title: FGF14 regulates presynaptic Ca2+ channels and synaptic transmission.
abstract: Fibroblast growth factor homologous factors (FHFs) are not growth factors, but instead bind to voltage-gated Na+ channels (NaV) and regulate their function. Mutations in FGF14, an FHF that is the locus for spinocerebellar ataxia 27 (SCA27), are believed to be pathogenic because of a dominant-negative reduction of NaV currents in cerebellar granule cells. Here, we demonstrate that FGF14 also regulates members of the presynaptic CaV2 Ca2+ channel family. Knockdown of FGF14 in granule cells reduced Ca2+ currents and diminished vesicular recycling, a marker for presynaptic Ca2+ influx. As a consequence, excitatory postsynaptic currents (EPSCs) at the granule cell to Purkinje cell synapse were markedly diminished. Expression of the SCA27-causing FGF14 mutant in granule cells exerted a dominant-negative reduction in Ca2+ currents, vesicular recycling, and the resultant EPSCs in Purkinje cells. Thus, FHFs are multimodal, regulating several discrete neuronal signaling events. SCA27 most likely results at least in part from dysregulation of Ca2+ channel function.
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Haidun
authors.initials: H
authors.lastname: Yan
authors.forename: Juan L
authors.initials: JL
authors.lastname: Pablo
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D021381:Protein Transport; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D020864:Calcium Channels, N-Type; D005346:Fibroblast Growth Factors; C112971:fibroblast growth factor 14