Fibroblast growth factor homologous factor 2B: association with Nav1.6 and selective colocalization at nodes of Ranvier of dorsal root axons.
Voltage-gated sodium channels interact with cytosolic proteins that regulate channel trafficking and/or modulate the biophysical properties of the channels. Na(v)1.6 is heavily expressed at the nodes of Ranvier along adult CNS and PNS axons and along unmyelinated fibers in the PNS. In an initial yeast two-hybrid screen using the C terminus of Na(v)1.6 as a bait, we identified FHF2B, a member of the FGF homologous factor (FHF) subfamily, as an interacting partner of Na(v)1.6. Members of the FHF subfamily share approximately 70% sequence identity, and individual members demonstrate a cell- and tissue-specific expression pattern. FHF2 is abundantly expressed in the hippocampus and DRG neurons and colocalizes with Na(v)1.6 at mature nodes of Ranvier in myelinated sensory fibers in the dorsal root of the sciatic nerve. However, retinal ganglion cells and spinal ventral horn motor neurons show very low levels of FHF2 expression, and their axons exhibit no nodal FHF2 staining within the optic nerve and ventral root, respectively. Thus, FHF2 is selectively localized at nodes of dorsal root sensory but not ventral root motor axons. The coexpression of FHF2B and Na(v)1.6 in the DRG-derived cell line ND7/23 significantly increases the peak current amplitude and causes a 4 mV depolarizing shift of voltage-dependent inactivation of the channel. The preferential expression of FHF2B in sensory neurons may provide a basis for physiological differences in sodium currents that have been reported at the nodes of Ranvier in sensory versus motor axons.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Ellen K
EK
Wittmack
Anthony M
AM
Rush
Matthew J
MJ
Craner
Mitchell
M
Goldfarb
Stephen G
SG
Waxman
Sulayman D
SD
Dib-Hajj
D000818:Animals; D000870:Anterior Horn Cells / Q000737:chemistry; D001369:Axons / Q000737:chemistry / Q000648:ultrastructure; D001923:Brain Chemistry; D002478:Cells, Cultured / Q000737:chemistry; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000737:chemistry* / Q000166:cytology; D006624:Hippocampus / Q000737:chemistry*; D006801:Humans; D051379:Mice; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009475:Neurons, Afferent / Q000737:chemistry* / Q000502:physiology; D009928:Organ Specificity; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011901:Ranvier's Nodes / Q000737:chemistry*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000737:chemistry; D012584:Sciatic Nerve / Q000737:chemistry / Q000166:cytology; D015222:Sodium Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques
C496249:Fgf13 protein, rat; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C491046:Scn8a protein, mouse; D015222:Sodium Channels; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors