Review
Prostaglandin D2 and sleep regulation

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Abstract

Prostaglandin (PG) D2 is recognized as the most potent endogenous sleep-promoting substance whose action mechanism is the best characterized among the various sleep-substances thus far reported. The PGD2 concentration in rat cerebrospinal fluid (CSF) shows a circadian change coupled to the sleep-wake cycle and elevates with an increase in sleep propensity during sleep deprivation. Lipocalin-type PGD synthase is dominantly produced in the arachnoid membrane and choroid plexus of the brain, and is secreted into the CSF to become β-trace, a major protein component of the CSF. The PGD synthase as well as the PGD2 thus produced circulates in the ventricular system, subarachnoidal space, and extracellular space in the brain system. PGD2 then interacts with DP receptors in the chemosensory region of the ventro-medial surface of the rostral basal forebrain to initiate the signal to promote sleep probably via the activation of adenosine A2A receptive neurons. The activation of DP receptors in the PGD2-sensitive chemosensory region results in activation of a cluster of neurons within the ventrolateral preoptic area, which may promote sleep by inhibiting tuberomammillary nucleus, the source of the ascending histaminergic arousal system.

Introduction

Sleep is one of the most important and yet most mysterious events that occurs in the brain. We spend almost one-third of our lifetime asleep and repeat the sleep–wake cycle every day and night. However, the biochemical mechanism of sleep–wake regulation remains unclear. There is little doubt that sleep is controlled by chemical processes. Although more than 30 so-called endogenous sleep substances have been identified in the brain, cerebrospinal fluid (CSF), and other organs and tissues of mammals by numerous investigators, the physiological relevance of these agents remains uncertain in most instances [1]. However, as a result of our study on the sleep induction by prostaglandin D2 (PGD2), this prostanoid is recognized as the most potent endogenous sleep-promoting substance whose action mechanism is the best characterized among the various sleep-substances thus far reported [2], [3], [4], [5]. This review summarizes the studies on PGD2, PGD synthase (PGDS), PGD2 receptor, and the action mechanism of sleep promotion by PGD2.

Section snippets

Prostaglandin D2 and sleep

PGD2 is a major prostanoid produced in the central nervous system (CNS) of various mammals [6], [7], [8], including humans [9], in which it exerts a variety of functions, e.g. induction of sleep and sedation [10], regulation of body temperature [11], [12], [13], hormone release [14], [15], [16], and nociception [17]. Among those functions, the sleep induction has been the most extensively studied.

In the 1980s, it was demonstrated that PGD2 induces sleep in rats [18] and monkeys [19] after the

Prostaglandin D synthase

PGDS (EC 5.3.99.2) catalyzes the isomerization of a 9–11 endoperoxide group of PGH2, a common precursor of various prostanoids, to produce PGD2 with 9-hydroxy and 11-keto groups, in the presence of sulfhydryl compounds (Fig. 1). There are two distinct types of PGDS [25], i.e. one is the lipocalin-type PGDS that was previously known as the brain-type enzyme or glutathione (GSH)-independent enzyme and the other is hematopoietic PGDS, the spleen-type enzyme or GSH-requiring enzyme. We have

Prostanoid DP receptor

The actions of PGD2 are mediated by a prostanoid receptor specific for PGD2, i.e. the DP receptor [97], [98]. The cDNA for this receptor was cloned from mice [99], humans [100], and rats [101]. The DP receptor contains seven hydrophobic transmembrane domains and is a member of the G-protein-coupled, rhodopsin-type receptor family. The activation of this DP receptor results in an elevation of intracellular cAMP and mobilization of Ca2+ [99], [100].

As examined by Northern blot analysis, the

Signal transduction of PGD2 to promote sleep

Dominant localization of the DP receptor in the leptomeninges, and not in the brain parenchyma, indicates that the initial event to promote sleep after PGD2 administration probably occurs at the surface of the brain. This idea was confirmed by our pharmacological study to identify the site of action of PGD2 to induce sleep. When PGD2 was continuously infused into a variety of regions of the rat brain through an implanted microdialysis probe, it promoted sleep the most effectively by infusion

Future studies

PGD2 is, therefore, not a typical neurotransmitter, but rather a ‘neurohormone’ or an ‘informational substance’ that circulates through the CSF and transmits certain chemical messages to promote sleep. The mode of communication through the CSF in the ventricular system and the extracellular space has advantages for global regulation of the brain to induce sleep or to increase the propensity for sleep. Studies are still in progress in our own and other laboratories concerning the regulatory

Concluding remarks

The PGD2 concentration in rat CSF was higher in the sleeping period than in the waking period and increased during sleep deprivation in parallel with an increase in sleep propensity. L-PGDS catalyzes production of PGD2 in the CNS and is likely to be the key enzyme for the regulation of physiological sleep. L-PGDS is present mainly in the membrane system surrounding the brain rather than in the brain parenchyma, and is secreted into the CSF to become β-trace, a major protein component of the

Acknowledgements

We are grateful to Drs. N. Eguchi, Y. Kanaoka, D. Gerashchenko, E. Pinzar, C. Beuckmann, and H. Onoe of our Institute for valuable discussions. We also thank D. Irikura, Y. Kuwahata, Shigeko Matsumoto, S. Ueta, and Shuko Matsumoto for technical and secretarial assistance. This work was supported in part by grants from the program Grants-in-Aid for Scientific Research of the Ministry of Education, Science, Sports, and Culture of Japan (07558108, 07457033 and 09044352 to Y.U. and 06508003 to

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