ArticleThe Journal of biological chemistry2016
Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 37 citations in OpenAlex.
- Long-term inactivation mediated by different FGF-A homologues on heterologously expressed NaV1.2 currents.The Journal of general physiology · 2026Article
- Genotype and Age at Onset Drive Vermis Atrophy in CACNA1A- and GAA-FGF14-related Ataxias.Cerebellum (London, England) · 2026Article
- Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.Cerebellum (London, England) · 2025Article
- GAA-FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- FGF14 Peptide Derivative Differentially Regulates Nav1.2 and NaLife (Basel, Switzerland) · 2025Article
- Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models.The Journal of clinical investigation · 2025Article
- Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/NaNature communications · 2025Article
- Experimental and computational evidence that Calpain-10 binds to the carboxy terminus of NaScientific reports · 2024Article
- TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria.Journal of neuroinflammation · 2023Article
- FGF12 is a novel component of the nucleolar NOLC1/TCOF1 ribosome biogenesis complex.Cell communication and signaling : CCS · 2022Article
- New developments in the biology of fibroblast growth factors.WIREs mechanisms of disease · 2022Review
- Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases.International journal of molecular sciences · 2022Review
- Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated NaInternational journal of molecular sciences · 2021Article
- Article
- Review
- Differential Modulation of the Voltage-Gated NaFrontiers in molecular biosciences · 2021Article
- Development of Allosteric Modulators of Voltage-Gated NaCurrent topics in medicinal chemistry · 2021Review
- Design, Synthesis, and Pharmacological Evaluation of Analogues Derived from the PLEV Tetrapeptide as Protein-Protein Interaction Modulators of Voltage-Gated Sodium Channel 1.6.Journal of medicinal chemistry · 2020Article
- JAK2 regulates Nav1.6 channel function via FGF14Biochimica et biophysica acta. Molecular cell research · 2020Article
- Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics.Molecules (Basel, Switzerland) · 2020Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The voltage-gated Na(+) (Nav) channel provides the basis for electrical excitability in the brain. This channel is regulated by a number of accessory proteins including fibroblast growth factor 14 (FGF14), a member of the intracellular FGF family. In addition to forming homodimers, FGF14 binds directly to the Nav1.6 channel C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons. Seeking amino acid residues with unique roles at the protein-protein interaction interface (PPI) of FGF14·Nav1.6, we engineered model-guided mutations of FGF14 and validated their impact on the FGF14·Nav1.6 complex and the FGF14:FGF14 dimer formation using a luciferase assay. Divergence was found in the β-9 sheet of FGF14 where an alanine (Ala) mutation of Val-160 impaired binding to Nav1.6 but had no effect on FGF14:FGF14 dimer formation. Additional analysis revealed also a key role of residues Lys-74/Ile-76 at the N-terminal of FGF14 in the FGF14·Nav1.6 complex and FGF14:FGF14 dimer formation. Using whole-cell patch clamp electrophysiology, we demonstrated that either the FGF14(V160A) or the FGF14(K74A/I76A) mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na(+) currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. Intrinsic fluorescence spectroscopy of purified proteins confirmed a stronger binding reduction of FGF14(V160A) to the Nav1.6 C-tail compared with FGF14(K74A/I76A) Altogether these studies indicate that the β-9 sheet and the N terminus of FGF14 are well positioned targets for drug development of PPI-based allosteric modulators of Nav channels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.