TY - JOUR
T1 - FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels
AU - Laezza, Fernanda
AU - Lampert, Angelika
AU - Kozel, Marie A.
AU - Gerber, Benjamin R.
AU - Rush, Anthony M.
AU - Nerbonne, Jeanne M.
AU - Waxman, Stephen G.
AU - Dib-Hajj, Sulayman D.
AU - Ornitz, David M.
N1 - Funding Information:
This work was supported by the Hope Center for Neurological Disorders, the National Ataxia Foundation, the McDonnell Center for Cellular and Molecular Neurobiology and NIH grant R01NS065761 (DMO and JMN). Work in SGW laboratory was supported in part by grants from the National Multiple Sclerosis Society and the Rehabilitation Research and Development Service and Medical Research Service, Department of Veterans Affairs. We thank L. Li and L. Tyrrell for technical assistance and M. Komada (Tokyo Institute of Technology) for providing the affinity purified chicken anti-βIV-spectrin antibody.
PY - 2009/9
Y1 - 2009/9
N2 - 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 (α) 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.
AB - 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 (α) 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.
UR - http://www.scopus.com/inward/record.url?scp=68349095136&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=68349095136&partnerID=8YFLogxK
U2 - 10.1016/j.mcn.2009.05.007
DO - 10.1016/j.mcn.2009.05.007
M3 - Article
C2 - 19465131
AN - SCOPUS:68349095136
SN - 1044-7431
VL - 42
SP - 90
EP - 101
JO - Molecular and Cellular Neuroscience
JF - Molecular and Cellular Neuroscience
IS - 2
ER -