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.