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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 569/1/179    most recent jphysiol.2005.097220v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lou, J.-Y. Articles by Ornitz, D. M. Search for Related Content PubMed PubMed Citation Articles by Lou, J.-Y. Articles by Ornitz, D. M.

Departments of
¹ Molecular Biology & Pharmacology
² Anatomy & Neurobiology
³ Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
⁴ Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA

Genetic ablation of the fibroblast growth factor (Fgf) 14 gene in mice or a missense mutation in Fgf14 in humans causes ataxia and cognitive deficits. These phenotypes suggest that the neuronally expressed Fgf14 gene is essential for regulating normal neuronal activity. Here, we demonstrate that FGF14 interacts directly with multiple voltage-gated Na⁺ (Nav) channel subunits heterologously expressed in non-neuronal cells or natively expressed in a murine neuroblastoma cell line. Functional studies reveal that these interactions result in the potent inhibition of Nav channel currents (I_Na) and in changes in the voltage dependence of channel activation and inactivation. Deletion of the unique amino terminus of the splice variant of Fgf14, Fgf14-1b, or expression of the splice variant Fgf14-1a modifies the modulatory effects on I_Na, suggesting an important role for the amino terminus domain of FGF14 in the regulation of Na_v channels. To investigate the function of FGF14 in neurones, we directly expressed Fgf14 in freshly isolated primary rat hippocampal neurones. In these cells, the addition of FGF14-1a–GFP or FGF14-1b–GFP increased I_Na density and shifted the voltage dependence of channel activation and inactivation. In fully differentiated neurones, FGF14-1a–GFP or FGF14-1b–GFP preferentially colocalized with endogenous Nav channels at the axonal initial segment, a critical region for action potential generation. Together, these findings implicate FGF14 as a unique modulator of Nav channel activity in the CNS and provide a possible mechanism to explain the neurological phenotypes observed in mice and humans with mutations in Fgf14.

(Received 24 August 2005; accepted after revision 13 September 2005; first published online 15 September 2005)
Corresponding author David M. Ornitz: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Campus Box 8103, 660 S. Euclid Ave., Saint Louis, MO 63110, USA. Email: dornitz{at}wustl.edu

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