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TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

View ORCID ProfileKi Bum Um, Suyun Hahn, So Woon Kim, Yoon Je Lee, Lutz Birnbaumer, Hyun Jin Kim, View ORCID ProfileMyoung Kyu Park
doi: https://doi.org/10.1101/2021.06.03.447013
Ki Bum Um
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
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  • ORCID record for Ki Bum Um
Suyun Hahn
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
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So Woon Kim
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
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Yoon Je Lee
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
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Lutz Birnbaumer
3Neurobiology Laboratory. National Institute of Environmental Health Sciences, North Carolina 27709, USA; and Institute of Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF, Autonomous City of Buenos Aires, Argentina
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Hyun Jin Kim
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
2Samsung Biomedical Research Institute, Samsung Medical Center, 81 Irwon-Ro Gangnam-gu, Seoul, 06351, Korea
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  • For correspondence: mkpark@skku.edu kimhyunjin@skku.edu
Myoung Kyu Park
1Department of Physiology, Sungkyunkwan University School of Medicine, 2066, Seoburo, Jangan-gu, Suwon, 16419, Korea
2Samsung Biomedical Research Institute, Samsung Medical Center, 81 Irwon-Ro Gangnam-gu, Seoul, 06351, Korea
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  • ORCID record for Myoung Kyu Park
  • For correspondence: mkpark@skku.edu kimhyunjin@skku.edu
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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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 04, 2021.
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TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons
Ki Bum Um, Suyun Hahn, So Woon Kim, Yoon Je Lee, Lutz Birnbaumer, Hyun Jin Kim, Myoung Kyu Park
bioRxiv 2021.06.03.447013; doi: https://doi.org/10.1101/2021.06.03.447013
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TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons
Ki Bum Um, Suyun Hahn, So Woon Kim, Yoon Je Lee, Lutz Birnbaumer, Hyun Jin Kim, Myoung Kyu Park
bioRxiv 2021.06.03.447013; doi: https://doi.org/10.1101/2021.06.03.447013

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