Melatonin promotes sleep by activating the BK channel in <i>C. elegans</i>.

Abstract

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