Melatonin Enhances Sleep via MT ₁ -Driven Activation of Slo1 in Suprachiasmatic Nucleus Neurons

Melatonin is known to promote sleep, but its underlying molecular mechanisms remain poorly understood. Using CBA/CaJ mice, a strain capable of melatonin synthesis, we explored the roles of the BK channel (Slo1) and the melatonin receptor MT ₁ in regulating sleep behavior and action potentials in the suprachiasmatic nucleus (SCN). Global knockout of Slo1 or MT ₁ reduced REM and NREM sleep, increased wakefulness, and broadened action potentials while abolishing afterhyperpolarization in SCN neurons. These effects were primarily or exclusively observed during the subjective daytime, when mice are less active. Consistent with this, Slo1 expression in the SCN was markedly higher during the day than at night. Slo1 knockout mice also exhibited pronounced seizure activity. Through deletion analyses, we identified key domains in MT ₁ and Slo1 that are essential for their physical interaction. Together, these findings suggest that melatonin promotes sleep by activating Slo1 in the SCN through an MT ₁ -mediated signaling pathway.