scopus citations

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 novelGSK3-dependent signaling pathway that might control excitability through specific protein/protein interactions.

Original languageEnglish (US)
Pages (from-to)19370-19385
Number of pages16
JournalJournal of Biological Chemistry
Volume288
Issue number27
DOIs
StatePublished - Jul 5 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shavkunov, A. S., Wildburger, N. C., Nenov, M. N., James, T. F., Buzhdygan, T. P., Panova-Elektronova, N. I., Green, T. A., Veselenak, R. L., Bourne, N., & Laezza, F. (2013). The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). Journal of Biological Chemistry, 288(27), 19370-19385. https://doi.org/10.1074/jbc.M112.445924