TheFGF14F145SMutation Disrupts the Interaction of FGF14 with Voltage-Gated Na+Channels and Impairs Neuronal Excitability

Laezza, Fernanda; Gerber, Benjamin; Lou, Jun; Kozel, Marie; Hartman, Hali; Craig, Ann Marie; Ornitz, David M.; Nerbonne, Jeanne M.

doi:10.1523/jneurosci.2282-07.2007

Cited by 137 publications

(213 citation statements)

References 47 publications

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“…An initial clue that these VGSC regulators may have distinct, nonredundant roles came from their strikingly dissimilar subcellular distributions within the same neuron. As expected by its localization to the axons of cerebellar granule neurons (23) and previous work in hippocampal neurons (31,32), FGF14 was concentrated in the axons of cultured hippocampal neurons (Fig. 1C, Left).…”

Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalsupporting

confidence: 86%

“…Having thus validated the specificity of our Ab, we observed FGF13 localization in the hippocampus in brain slices, wherein the FGF13 signal is prominent in pyramidal neurons (Fig. 1B, Left), a cell population in which FGF14 is also highly expressed (31,32). As in cultured hippocampal neurons, FGF13 localized to axons (Fig.…”

Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalsupporting

confidence: 65%

“…To gain insight into possible regulatory roles for FGF13 and FGF14, we first examined their neuronal localizations. Although the localization of FGF14 to the axons of neurons has been well studied (23,31,32), the localization of FGF13 in the CNS has not been as extensively detailed. We have previously used a custom-made FGF13 Ab and FGF13 shRNA to examine FGF13 function in cardiomyocytes (33,34).…”

Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalmentioning

confidence: 99%

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Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Pablo

Wang

Presby

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated within the axon through mechanisms that include preferential axonal targeting and selective somatodendritic endocytosis. How the endocytic machinery specifically targets somatic VGSCs is unknown. Here, using knockdown strategies, we show that noncanonical FGF13 binds directly to VGSCs in hippocampal neurons to limit their somatodendritic surface expression, although exerting little effect on VGSCs within the AIS. In contrast, homologous FGF14, which is highly concentrated in the proximal axon, binds directly to VGSCs to promote their axonal localization. Single-point mutations in FGF13 or FGF14 abrogating VGSC interaction in vitro cannot support these specific functions in neurons. Thus, our data show how the concerted actions of FGF13 and FGF14 regulate the polarized localization of VGSCs that supports efficient action potential initiation.voltage-gated sodium channels | FGF homologous factors | FGF13 | FGF14

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Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalsupporting

confidence: 86%

Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalsupporting

confidence: 65%

Section: Fgf13 and Fgf14 Are Differentially Localized Within Hippocampalmentioning

confidence: 99%

See 1 more Smart Citation

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Pablo

Wang

Presby

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The fibroblast growth factor 14 cDNA construct pFGF14‐1b‐myc tag was a gift from Dr. David Ornitz 22. Plasmids pG β 2 IRES‐YFP and pG γ 3 IRES‐cyan encoding the G‐protein subunits G β 2 and G γ 3 were kindly provided by Dr. Massimo Mantegazza 23…”

Section: Methodsmentioning

confidence: 99%

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage‐gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.MethodsClinical exome sequencing was carried out on patients with early‐onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G‐protein subunit Gβγ, and sodium channel subunit β1 were assessed by coimmunoprecipitation.ResultsWe identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady‐state inactivation. Protein interactions were not affected.InterpretationRecurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain‐of‐function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss‐of‐function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene‐ and mutation‐specific treatments.

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“…This is because the stability of FGF14 F145S is reduced, which leads to a loss of FGF14 function [18,41]. Furthermore, FGF14 F145S may disrupt the interaction of FGF14 with Na v 1.2 channel and impair neuronal excitability [42]. Frameshift mutation and polymorphisms of Fgf14 are also found in patients with inherited ataxias [20].…”

Section: Role Of Intracellular Fgfs In Modulation Of Na V Channel Actmentioning

confidence: 99%

Roles of intracellular fibroblast growth factors in neural development and functions

Liu

et al. 2012

Sci. China Life Sci.

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Fibroblast growth factors (FGFs) can be classified as secretory (FGF1-10 and FGF15-23) or intracellular non-secretory forms (FGF11-14). Secretory forms of FGF and their receptors are best known for their regulatory roles in cell growth, differentiation and morphogenesis in the early stages of neural development. However, the functions of intracellular FGFs remain to be explored. FGF12 and FGF14 are found to interact with voltage-gated sodium channels, and regulate the channel activity in neurons. FGF13 is expressed in primary sensory neurons, and is colocalized with sodium channels at the nodes of Ranvier along the myelinated afferent fibers. FGF13 is also expressed in cerebral cortical neurons during the late developmental stage. A recent study showed that FGF13 is a microtubule-stabilizing protein required for regulating the neuronal development in the cerebral cortex. Thus, non-secretory forms of FGF appear to have important roles in the brain, and it would be interesting to further investigate the functions of intracellular FGFs in the nervous system and in neural diseases. fibroblast growth factors, nervous system, development, microtubule, ion channel, X-linked mental retardation Citation:Zhang X, Bao L, Yang L, et al. Roles of intracellular fibroblast growth factors in neural development and functions.

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TheFGF14^F145SMutation Disrupts the Interaction of FGF14 with Voltage-Gated Na⁺Channels and Impairs Neuronal Excitability

Cited by 137 publications

References 47 publications

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Roles of intracellular fibroblast growth factors in neural development and functions

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TheFGF14F145SMutation Disrupts the Interaction of FGF14 with Voltage-Gated Na+Channels and Impairs Neuronal Excitability

Cited by 137 publications

References 47 publications

Polarized localization of voltage-gated Na + channels is regulated by concerted FGF13 and FGF14 action

Polarized localization of voltage-gated Na + channels is regulated by concerted FGF13 and FGF14 action

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Roles of intracellular fibroblast growth factors in neural development and functions

Contact Info

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TheFGF14^F145SMutation Disrupts the Interaction of FGF14 with Voltage-Gated Na⁺Channels and Impairs Neuronal Excitability

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action

Polarized localization of voltage-gated Na ⁺ channels is regulated by concerted FGF13 and FGF14 action