Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewProstaglandin D2 and sleep regulation
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
References (111)
Sleep–wake regulation by prostaglandins D2 and E2
J. Biol. Chem.
(1988)- et al.
Prostaglandins and sleep
Adv. Neuroimmunol.
(1995) - et al.
Molecular mechanism of sleep regulation by prostaglandin D2
J. Lipid Mediators Cell Signal.
(1996) - et al.
Prostaglandin profiles in nervous tissue and blood vessels of the brain of various animals
Prostaglandins
(1980) - et al.
Prostaglandin D2 in rat brain, spinal cord and pituitary: basal level and regional distribution
Life Sci.
(1982) - et al.
Basal level of prostaglandin D2 in rat brain by a solid-phase enzyme immunoassay
Prostaglandins
(1986) - et al.
PGD2 effects on rodent behavior and EEG patterns in cats
Pharmacol. Biochem. Behav.
(1980) - et al.
Effects of prostaglandin D2, lipoxins and leukotrienes on sleep and brain temperature of rats
Prostaglandins Leukotrienes Essent. Fatty Acids
(1994) - et al.
The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients
Trans. R. Soc. Trop. Med. Hyg.
(1990) - et al.
Circadian variations of prostaglandin D2, E2, and F2α in the cerebrospinal fluid of anesthetized rats
Biochem. Biophys. Res. Commun.
(1995)
CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats
Brain Res.
Seasonal variation in levels of prostaglandin D2, E2, and F2α in the brain of a mammalian hibernator, the Asian chipmunk
Prostaglandins Leukotrienes Essent. Fatty Acids
Prostaglandin D, E, and F synthases
J. Lipid Mediators Cell Signal.
Purification and characterization of rat brain prostaglandin D synthetase
J. Biol. Chem.
Inhibition of rat brain prostaglandin D synthase by inorganic selenocompounds
Arch. Biochem. Biophys.
Primary structure of rat brain prostaglandin D synthetase deduced from cDNA sequence
J. Biol. Chem.
Protein synthesis at the blood–brain barrier. The major protein secreted by amphibian choroid plexus is a lipocalin
J. Biol. Chem.
Structural and chromosomal localization of the human gene for a brain form of prostaglandin D2 synthase
J. Biol. Chem.
Comparative mapping of lipocalin genes in human and mouse: the four genes for complement C8 γ chain, prostaglandin-D-synthase, oncogene-24p3 and progestagen-associated endometrial protein map to HSA9 and MMU2
Genomics
Postnatal changes in the localization of prostaglandin D synthetase from neurons to oligodendrocytes in the rat brain
J. Biol. Chem.
Brain-specific prostaglandin D2 synthetase mRNA is dependent on thyroid hormone during rat brain development
Biochem. Biophys. Res. Commun.
Identification of a thyroid hormone response element in the promoter region of the rat lipocalin-type prostaglandin D synthase (β-trace) gene
Mol. Brain Res.
Identification of a thyroid hormone response element in the promoter region of the rat lipocalin-type prostaglandin D synthase (β-trace) gene
Mol. Brain Res.
β-Trace gene expression is regulated by a core promoter and a distal thyroid hormone response element
J. Biol. Chem.
The first lipocalin with enzymatic activity
Trends Biochem. Sci.
Crystal structure of the trigonal form of bovine beta-lactoglobulin and its complex with retinol at 2.5 A resolution
J. Mol. Biol.
Structural and functional significance of cysteine residues of glutathione-independent prostaglandin D synthase. Identification of Cys65 as an essential thiol
J. Biol. Chem.
Choroid plexus: the major site of mRNA expression for the β-trace protein (prostaglandin D synthase) in human brain
Neurosci. Lett.
Isolation and amino terminal sequence of β-trace, a novel protein from human cerebrospinal fluid
Brain Res.
Purification and N-terminal sequence of β-trace, a protein abundant in human cerebrospinal fluid
Neurosci. Lett.
Identification of β-trace as prostaglandin D synthase
Biochem. Biophys. Res. Commun.
Lipocalin-type prostaglandin D synthase (β-trace) is a newly recognized type of retinoid transporter
J. Biol. Chem.
Prostaglandin D2 formation and characterization of its synthetases in various tissues of adult rats
Arch. Biochem. Biophys.
Prostaglandin D2: a biochemical perspective
Prostaglandins Leukotrienes Essent. Fatty Acids
15-Deoxy-delta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma
Cell
A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation
Cell
Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ
Cell
PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL
Cell
Purification and characterization of prostaglandin endoperoxide D-isomerase, a cytoplasmic, glutathione-requiring enzyme
Biochim. Biophys. Acta
Biochemical and immunological characterization of rat spleen prostaglandin D synthetase
J. Biol. Chem.
Characterization and distribution of prostaglandin D synthetase in rat skin
J. Invest. Dermatol.
Mast cells contain spleen-type prostaglandin D synthetase
J. Biol. Chem.
c-Kit ligand mediates increased expression of cytosolic phospholipase A2, prostaglandin endoperoxide synthase-1, and hematopoietic prostaglandin D2 synthase and increased IgE-dependent prostaglandin D2 generation in immature mouse mast cells
J. Biol. Chem.
Prostaglandin D synthase in human megakaryoblastic cells
J. Biol. Chem.
Induction of hematopoietic prostaglandin D synthase in human megakaryocytic cells by phorbol ester
Biochem. Biophys. Res. Commun.
Cloning and crystal structure of hematopoietic prostaglandin D synthase
Cell
Isozyme specificity of rat liver glutathione S-transferases in the formation of PGF2α and PGE2 from PGH2
Arch. Biochem. Biophys.
Biochemical and immunological demonstration of prostaglandin D2, E2, and F2α formation from prostaglandin H2 by various rat glutathione S-transferase isozymes
Arch. Biochem. Biophys.
Prostanoid receptors and their biological actions
Prog. Lipid Res.
Molecular cloning and characterization of the human prostanoid DP receptor
J. Biol. Chem.
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