Intrinsic mechanisms in the gating of resurgent Na+ currents

  1. Joseph L Ransdell
  2. Jonathan D Moreno PhD
  3. Druv Bhagavan
  4. Jonathan R Silva
  5. Jeanne M Nerbonne  Is a corresponding author
  1. Washington University in Saint Louis, United States
  2. Washington University in St. Louis, United States

Abstract

The resurgent component of the voltage-gated sodium current (INaR) is a depolarizing conductance, revealed on membrane hyperpolarizations following brief depolarizing voltage steps, which has been shown to contribute to regulating the firing properties of numerous neuronal cell types throughout the central and peripheral nervous systems. Although mediated by the same voltage-gated sodium (Nav) channels that underlie the transient and persistent Nav current components, the gating mechanisms that contribute to the generation of INaR remain unclear. Here, we characterized Nav currents in mouse cerebellar Purkinje neurons, and used tailored voltage-clamp protocols to define how the voltage and the duration of the initial membrane depolarization affect the amplitudes and kinetics of INaR. Using the acquired voltage-clamp data, we developed a novel Markov kinetic state model with parallel (fast and slow) inactivation pathways and, we show that this model reproduces the properties of the resurgent, as well as the transient and persistent, Nav currents recorded in (mouse) cerebellar Purkinje neurons. Based on the acquired experimental data and the simulations, we propose that resurgent Na+ influx occurs as a result of fast inactivating Nav channels transitioning into an open/conducting state on membrane hyperpolarization, and that the decay of INaR reflects the slow accumulation of recovered/opened Nav channels into a second, alternative and more slowly populated, inactivated state. Additional simulations reveal that extrinsic factors that affect the kinetics of fast or slow Nav channel inactivation and/or impact the relative distribution of Nav channels in the fast- and slow-inactivated states, such as the accessory Navβ4 channel subunit, can modulate the amplitude of INaR.

Data availability

Model definition files and Matlab scripts used for the simulations are available at https://github.com/morenomdphd/Resurgent_INa.

Article and author information

Author details

  1. Joseph L Ransdell

    Department of Medicine, Washington University in Saint Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jonathan D Moreno PhD

    Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Druv Bhagavan

    Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jonathan R Silva

    Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3696-3955
  5. Jeanne M Nerbonne

    Department of Medicine, Washington University in Saint Louis, Saint Louis, United States
    For correspondence
    jnerbonne@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8334-8499

Funding

National Institute of Neurological Disorders and Stroke (NS065761)

  • Jeanne M Nerbonne

National Heart, Lung, and Blood Institute (HL136553)

  • Jonathan R Silva

National Institute of Neurological Disorders and Stroke (NS090765)

  • Joseph L Ransdell

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Teresa Giraldez, Universidad de La Laguna, Spain

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 an approved institutional animal care and use committee (IACUC) protocol (20180045) of Washington University in St. Louis (Animal Welfare Assurance # A-3381-01).

Version history

  1. Preprint posted: April 11, 2021 (view preprint)
  2. Received: May 8, 2021
  3. Accepted: January 24, 2022
  4. Accepted Manuscript published: January 25, 2022 (version 1)
  5. Version of Record published: February 8, 2022 (version 2)

Copyright

© 2022, Ransdell 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. Joseph L Ransdell
  2. Jonathan D Moreno PhD
  3. Druv Bhagavan
  4. Jonathan R Silva
  5. Jeanne M Nerbonne
(2022)
Intrinsic mechanisms in the gating of resurgent Na+ currents
eLife 11:e70173.
https://doi.org/10.7554/eLife.70173

Share this article

https://doi.org/10.7554/eLife.70173

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