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 co-expression 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-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.