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.

褪黑激素（Mel）通过G蛋白偶联受体促进睡眠。然而，下游分子靶标是未知的。我们确定秀丽隐杆线虫BK通道SLO-1是Mel受体PCDR-1-的分子靶标。敲除pcdr-1，slo-1或homt-1（Mel合成所需的基因）会导致神经递质的释放显着增加，并缩短睡眠时间，这些作用在双重敲除中是不可累加的。外源Mel抑制神经递质的释放并促进野生型（WT）的睡眠，但不刺激pcdr-1和slo-1突变体。在异源表达系统中，Mel在存在Mel受体MT ₁而非MT ₂的情况下以膜定界的方式激活人BK通道（hSlo1）。释放自由Gβγ的肽也以MT ₁依赖性和膜定界的方式激活hSlo1 ，而Gβλ抑制剂消除了Mel的刺激作用。我们的结果表明，Mel通过激活特定的Mel受体和Gβλ激活BK通道来促进睡眠。