Melatonin Enhances Sleep via MT1-Driven Activation of Slo1 in Suprachiasmatic Nucleus Neurons

Abstract

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 MT1 receptors in the suprachiasmatic nucleus (SCN), the brains master circadian clock. In melatonin-proficient CBA/CaJ mice, knockout of either MT1 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 MT1, deletion also triggers spontaneous seizures, highlighting broader functions beyond circadian control. Structural mapping identifies critical domains mediating MT1-Slo1 coupling. Together, these findings position the MT1-Slo1 signaling axis as a core circadian mechanism linking melatonin to sleep regulation and a potential therapeutic target for sleep disorders.