[Sleep-wake regulation by prostaglandin D2 and adenosine].
Prostaglandin (PG) D2 and adenosine are potent endogenous somnogens that accumulate in the brain during prolonged wakefulness. Lipocalin-type PGD synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of various prostanoids, to produce PGD2. L-PGDS is localized in the leptomeninges, choroid plexus, and oligodendrocytes of the central nervous system. PGD2 stimulates DP1 receptors localized in the basal forebrain and increases the local extracellular concentration of adenosine, a paracrine signaling molecule, to promote sleep. Adenosine activates adenosine A2A receptor-expressing neurons in the basal forebrain and ventrolateral preoptic area (VLPO) and inhibits adenosine A1 receptor-possessing arousal neurons. Sleep-promoting neurons in the VLPO send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus (TMN); the histaminergic neurons contribute to arousal through histamine H1 receptors. GABAergic inhibition of TMN is involved in the induction of non-rapid eye movement (non-REM) sleep by PGD2 and adenosine A2A agonists. The neural network between the VLPO and TMN is considered to play a key role in regulation of vigilance states. Administering an L-PGD inhibitor (SeCl4), DP1 antagonist (ONO-4127Na), or adenosine A2A receptor antagonist (caffeine) suppresses both non-REM and REM sleep, indicating that the PGD2-adenosine system is crucial for maintaining physiological sleep. Selective gene-deletion strategies based on Cre/loxP technology and focal RNA interference have been used for silencing the expression of the A2A receptor by local infection with adeno-associated virus carrying Cre-recombinase or short hairpin RNA. The results of these studies have shown that the A2Asubreceptors in the shell region of the nucleus accumbens are responsible for the effect of caffeine on wakefulness.
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Japan.
Nanae
N
Nagata
Yoshihiro
Y
Urade
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000502:physiology; D006801:Humans; D015230:Prostaglandin D2 / Q000378:metabolism*; D015398:Signal Transduction; D012890:Sleep / Q000235:genetics / Q000502:physiology*; D014851:Wakefulness / Q000235:genetics / Q000502:physiology*
D000241:Adenosine; D015230:Prostaglandin D2