title: The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3).
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.
authors: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors: Alexander S
authors: AS
authors: Shavkunov
authors: Norelle C
authors: NC
authors: Wildburger
authors: Miroslav N
authors: MN
authors: Nenov
authors: Thomas F
authors: TF
authors: James
authors: Tetyana P
authors: TP
authors: Buzhdygan
authors: Neli I
authors: NI
authors: Panova-Elektronova
authors: Thomas A
authors: TA
authors: Green
authors: Ronald L
authors: RL
authors: Veselenak
authors: Nigel
authors: N
authors: Bourne
authors: Fernanda
authors: F
authors: Laezza
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D062557:NAV1.6 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human; C491046:Scn8a protein, mouse; C507811:Scn8a protein, rat; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D038362:Glycogen Synthase Kinase 3
keywords: Excitability; FGF14; GSK3; Ion Channels; Neurons; Phosphorylation; Protein/Protein Interactions; Sodium Channels
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