TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

  1. Ki Bum Um
  2. Suyun Hahn
  3. So Woon Kim
  4. Yoon Je Lee
  5. Lutz Birnbaumer
  6. Hyun Jin Kim  Is a corresponding author
  7. Myoung Kyu Park  Is a corresponding author
  1. Sungkyunkwan University School of Medicine, Republic of Korea
  2. Catholic University of Argentina, Argentina

Abstract

Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold slow depolarization underlies autonomous pacemaking and determines its rate. However, the ion channels that determine slow depolarization are unknown. Here we show that TRPC3 and NALCN channels together form sustained inward currents responsible for the slow depolarization of nigral DA neurons. Specific TRPC3 channel blockade completely blocked DA neuron pacemaking, but the pacemaking activity in TRPC3 knock-out (KO) mice was perfectly normal, suggesting the presence of compensating ion channels. Blocking NALCN channels abolished pacemaking in both TRPC3 KO and wild-type mice. The NALCN current and mRNA and protein expression are increased in TRPC3 KO mice, indicating that NALCN compensates for TRPC3 currents. In normal conditions, TRPC3 and NALCN contribute equally to slow depolarization. Therefore, we conclude that TRPC3 and NALCN are two major leak channels that drive robust pacemaking in nigral DA neurons.

Data availability

Data used to generate summary plots presented in Figures 1-6 are included in the manuscript and are provided as source data files.

Article and author information

Author details

  1. Ki Bum Um

    Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4882-5736
  2. Suyun Hahn

    Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  3. So Woon Kim

    Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoon Je Lee

    Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Lutz Birnbaumer

    Institute of Biomedical Research (BIOMED), School of Medical Sciences, Catholic University of Argentina, Buenos Aires, Argentina
    Competing interests
    The authors declare that no competing interests exist.
  6. Hyun Jin Kim

    Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    For correspondence
    kimhyunjin@skku.edu
    Competing interests
    The authors declare that no competing interests exist.
  7. Myoung Kyu Park

    Physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
    For correspondence
    mkpark@skku.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8111-6096

Funding

National Research Foundation of Korea (2017R1A2B3005656)

  • Myoung Kyu Park

National Institutes of Health (Z01ES101648)

  • Lutz Birnbaumer

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 Research Center (LARC) in Sungkyunkwan University. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (SKKU IACUC2021-03-11-1) of Sungkyunkwan University.

Reviewing Editor

  1. Julie A Kauer, Stanford University, United States

Version history

  1. Received: June 2, 2021
  2. Preprint posted: June 4, 2021 (view preprint)
  3. Accepted: August 18, 2021
  4. Accepted Manuscript published: August 19, 2021 (version 1)
  5. Version of Record published: August 31, 2021 (version 2)

Copyright

© 2021, Um 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. Ki Bum Um
  2. Suyun Hahn
  3. So Woon Kim
  4. Yoon Je Lee
  5. Lutz Birnbaumer
  6. Hyun Jin Kim
  7. Myoung Kyu Park
(2021)
TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons
eLife 10:e70920.
https://doi.org/10.7554/eLife.70920

Share this article

https://doi.org/10.7554/eLife.70920

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