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.voltage-gated sodium channels | FGF homologous factors | FGF13 | FGF14

Another piece to the intracellular FGF/Na + channel puzzle

“…Pablo et al (9) show that expression of shRNAresistant FGF13VY, but not FGF13S, restored the current density after FGF13 knockdown. Interestingly, both FGF13S and FGF13U (also known as FGF13B or FHF2B) expression increase Na v 1.6 current density in DRG-derived ND7/23 cells (5,6), in direct contrast to the role of FGF13VY in decreasing current density as discussed above.…”

“…Interestingly, mutations in human FGF14 have been linked to spinocerebellar ataxia (7), and mice lacking FGF14 are ataxic (8). Clearly, FGF−Na v channel interactions are worthy of extensive study, and, in PNAS, Pablo et al (9) use multiple experimental approaches with cultured hippocampal neurons to support the idea that FGF13 and FGF14 differentially regulate Na v channel cell surface expression within somatodendritic and axonal compartments. Thus, FGFs are likely to be central players in the regulation of Na v channel cell biology.…”

“…Based on these results, Pablo et al (9) hypothesized that FGF14 is involved in trafficking Na v channels to the AIS, whereas FGF13 mediates endocytosis of Na v channels within the somadendritic domain. The authors next used a biotinylation assay to measure surface expression of Na v channels in cultured hippocampal neurons after either FGF13 or FGF14 knockdown.…”

“…Such experiments have been done for other ion channels, such as K v 2.1 (19). Pablo et al (9) suggest FGF14 may enhance trafficking of Na v channels to the axonal compartment. The authors also performed rescue experiments with FGF14 that indicate direct binding is required for the regulation of Na v expression within the AIS.…”

“…Pablo et al (9) provide a valuable contribution to our understanding of FGFs' complex influence on neuronal excitability. Although previous studies have tackled FGF isoforms separately, these investigators explore the differing effects of two FGF isoforms in the same neuronal type.…”