TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

eLife

So Woon Kim¹  Ki Bum Um¹  Yoon Je Lee¹  Suyun Hahn¹  Hyun Jin Kim²  Myoung Kyu Park²  Lutz Birnbaumer³ 

[1] Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea;Department of physiology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea;Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea;Neurobiology Laboratory. National Institute of Environmental Health Sciences, North Carolina 27709, USA; and Institute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires, Argentina;

关键词: dopaminergic neurons;    substantia nigra;    pacemaker channels;    pacemaking;    TRPC3;    NALCN;    Mouse;   

DOI  :  10.7554/eLife.70920

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY