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

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Abstract

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 co-expression 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-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.

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All data generated or analyzed during this study are included in the manuscript.

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Yucheng Xiao

Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States

For correspondence
yuchxiao@indiana.edu

Competing interests
No competing interests declared.
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..
Agnes Zybura

Paul and Carole Stark Neurosciences Research Institute, Indiana University, Indianapolis, United States

Competing interests
No competing interests declared.
Yanling Pan

Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States

Competing interests
No competing interests declared.
Zhixin Lin

Icagen, LLC, Durham, United States

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

Biology Department, Indiana University - Purdue University Indianapolis, Indianapolis, United States

For correspondence
trcummin@iu.edu

Competing interests
No competing interests declared.

"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

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.