Biochimica et Biophysica Acta 1436 (1999) 606^615

Review

Prostaglandin D2 and sleep regulation

Yoshihiro Urade *, Osamu Hayaishi
Department of Molecular Behavioral Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan
Received 26 August 1998; accepted 23 October 1998

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 L-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. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Sleep; Prostaglandin D2 ; Prostaglandin D synthase; L-Trace; Cerebrospinal uid; DP receptor

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

607

2.

Prostaglandin D2 and sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

607

3.

Prostaglandin D synthase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Lipocalin-type prostaglandin D synthase (L-trace) . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Hematopoietic prostaglandin D synthase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

607
608
609

4.

Prostanoid DP receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

609

5.

Signal transduction of PGD2 to promote sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

610

6.

Future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

610

7.

Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

611

* Corresponding author. Fax: +81 (6) 872-2841; E-mail: uradey@obi.or.jp

1388-1981 / 99 / $ ^ see front matter 1999 Elsevier Science B.V. All rights reserved.
PII: S 0 0 0 5 - 2 7 6 0 ( 9 8 ) 0 0 1 6 3 - 5

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607

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

611

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

611

1. 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
identied in the brain, cerebrospinal uid (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 [2^5]. This review summarizes
the studies on PGD2 , PGD synthase (PGDS), PGD2
receptor, and the action mechanism of sleep promotion by PGD2 .
2. Prostaglandin D2 and sleep
PGD2 is a major prostanoid produced in the central nervous system (CNS) of various mammals [6^
8], including humans [9], in which it exerts a variety
of functions, e.g. induction of sleep and sedation [10],
regulation of body temperature [11^13], hormone release [14^16], 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
cerebroventricular infusion. Interestingly and most
importantly, the PGD2 -induced sleep is indistinguishable from physiological sleep, as judged by the
electroencephalogram, electromyogram, brain temperature, heart rate, and general behavior of animals
injected with it. The relationship between PGD2 and

sleep in humans has also been suggested in two diseases, mastocytosis [20] and African sleeping sickness
[21]. Profound lethargy in patients with these diseases
was considered to be primarily due to the remarkable
increase in endogenous production of PGD2 . The
PGD2 concentration in rat CSF shows a circadian
change coupled to the sleep^wake cycle [22] and elevates with an increase in sleep propensity during
sleep deprivation [23]. A transient increase in the
PGD2 content in the squirrel brain has been found
during hibernation [24]. These observations in rats
and squirrels, in addition to the above reported studies on monkeys and humans, strongly suggest that
PGD2 plays a signicant role in sleep regulation of
mammals.
3. 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 spleentype enzyme or GSH-requiring enzyme. We have puried these two types of PGDS, isolated their cDNAs
and genes, and produced the recombinant proteins
for use in structural analyses and screening for inhibitors.

Fig. 1. Chemical reaction catalyzed by PGDS.

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3.1. Lipocalin-type prostaglandin D synthase

(L-trace)
Production of PGD2 in the CNS is catalyzed by
lipocalin-type PGDS (L-PGDS), which was originally puried from rat brain as a monomeric glycoprotein with a molecular weight of approximately
26 000 [26]. Inorganic quadrivalent selenium (Se4 )
compounds are non-competitive and reversible inhibitors of L-PGDS but do not aect hematopoietic
PGDS [27]. When SeCl4 was infused into the third
ventricle of rats, it inhibited the sleep of the animals
in a time- and dose-dependent manner [28]. Thus,
L-PGDS is considered to be the key enzyme in the
regulation of physiological sleep.
The cDNAs for L-PGDS have been isolated by
our group and others from several mammals and
amphibians, such as rats [29], humans [30], mice
[31], pigs [32], bulls [33], cats [34], bears [35], Xenopus
[36,37], and frogs [38]. The genes have also been
cloned from rats [39], humans [40], and mice [41]
and mapped to mouse chromosome 4 [42] and human chromosome 9 [40,42]. In the adult rat brain,
L-PGDS was immunohistochemically detected in
oligodendrocytes [43]. The mRNA for L-PGDS was
found to be down-regulated in hypothyroid rats
[44,45], similar to the transcripts for several myelinassociated proteins [46]. The thyroid hormone response element was then identied in the promoter
region of the rat [47] and human [48] genes of
L-PGDS.
A homology search in data bases of protein primary structure and comparison of the gene structure
revealed that PGD synthase is a member of the lipocalin superfamily [49], which is composed of various
secretory lipid-transporter proteins, such as L-lactoglobulin, plasma retinol-binding protein, major urinary protein, and epididymal retinoic acid-binding
protein. All these proteins are small secretory proteins sharing a common feature of binding and transporting small lipophilic molecules [50,51]. The only
exception to this rule is L-PGDS [30,52], which has
been isolated as an enzyme rather than as a lipid
transporter. Because of the high evolutionary divergence of the lipocalin superfamily, the homology of
the amino acid sequences of the members is rather
weak [49^51]. However, the tertiary structure is well
conserved to form a remarkably similar L-barrel

structure, as revealed by X-ray crystallographic studies of members of this family, such as L-lactoglobulin
[53], plasma retinol-binding protein [54], major urinary protein [55], epididymal retinoic acid-binding
protein [56], and nitrophorin 1 [57].
When the tertiary structure of rat L-PGDS was
constructed by homology modeling based on the
crystal structure of the above lipocalins, one free
SH group due to cysteine residue 65 was found to
be located in the hydrophobic pocket of the model
structure [49,58]. This residue is conserved in the
mammalian and amphibian L-PGDS thus far identied, but never found, in other lipocalins [49]. When
cysteine-65 of L-PGDS was chemically modied or
replaced with serine or alanine by site-directed mutagenesis, the enzyme activity disappeared completely
[58]. Therefore, this residue is considered to be a key
one for the catalytic function of L-PGDS. Quadravalent selenium compounds are predicted to interact
with this free sulfhydryl group in the active center
and thus inhibit L-PGDS.
By immunoperoxidase staining with specic polyclonal or monoclonal antibodies and by in situ hybridization with the antisense RNA, L-PGDS in the
rat [57] and human [60,61] brain was shown to be
mainly produced in the leptomeninges (pia-arachnoid
membrane) and choroid plexus, rather than in the
oligodendrocytes of the parenchyma. Moreover,
L-PGDS was demonstrated to be secreted into the
CSF as L-trace [62^65]. L-Trace was originally discovered in the early 1960s as a protein specic to the
human CSF [66,67], but its structure, sites of synthesis, and function were not elucidated until recently. From 1991 to 1993, several groups of investigators reported independently and almost
concurrently that the N-terminal partial amino acid
sequence of L-trace is highly homologous to that of
rat and human L-PGDS enzymes except that L-trace
has no signal peptide [62,63]. Finally, the full aminoacid sequence of L-trace was determined to be essentially identical to that of human L-PGDS except for
the absence of the signal peptide in L-trace [64]. We
also conrmed that L-PGDS puried from human
CSF and L-trace are structurally, enzymatically,
and immunologically identical [65].
Although L-PGDS is considered to have evolved
from lipophilic-ligand carrier proteins, it retains the
ancestral characteristic of binding lipophilic ligands.

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Rat [68] and Xenopus [36] L-PGDS bind retinoids

and thyroids with a high anity comparable to
that of other lipocalins. In the brain and eye
[69,70], L-PGDS (L-trace) is produced at the sites
of blood^CSF and blood^retinal barriers, respectively, and is secreted into a closed compartment
separated from the systemic circulation. In the retina,
L-PGDS is produced in pigmented epithelial cells
and accumulates within the interphotoreceptor matrix [69], a compartment possessing the most active
retinoid-transporting system in the body. These results, taken together, indicate that L-PGDS (L-trace)
may also act as a novel extracellular retinoid transporter in those compartments.
3.2. Hematopoietic prostaglandin D synthase
PGD2 is also actively produced in a variety of
peripheral tissues [71], in which it prevents platelet
aggregation and induces vasodilation and bronchoconstriction [72]. PGD2 is also released from mast
cells upon stimulation with various immunological
stimuli and functions as a lipid mediator in allergy
and inammation [73]. PGD2 is further converted to
the J series of PGs, such as PGJ2 , v12-PGJ2 , and 15deoxy-v12,14-PGJ2 , the last of which has been recently identied to be an endogenous ligand for a
nuclear receptor, the peroxisome proliferator-activated receptor (PPAR) Q [74,75]. The ligand activation of PPARQ was found to regulate macrophage
and monocyte functions [76^80].
Production of PGD2 in the peripheral tissues is
mainly catalyzed by hematopoietic PGDS (HPGDS), which was originally puried from rat spleen
as a cytosolic, GSH-requiring enzyme with a molecular weight of approximately 26 000 [81,82]. HPGDS was immunohistochemically localized in antigen-presenting cells [83,84] and mast cells [85]. The
induction of H-PGDS is involved in mast cell activation [86^88] and also in megakaryocytic dierentiation [89,90]. The enzyme is considered to be involved in deep sleep of mastcytotic patients as
described above. The immunoreactivity of H-PGDS
was localized to be satellite and Schwann cells of
chick dorsal root ganglia [91]. However, the existence
of H-PGDS in the CNS and its cellular localization
there, if any, remain to be elucidated.
The cDNA for H-PGDS has been cloned from rats

609

[92] and chicken [93]. A homology search in data

bases of protein primary structure revealed that HPGDS is a member of the GSH S-transferase (GST)
family, as previously predicted by the results of partial amino acid sequence analyses [84,94]. However,
H-PGDS showed a weak homology against mammalian GST isozymes of the previously known four
classes (K, W, Z, and a) and yet revealed a relatively
high homology with GST isozymes of the c-class,
which had been observed only in invertebrates. Finally, the enzyme was demonstrated to be the rst
recognized vertebrate homolog of the c-class of the
GST family [92^94].
The recombinant rat H-PGDS was then crystallized, and the tertiary structure of the enzyme complexed with GSH was determined with a resolution
by X-ray diraction analysis [92]. This was
of 2.3 A
the rst report of the tertiary structure of an enzyme
that utilizes PGH2 as a substrate. The X-ray crystallographic analysis revealed that H-PGDS possesses a
prominent cleft as the active site, which feature has
never seen among other members of the GST family.
This nding is in agreement with the fact that other
GST isozymes catalyze the conversion of PGH2 to
produce PGE2 and PGF2K [95,96] whereas H-PGDS
selectively forms PGD2 .
4. Prostanoid DP receptor
The actions of PGD2 are mediated by a prostanoid
receptor specic 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-proteincoupled, 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 tissue
distribution prole of the mRNA for the DP receptor varied signicantly among mice, rats, and humans [99^101], which variation is consistent with
the highly species-specic pharmacological activities
of PGD2 [102]. In the same species, for example in
rats, the tissue distribution prole of the mRNA for
the DP receptor overlaps those proles of L-PGDS

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and H-PGDS [101]. In situ hybridization utilizing

mouse [103] and rat [101] brain revealed that the
mRNA for the DP receptor was dominantly expressed in the leptomeninges rather than in the parenchyma, similar to the case of L-PGDS [59,61].
These results are in agreement with the classical
idea that PGD2 acts as a local mediator in an autocrine or paracrine fashion.
5. 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 conrmed 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 eectively by infusion into
the subarachnoidal space at the ventral surface of the
rostral basal forebrain [104]. Interestingly, the PGD2
infusion into the subarachnoidal space preferentially
induced slow-wave sleep (SWS), but not rapid eye
movement (REM) sleep (paradoxical sleep), whereas
the cerebroventricular infusion of PGD2 induced
both SWS and REM sleep [18,19]. The SWS level
during the PGD2 infusion into the subarachnoidal
space was comparable to the level of the daytime
SWS of rats, i.e. PGD2 induced the maximum, saturation amount of sleep with the minimum awaking
time in rats [104].
We then attempted to identify the chemical transmitter(s) that sends the PGD2 -produced signal to the
neural circuits responsible for the sleep promotion
and found that an adenosine A2A -receptor antagonist, KF17837, attenuated the PGD2 -induced sleep
[105]. Furthermore, when adenosine A2A -receptor agonists, such as 2-(4-(2-carboxyethyl)phenylethylamino)-5P-N-ethylcarboxamidoadenosine
(CGS21680)
and 2-(4-(2-(2-aminoethylaminocarbonyl)ethyl)phenylethylamino)-5P-N-ethylcarboxamido-adenosine
(APEC), were infused into the subarachnoidal space
of the rostral basal forebrain, these compounds also
induced a remarkable SWS and REM sleep
[105,106]. These results, taken together, indicate

that the signal of PGD2 to induce sleep is mediated

by the adenosine A2A -receptive neurons [107,108].
We then used Fos immunohistochemistry to identify neuroanatomically the neurons activated by infusion of PGD2 into the subarachnoid space of the
rostral basal forebrain [109]. PGD2 increased SWS
(non-REM sleep) and induced striking expression
of Fos in neurons within the ventrolateral preoptic
area (VLPO), which was recently proposed to play a
critical role in the generation of sleep [110]. The
VLPO sends specic GABAergic and galaninergic
eerents to the core of the tuberomammillary nucleus (TMN) [111], the source of the ascending histaminergic arousal system and receives aerents from
the suprachiasmatic nucleus and retina. Fos expression in the VLPO after the PGD2 infusion was positively correlated with the preceding amount of sleep
and negatively correlated with Fos expression in the
TMN [109]. These observations indicate that PGD2
may induce sleep through activation of the VLPO
and inhibition of the TMN. PGD2 also increased
Fos-immunoreactivity in the basal leptomeninges
[109], which nding is in good agreement with the
fact that the DP receptor is localized in the leptomeninges [101]. These results also suggest that the leptomeninges may be the site for transmission of the
signal of PGD2 to the next substance (adenosine?) to
induce sleep.
6. 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 mechanisms
of PGD2 biosynthesis and the molecular mechanisms
involved in the transmission of the message initiated
by PGD2 to induce sleep. We recently crystallized
recombinant mouse L-PGDS and human H-PGDS
and have started the X-ray diraction analyses.
The three-dimensional coordinates of these enzymes

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Fig. 2. Possible mechanisms for sleep induction by PGD2 .

L-PGDS is present mainly in the membrane system surrounding
the brain (arachnoid membrane) and within the ventricles (choroid plexus), and is secreted into the CSF. L-PGDS 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 surface of the basal forebrain. The activation
of these receptors initiates the signal to activate adenosine A2A
receptive neurons. This results in activation of VLPO neurons,
which in turn inhibits the TMN, the source of the ascending
histaminergic arousal system, to induce sleep.

will be useful for designing selective and non-selective inhibitors for each enzyme. Gene-knockout or
transgenic mice for L-PGDS, H-PGDS, DP receptor,
and adenosine A2A receptor have also been generated
by our group and by others. Further investigation to
examine the functional abnormality of sleep^wake
regulation in such genetically engineered mutant
mice should provide us with new insight into the
molecular mechanism of sleep^wake regulation.
7. 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
L-trace, a major protein component of the CSF.
L-PGDS as well as the PGD2 thus produced circu-

611

lates 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 ventromedial 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 of the rostral
basal forebrain results in activation of a cluster of
neurons within the VLPO, which may promote sleep
by inhibiting TMN, the source of the ascending histaminergic arousal system. The proposed mechanism
of PGD2 to promote sleep is schematically summarized in Fig. 2.
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 Grantsin-Aid for Scientic Research of the Ministry of
Education, Science, Sports, and Culture of Japan
(07558108, 07457033 and 09044352 to Y.U. and
06508003 to O.H.), a grant from the program for
Core Research for Evolutional Science and Technology from Japan Science and Technology Corporation (to Y.U.), and by grants from the Ministry of
Health and Welfare of Japan (100107 to O.H.), the
Suntory Institute for Bioorganic Research (to Y.U.),
and the Japan Foundation for Applied Enzymology
(to Y.U.).

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