Circadian Control of Sleep by Melatonin via MT ₁ -Dependent Activation of BK Channels in the Suprachiasmatic Nucleus

Melatonin promotes sleep through mechanisms that have remained elusive. Here, we identify a molecular pathway by which melatonin promotes sleep by activating BK channels (Slo1) via MT ₁ receptors in the suprachiasmatic nucleus (SCN), the brain’s master circadian clock. In melatonin-proficient CBA/CaJ mice, knockout of either MT ₁ or Slo1 reduces REM and NREM sleep during the rest phase (daytime), accompanied by prolonged action potentials and diminished afterhyperpolarization in SCN neurons. These electrophysiological and behavioral changes are minimal during the active phase (nighttime). Strikingly, Slo1 expression in the SCN peaks during the daytime, contrary to previous reports, but aligning with its sleep-promoting function. Slo1 , but not MT ₁ , deletion also triggers spontaneous seizures, highlighting broader functions beyond circadian control. Structural mapping identifies critical domains mediating MT ₁ -Slo1 coupling. Together, these findings position the MT ₁ -Slo1 signaling axis as a core circadian mechanism linking melatonin to sleep regulation and a potential therapeutic target for sleep disorders.