FGF14 Regulates Presynaptic Ca2+ Channels and Synaptic Transmission

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. [Display omitted] •FGF14 regulates presynaptic CaV2.1 at the granule cell to Purkinje cell synapse•FGF14 regulates presynaptic Ca2+ influx at the granule cell to Purkinje cell synapse•FGF14 regulates synaptic transmission at the granule cell to Purkinje cell synapse•Mutant FGF14 affects all of these processes adversely Fibroblast growth factor homologous factors, which are known to interact with Na+ channels, are now shown by Yan, Pablo, and Pitt to regulate presynaptic CaV2-type Ca2+ channels in cerebellar granule cells. Furthermore, the authors show that the spinocerebellar ataxia 27 (SCA27)-associated mutant, FGF14bF150S, acts in a dominant-negative manner to suppress CaV2 Ca2+ channels and thereby reduce synaptic transmission at the granule cell to Purkinje cell synapse. These data provide insights into the pathological mechanisms of SCA27.