The Fibroblast Growth Factor 14·Voltage-gated Sodium Channel Complex Is a New Target of Glycogen Synthase Kinase 3 (GSK3)

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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. Background: Fibroblast growth factor 14 (FGF14) binds to and regulates the voltage-gated Na + (Nav) channel. Results: Inhibition of glycogen synthase kinase 3 (GSK3) modifies FGF14/Nav channel interaction, with effects on Na + currents and subcellular distribution of the FGF14·Nav channel complex. Conclusion: The FGF14·Nav channel complex is a new target of GSK3. Significance: We provide evidence for modulation of Nav channels by GSK3 through FGF14.