Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels.
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 alpha 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.
Lou
Jun-Yang
JY
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Laezza
Fernanda
F
Gerber
Benjamin R
BR
Xiao
Maolei
M
Yamada
Kathryn A
KA
Hartmann
Hali
H
Craig
Ann Marie
AM
Nerbonne
Jeanne M
JM
Ornitz
David M
DM
D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology*; D007668:Kidney / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013329:Structure-Activity Relationship
D011994:Recombinant Proteins; D015222:Sodium Channels; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D012964:Sodium