Melatonin is a sleep-promoting hormone acting through melatonin receptors. However, the downstream molecular target(s) for its sleep-promoting effect has remained elusive. In a recent study from Dr. Wang’s lab (Niu et al., PNAS 117: 25128-25137, 2020), it was found that melatonin promotes sleep in C. elegans by activating the BK channel (also known as SLO-1 in worms and Slo1 in mammals) through a specific melatonin receptor. In addition, it was found that human Slo1 may be activated by melatonin in the presence of the MT1 but not MT2 melatonin receptor in the Xenopus oocyte heterologous expression system. SLO-1/Slo1 is a key regulator of neurotransmitter release, and plays important roles in the circadian rhythm. These findings with C. elegans and Xenopus oocytes suggest that melatonin might promote sleep in mammals by activating Slo1 through the MT1 melatonin receptor. This NIH award supports the efforts of Dr. Wang’s lab to investigate whether melatonin can activate Slo1 in mice through a specific melatonin receptor, how SLO-1 contributes to sleep in C. elegans, and how SLO-1 endocytosis is regulated by a novel molecular pathway. Please visit the website of C. elegans Neurobiology Lab (https://health.uconn.edu/worm-lab/) for additional information about the lab, including potential lab rotation projects.