RT Journal Article
SR Electronic
T1 A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.04.482974
DO 10.1101/2022.03.04.482974
A1 Yucheng Xiao
A1 Jonathan W. Theile
A1 Agnes Zybura
A1 Yanling Pan
A1 Zhixin Lin
A1 Theodore R. Cummins
YR 2022
UL http://biorxiv.org/content/early/2022/03/05/2022.03.04.482974.abstract
AB Resurgent currents (INaR) 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 INaR 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 INaR 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 INaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 INaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces INaR amplitude and the percentage of neurons that generate INaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant INaR generation and provides important potential targets for pain treatment.Competing Interest StatementThe authors have declared no competing interest.