Melatonin promotes sleep by activating the BK channel in C. elegans

Melatonin (Mel) promotes sleep through G protein-coupled receptors. However, the downstream molecular target(s) is unknown. We identified the Caenorhabditis elegans BK channel SLO-1 as a molecular target of the Mel receptor PCDR-1-. Knockout of pcdr-1, slo-1, or homt-1 (a gene required for Mel synth...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2020-10, Vol.117 (40), p.25128-25137
Main Authors: Niu, Longgang, Li, Yan, Zong, Pengyu, Liu, Ping, Shui, Yuan, Chen, Bojun, Wang, Zhao-Wen
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Caenorhabditis elegans Proteins - genetics
G protein-coupled receptors
Gene Knockout Techniques
Humans
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - genetics
Large-Conductance Calcium-Activated Potassium Channels - genetics
Melatonin
Melatonin - metabolism
Melatonin - pharmacology
Membranes
Neurons - drug effects
Neurons - metabolism
Neurotransmitter release
Neurotransmitters
Potassium
Receptor, Melatonin, MT2 - genetics
Receptors
Sleep
Sleep - drug effects
Sleep - genetics
Synaptic Transmission - genetics
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Summary:Melatonin (Mel) promotes sleep through G protein-coupled receptors. However, the downstream molecular target(s) is unknown. We identified the Caenorhabditis elegans BK channel SLO-1 as a molecular target of the Mel receptor PCDR-1-. Knockout of pcdr-1, slo-1, or homt-1 (a gene required for Mel synthesis) causes substantially increased neurotransmitter release and shortened sleep duration, and these effects are nonadditive in double knockouts. Exogenous Mel inhibits neurotransmitter release and promotes sleep in wild-type (WT) but not pcdr-1 and slo-1 mutants. In a heterologous expression system, Mel activates the human BK channel (hSlo1) in a membrane-delimited manner in the presence of the Mel receptor MT₁ but not MT₂. A peptide acting to release free Gβγ also activates hSlo1 in a MT₁-dependent and membrane-delimited manner, whereas a Gβλ inhibitor abolishes the stimulating effect of Mel. Our results suggest that Mel promotes sleep by activating the BK channel through a specific Mel receptor and Gβλ.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2010928117