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Edited by Richard W. Aldrich, The University of Texas at Austin, Austin, TX, and approved August 28, 2020 (received for review May 28, 2020)
Significance
Melatonin (Mel) promotes sleep through G protein-coupled Mel receptors. However, the downstream molecular target(s) of the Mel receptors to produce the sleep effect remains enigmatic. The study shows that a potassium channel, the BK channel, plays a role in sleep and that Mel promotes sleep by activating this channel through a specific Mel receptor.
Abstract
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.
Footnotes
↵1Present address: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
↵2Present address: Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- ↵3To whom correspondence may be addressed. Email: bochen{at}uchc.edu or zwwang{at}uchc.edu.
Author contributions: L.N., B.C., and Z.-W.W. designed research; L.N., Y.L., P.Z., P.L., Y.S., and B.C. performed research; L.N., P.Z., and P.L. analyzed data; and Z.-W.W. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2010928117/-/DCSupplemental.
Data Availability.
All study data are included in the article and SI Appendix.
Published under the PNAS license.
References
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Melatonin promotes sleep by activating the BK channel in C. elegans
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- Neuroscience
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