title: FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons.
abstract: Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na(+) (NaV) 'resurgent' current, which allows renewed Na(+) influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent current have not been fully identified. In this study, we show that the NaV channel auxiliary subunit FGF14 'b' isoform, a locus for inherited spinocerebellar ataxias, controls resurgent current and repetitive firing in Purkinje neurons. FGF14 knockdown biased NaV channels towards the inactivated state by decreasing channel availability, diminishing the 'late' NaV current, and accelerating channel inactivation rate, thereby reducing resurgent current and repetitive spiking. Critical for these effects was both the alternatively spliced FGF14b N-terminus and direct interaction between FGF14b and the NaV C-terminus. Together, these data suggest that the FGF14b N-terminus is a potent regulator of resurgent NaV current in cerebellar Purkinje neurons.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, United States.
authors.forename: Haidun
authors.initials: H
authors.lastname: Yan
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, United States.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Pablo
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, United States.
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, United States.
authors.forename: Geoffrey S
authors.identifier: http://orcid.org/0000-0003-2246-0289
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000200:Action Potentials; D000818:Animals; D002531:Cerebellum / Q000166:cytology*; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism*; D005799:Genes, Dominant; D015640:Ion Channel Gating; D007700:Kinetics; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D011689:Purkinje Cells / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D034741:RNA, Small Interfering; D015222:Sodium Channels; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors
keywords: cerebellar Purkinje neurons; cerebellum; electrophysiology; mouse; neuroscience; resurgent sodium current; spinocerebellar ataxia