A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS109896)
- Yucheng Xiao
- Theodore R Cummins
National Institute of Neurological Disorders and Stroke (NS053422)
- Theodore R Cummins
Indiana State Department of Health
- Yucheng Xiao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#SC307R) of the Indiana University - Purdue University Indianapolis.
Reviewing Editor
- Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
Version history
- Received: February 3, 2022
- Preprint posted: March 5, 2022 (view preprint)
- Accepted: April 19, 2022
- Accepted Manuscript published: April 20, 2022 (version 1)
- Version of Record published: May 5, 2022 (version 2)
Copyright
© 2022, Xiao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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