title: Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action.
abstract: Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated within the axon through mechanisms that include preferential axonal targeting and selective somatodendritic endocytosis. How the endocytic machinery specifically targets somatic VGSCs is unknown. Here, using knockdown strategies, we show that noncanonical FGF13 binds directly to VGSCs in hippocampal neurons to limit their somatodendritic surface expression, although exerting little effect on VGSCs within the AIS. In contrast, homologous FGF14, which is highly concentrated in the proximal axon, binds directly to VGSCs to promote their axonal localization. Single-point mutations in FGF13 or FGF14 abrogating VGSC interaction in vitro cannot support these specific functions in neurons. Thus, our data show how the concerted actions of FGF13 and FGF14 regulate the polarized localization of VGSCs that supports efficient action potential initiation.
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710;
authors.forename: Juan Lorenzo
authors.initials: JL
authors.lastname: Pablo
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Presby
authors.affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC 27710; Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710; Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC 27710 geoffrey.pitt@duke.edu.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000200:Action Potentials; D001369:Axons / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D015222:Sodium Channels; D061566:Voltage-Gated Sodium Channels; D012964:Sodium
keywords: FGF homologous factors; FGF13; FGF14; voltage-gated sodium channels