A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels

• Published in: eLife Vol. 11
• Main Authors: Xiao, Yucheng, Theile, Jonathan W, Zybura, Agnes, Pan, Yanling, Lin, Zhixin, Cummins, Theodore R
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 20.04.2022; eLife Sciences Publications, Ltd
• Subjects: Action Potentials - physiology; dorsal root ganglion; Excitability; FHF; Fibroblast growth factors; Fibroblasts; Firing rate; Ganglia, Spinal - metabolism; Growth factors; N-Terminus; Navβ4; Neurogenesis; Neurons; Neuroscience; Pain perception; Peptides; Protein Isoforms - metabolism; resurgent currents; Sensory neurons; Sensory Receptor Cells - physiology; Sodium; sodium channel; Sodium channels (voltage-gated); Tetrodotoxin; Tetrodotoxin - pharmacology; Voltage-Gated Sodium Channels - genetics; Voltage-Gated Sodium Channels - metabolism; rat; sodium channel; FHF; neuroscience; dorsal root ganglion; resurgent currents; Navβ4
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.77558

Resurgent currents ( ) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that can be reconstituted in a heterologous system by coexpression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces from Nav1.8, Nav1.9 tetrodotoxin (TTX)-resistant neuronal channels, and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated . Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 . In nociceptive sensory neurons, FHF4A knockdown significantly reduces amplitude and the percentage of neurons that generate , substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant generation and provides important potential targets for pain treatment.