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

Resurgent currents (I_NaR) 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 I_NaR 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 I_NaR 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 I_NaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 I_NaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces I_NaR amplitude and the percentage of neurons that generate I_NaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant I_NaR generation and provides important potential targets for pain treatment.