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 Green, Ronald L. Veselenak, Nigel Bourne, Fernanda Laezza

Research output: Contribution to journalArticle

48 Citations (Scopus)

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

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Glycogen Synthase Kinase 3
Fibroblast Growth Factors
Sodium Channels
Proteins
Small Molecule Libraries
Electrophysiology
Macromolecular Substances
Clamping devices
Electric potential
Luminescence
Luciferases
Immunoprecipitation
Neurons
Fluorescent Antibody Technique
Assays
Screening
Phosphotransferases
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Shavkunov, A. S., Wildburger, N. C., Nenov, M. N., James, T. F., Buzhdygan, T. P., Panova-Elektronova, N. I., ... 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

The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). / Shavkunov, Alexander S.; Wildburger, Norelle C.; Nenov, Miroslav N.; James, Thomas F.; Buzhdygan, Tetyana P.; Panova-Elektronova, Neli I.; Green, Thomas; Veselenak, Ronald L.; Bourne, Nigel; Laezza, Fernanda.

In: Journal of Biological Chemistry, Vol. 288, No. 27, 05.07.2013, p. 19370-19385.

Research output: Contribution to journalArticle

Shavkunov, AS, Wildburger, NC, Nenov, MN, James, TF, Buzhdygan, TP, Panova-Elektronova, NI, Green, T, Veselenak, RL, 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, vol. 288, no. 27, pp. 19370-19385. https://doi.org/10.1074/jbc.M112.445924
Shavkunov AS, Wildburger NC, Nenov MN, James TF, Buzhdygan TP, Panova-Elektronova NI et al. The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). Journal of Biological Chemistry. 2013 Jul 5;288(27):19370-19385. https://doi.org/10.1074/jbc.M112.445924
Shavkunov, Alexander S. ; Wildburger, Norelle C. ; Nenov, Miroslav N. ; James, Thomas F. ; Buzhdygan, Tetyana P. ; Panova-Elektronova, Neli I. ; Green, Thomas ; Veselenak, Ronald L. ; Bourne, Nigel ; Laezza, Fernanda. / The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 27. pp. 19370-19385.
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