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

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.

The neuropeptidergic connectome ofC. elegans

“…Six neurons (AVKL/R, PVQL/R, PVT and PVR) had higher short-range neuropeptide degree than any of the synaptic rich club neurons (Figure 6A); if mid-range signaling is considered these same six neurons remain the highest-degree hubs (Figure 6B). Interestingly, the AVKL/R and PVT neurons are notable for expressing no classical neurotransmitters or monoamines 75 , while the PVQL/R neurons appear anatomically specialized for neuropeptide signaling due to a preponderance of dense core vesicles 14, 76 . AVKL/R, and PVT have been previously linked to the control of global behavioral states related to sleep and arousal 14, 73 , but the functions of the other neuropeptide hub neurons PVQ and PVR are not well-characterized.…”

“…Perhaps not surprisingly, the premotor neurons of the synaptic rich club are also highly connected in the neuropeptide connectome; all 11 of these neurons show a neuropeptide degree above 400 in the short-range network. Since these neurons are known to play important roles in driving global brain states 14, 74, 76 it is logical that they would also be important targets of neuromodulatory control. In addition, the neuropeptide connectome contains 6 neurons whose neuropeptide degree is higher than any of the synaptic rich club (degree > 490).…”

Sleep–Wake Disorders in Alzheimer’s Disease: A Review

“…5-HT is a precursor to synthesize melatonin ( N -acetyl-5-methoxytryptamine), and melatonin is released from the pineal gland to the bloodstream exclusively at night through the circadian rhythm and contributes to sleep . Melatonin contributes to sleep incidence possibly via the G-protein-coupled receptor . In AD patients, the levels of serotonin and melatonin are decreased .…”

“…122 Melatonin contributes to sleep incidence possibly via the G-protein-coupled receptor. 123 In AD patients, the levels of serotonin and melatonin are decreased. 124 Mitochondrial dysfunction in AD contributes to serotoninergic inefficiency and decreased serotoninergic transmission, leading to ROS accumulation, 125 and inefficiency of 5-HT in AD decreases the level of melatonin.…”

The Efficacy of V. odorata Extract in the Treatment of Insomnia: A Systematic Review and Meta-Analysis

“…Trace amounts of melatonin (1.1 ± 0.1 ng/g) were detected in a 50% methanol extract of the violet flower by using the enzyme-linked immunosorbent assay (ELISA) method of quantification ( 9 ). Melatonin, which promotes sleep by activating the BK channel through a specific melatonin receptor and Gβλ ( 10 ), is a widely available non-prescription nutritional supplement for the treatment of sleep disorders with significantly fewer side effects ( 11 ). It is an active ingredient of V. odorata ( 9 ), which can explain its hypnotic and circadian-shifting effects ( 12 ).…”