Molecular Mechanism of Sleep-wake Regulation

Prostaglandin (PG) D2 is the most potent endogenous sleep-promoting substance thus far reported and its sleep-inducing mechanism is the best characterized at the molecular level. PGD2 is produced by lipocalin-type PGD synthase (L-PGDS) localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain and is secreted into the cerebrospinal fl uid as a sleep hormone. PGD2 stimulates DP1 receptors localized in the arachnoid membrane at the basal forebrain to release adenosine as a paracrine sleep-promoting molecule, which activates adenosine A2A receptor-expressing neurons located in the basal forebrain. These cells subsequently excite the sleep-active neurons in the ventrolateral preoptic area and concomitantly suppress the tuberomammillary nucleus, a histaminergic arousal center, through GABAergic and galaninergic inhibitory projection, to induce sleep. The administration of a PGD synthase inhibitor (SeCl4), DP1 antagonist (ONO-4127Na) or adenosine A2 receptor antagonist (caffeine) induces insomnia, indicating that the PGD2-adenosine system is crucial for the maintenance of physiological sleep. Hirosaki Med.J. 61, Supplement:S164―S173,2010