Biology department, School of Science, Indiana University Purdue University Indianapolis, Indianapolis, United States.
Icagen LLC, 4222 Emperor Blvd #350, Durham, United States.
Elife. 2022 Apr 20;11:e77558. 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.
电压门控钠离子通道产生的再生电流对于许多神经元维持高频放电以及导致神经元过度兴奋和疾病病理生理学至关重要。在这里，我们首次表明，通过共表达钠离子通道α亚基和 A 型成纤维细胞生长因子同源因子（FHFs），可以在异源系统中重建。具体而言，A 型 FHFs 诱导 Nav1.8、Nav1.9 河豚毒素（TTX）抗性神经元通道产生 ，并且在较小程度上诱导神经元 Nav1.7 和心脏 Nav1.5 通道产生 。此外，我们确定 FHF 的 N 端是负责 A 型 FHFs 介导的 关键分子。在伤害感受感觉神经元中，FHF4A 的敲低显著降低 幅度和产生 的神经元比例，从而显著抑制兴奋性。因此，我们的工作揭示了 TTX 抗性 产生的新分子机制，并为疼痛治疗提供了重要的潜在靶点。
