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The Journal of Neuroscience, July 28, 2004, 24(30):6765-6775; doi:10.1523/JNEUROSCI.1628-04.2004

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Cellular/Molecular
Fibroblast Growth Factor Homologous Factor 2B: Association with Na_v1.6 and Selective Colocalization at Nodes of Ranvier of Dorsal Root Axons

Ellen K. Wittmack,^1,3,4 Anthony M. Rush,^2,3,4 Matthew J. Craner,^2,3,4 Mitchell Goldfarb,⁵ Stephen G. Waxman,^2,3,4 and Sulayman D. Dib-Hajj^2,3,4

Departments of ¹Pharmacology and ²Neurology and ³The Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, ⁴Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, and ⁵Department of Biological Sciences, Hunter College of City University, New York, New York 10021

Voltage-gated sodium channels interact with cytosolic proteins that regulate channel trafficking and/or modulate the biophysical properties of the channels. Na_v1.6 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_v1.6 as a bait, we identified FHF2B, a member of the FGF homologous factor (FHF) subfamily, as an interacting partner of Na_v1.6. Members of the FHF subfamily share 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_v1.6 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_v1.6 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.

Key words: dorsal root ganglia; sodium channels; nodes of Ranvier; yeast two-hybrid assay; ventral root; dorsal root

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Received April 28, 2004; revised June 14, 2004; accepted June 16, 2004.

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