Fibroblast Growth Factors and Voltage-Gated Sodium Channels in Neuronal Excitability

Neuronal excitability arises from the coordinated action of ion channels and their accessory proteins within specialised domains of the neuron. Fibroblast growth factor homologous factors (FHFs), a subset of intracellular fibroblast growth factors, have emerged as critical modulators of voltage-gated sodium channels (VGSCs) at the axon initial segment. By binding directly to the C-terminal regions of specific Nav α-subunits, FHFs influence channel gating kinetics, membrane targeting and phosphorylation state. These interactions fine-tune initiation and propagation of action potentials, regulating firing frequency, resurgent currents and synaptic integration. Dysfunction in FHF–VGSC complexes has been implicated in a spectrum of neurological disorders, ranging from spinocerebellar ataxia to mood and cognitive syndromes. Moreover, dynamic regulation of FHF–Nav interactions by kinase pathways integrates extracellular signals with intrinsic excitability, enabling adaptive plasticity in health and disease. Understanding the molecular architecture of FHF-channel assemblies and their modulation by post-translational modifications is therefore essential for comprehending and ultimately treating channelopathies and neuroinflammatory conditions marked by aberrant firing patterns.

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Fibroblast Growth Factors and Voltage-Gated Sodium Channels in Neuronal Excitability publication trend

The graph below shows the total number of articles in fibroblast growth factors and voltage-gated sodium channels in neuronal excitability across all publications each year (not limited to Nature Index journals).

Technical terms

Fibroblast growth factor homologous factors (FHFs): A family of intracellular FGFs that bind to Nav channel C-termini, modulating gating and localisation.

Voltage-gated sodium channels (VGSCs): Transmembrane pore-forming proteins that initiate and propagate action potentials in excitable cells.

Neuronal excitability: The capacity of a neuron to respond to stimuli by generating and transmitting action potentials.

Axon initial segment (AIS): A specialised region of the proximal axon where action potentials are initiated, enriched in VGSCs and scaffolding proteins.

Resurgent sodium current: A flow of sodium ions during repolarisation that enables high-frequency neuronal firing.

Gating kinetics: The dynamic processes of channel opening, closing and inactivation that determine ion flux.

References

1. TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria. Journal of Neuroinflammation (2023).
2. Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders. Frontiers in Cellular Neuroscience (2017).
3. Identification of Novel Interaction Sites that Determine Specificity between Fibroblast Growth Factor Homologous Factors and Voltage-gated Sodium Channels*. Journal of Biological Chemistry (2011).
4. FGF14 modulates resurgent sodium current in mouse cerebellar Purkinje neurons. eLife (2014).
5. Identifying a Kinase Network Regulating FGF14:Nav1.6 Complex Assembly Using Split-Luciferase Complementation. PLOS ONE (2015).