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Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action.

TitlePolarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action.
Publication TypeJournal Article
Year of Publication2016
AuthorsPablo JLorenzo, Wang C, Presby MM, Pitt GS
JournalProc Natl Acad Sci U S A
Volume113
Issue19
PaginationE2665-74
Date Published2016 May 10
ISSN1091-6490
KeywordsAction Potentials, Axons, Humans, Neurons, Sodium, Sodium Channels, Voltage-Gated Sodium Channels
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.

DOI10.1073/pnas.1521194113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27044086
PubMed Central IDPMC4868475
Grant ListR01 HL112918 / HL / NHLBI NIH HHS / United States
R01 HL122967 / HL / NHLBI NIH HHS / United States