A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels

  1. Yucheng Xiao  Is a corresponding author
  2. Jonathan W Theile
  3. Agnes Zybura
  4. Yanling Pan
  5. Zhixin Lin
  6. Theodore R Cummins  Is a corresponding author
  1. Indiana University - Purdue University Indianapolis, United States
  2. Icagen, LLC, United States
  3. Indiana University, United States

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

  1. Yucheng Xiao

    Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States
    For correspondence
    yuchxiao@indiana.edu
    Competing interests
    No competing interests declared.
  2. Jonathan W Theile

    Icagen, LLC, Durham, United States
    Competing interests
    Jonathan W Theile, is affiliated with Icagen, LLC. The author has no financial interests to declare..
  3. Agnes Zybura

    Paul and Carole Stark Neurosciences Research Institute, Indiana University, Indianapolis, United States
    Competing interests
    No competing interests declared.
  4. Yanling Pan

    Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States
    Competing interests
    No competing interests declared.
  5. Zhixin Lin

    Icagen, LLC, Durham, United States
    Competing interests
    Zhixin Lin, is affiliated with Icagen, LLC. The author has no financial interests to declare..
  6. Theodore R Cummins

    Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States
    For correspondence
    trcummin@iu.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9509-6380

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.

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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  1. Yucheng Xiao
  2. Jonathan W Theile
  3. Agnes Zybura
  4. Yanling Pan
  5. Zhixin Lin
  6. Theodore R Cummins
(2022)
A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels
eLife 11:e77558.
https://doi.org/10.7554/eLife.77558

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https://doi.org/10.7554/eLife.77558