FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels.
The Intracellular Fibroblast Growth Factor (iFGF) subfamily includes four members (FGFs 11-14) of the structurally related FGF superfamily. Previous studies showed that the iFGFs interact directly with the pore-forming (alpha) subunits of voltage-gated sodium (Nav) channels and regulate the functional properties of sodium channel currents. Sequence heterogeneity among the iFGFs is thought to confer specificity to this regulation. Here, we demonstrate that the two N-terminal alternatively spliced FGF14 variants, FGF14-1a and FGF14-1b, differentially regulate currents produced by Nav1.2 and Nav1.6 channels. FGF14-1b, but not FGF14-1a, attenuates both Nav1.2 and Nav1.6 current densities. In contrast, co-expression of an FGF14 mutant, lacking the N-terminus, increased Nav1.6 current densities. In neurons, both FGF14-1a and FGF14-1b localized at the axonal initial segment, and deletion of the N-terminus abolished this localization. Thus, the FGF14 N-terminus is required for targeting and functional regulation of Nav channels, suggesting an important function for FGF14 alternative splicing in regulating neuronal excitability.
Laezza
Fernanda
F
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Lampert
Angelika
A
Kozel
Marie A
MA
Gerber
Benjamin R
BR
Rush
Anthony M
AM
Nerbonne
Jeanne M
JM
Waxman
Stephen G
SG
Dib-Hajj
Sulayman D
SD
Ornitz
David M
DM
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C568251:SCN2A protein, human; C568253:Scn2A protein, rat; C000654500:Scn2a protein, mouse; C507811:Scn8a protein, rat; D015222:Sodium Channels; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors