Prostaglandin D2 and Sleep Regulation

Review

Prostaglandin D2 and sleep regulation

Yoshihiro Urade *, Osamu HayaishiDepartment 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 isthe best characterized among the various sleep-substances thus far reported. The PGD2 concentration in rat cerebrospinalfluid (CSF) shows a circadian change coupled to the sleep-wake cycle and elevates with an increase in sleep propensity duringsleep deprivation. Lipocalin-type PGD synthase is dominantly produced in the arachnoid membrane and choroid plexus ofthe brain, and is secreted into the CSF to become L-trace, a major protein component of the CSF. The PGD synthase as wellas the PGD2 thus produced circulates in the ventricular system, subarachnoidal space, and extracellular space in the brainsystem. PGD2 then interacts with DP receptors in the chemosensory region of the ventro-medial surface of the rostral basalforebrain to initiate the signal to promote sleep probably via the activation of adenosine A2A receptive neurons. Theactivation of DP receptors in the PGD2-sensitive chemosensory region results in activation of a cluster of neurons within theventrolateral preoptic area, which may promote sleep by inhibiting tuberomammillary nucleus, the source of the ascendinghistaminergic arousal system. ß 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6073.1. Lipocalin-type prostaglandin D synthase (L-trace) . . . . . . . . . . . . . . . . . . . . . . . . . . . 6083.2. Hematopoietic prostaglandin D synthase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609

4. Prostanoid DP receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609

5. Signal transduction of PGD2 to promote sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610

6. Future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610

7. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611

1388-1981 / 99 / $ ^ see front matter ß 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

* Corresponding author. Fax: +81 (6) 872-2841; E-mail : [email protected]

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611

1. Introduction

Sleep is one of the most important and yet mostmysterious events that occurs in the brain. We spendalmost one-third of our lifetime asleep and repeat thesleep^wake cycle every day and night. However, thebiochemical mechanism of sleep^wake regulation re-mains unclear. There is little doubt that sleep is con-trolled by chemical processes. Although more than30 so-called endogenous sleep substances have beenidenti¢ed in the brain, cerebrospinal £uid (CSF), andother organs and tissues of mammals by numerousinvestigators, the physiological relevance of theseagents remains uncertain in most instances [1]. How-ever, as a result of our study on the sleep inductionby prostaglandin D2 (PGD2), this prostanoid is rec-ognized as the most potent endogenous sleep-pro-moting substance whose action mechanism is thebest characterized among the various sleep-substan-ces thus far reported [2^5]. This review summarizesthe studies on PGD2, PGD synthase (PGDS), PGD2

receptor, and the action mechanism of sleep promo-tion by PGD2.

2. Prostaglandin D2 and sleep

PGD2 is a major prostanoid produced in the cen-tral nervous system (CNS) of various mammals [6^8], including humans [9], in which it exerts a varietyof functions, e.g. induction of sleep and sedation [10],regulation of body temperature [11^13], hormone re-lease [14^16], and nociception [17]. Among thosefunctions, the sleep induction has been the most ex-tensively studied.

In the 1980s, it was demonstrated that PGD2 in-duces sleep in rats [18] and monkeys [19] after thecerebroventricular infusion. Interestingly and mostimportantly, the PGD2-induced sleep is indistin-guishable from physiological sleep, as judged by theelectroencephalogram, electromyogram, brain tem-perature, heart rate, and general behavior of animalsinjected with it. The relationship between PGD2 and

sleep in humans has also been suggested in two dis-eases, mastocytosis [20] and African sleeping sickness[21]. Profound lethargy in patients with these diseaseswas considered to be primarily due to the remarkableincrease in endogenous production of PGD2. ThePGD2 concentration in rat CSF shows a circadianchange coupled to the sleep^wake cycle [22] and ele-vates with an increase in sleep propensity duringsleep deprivation [23]. A transient increase in thePGD2 content in the squirrel brain has been foundduring hibernation [24]. These observations in ratsand squirrels, in addition to the above reported stud-ies on monkeys and humans, strongly suggest thatPGD2 plays a signi¢cant role in sleep regulation ofmammals.

3. Prostaglandin D synthase

PGDS (EC 5.3.99.2) catalyzes the isomerization ofa 9^11 endoperoxide group of PGH2, a commonprecursor of various prostanoids, to produce PGD2

with 9-hydroxy and 11-keto groups, in the presenceof sulfhydryl compounds (Fig. 1). There are two dis-tinct types of PGDS [25], i.e. one is the lipocalin-typePGDS that was previously known as the brain-typeenzyme or glutathione (GSH)-independent enzymeand the other is hematopoietic PGDS, the spleen-type enzyme or GSH-requiring enzyme. We have pu-ri¢ed these two types of PGDS, isolated their cDNAsand genes, and produced the recombinant proteinsfor use in structural analyses and screening for inhib-itors.

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 bylipocalin-type PGDS (L-PGDS), which was origi-nally puri¢ed from rat brain as a monomeric glyco-protein with a molecular weight of approximately26 000 [26]. Inorganic quadrivalent selenium (Se4�)compounds are non-competitive and reversible inhib-itors of L-PGDS but do not a¡ect hematopoieticPGDS [27]. When SeCl4 was infused into the thirdventricle of rats, it inhibited the sleep of the animalsin a time- and dose-dependent manner [28]. Thus,L-PGDS is considered to be the key enzyme in theregulation of physiological sleep.

The cDNAs for L-PGDS have been isolated byour group and others from several mammals andamphibians, 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 beencloned from rats [39], humans [40], and mice [41]and mapped to mouse chromosome 4 [42] and hu-man chromosome 9 [40,42]. In the adult rat brain,L-PGDS was immunohistochemically detected inoligodendrocytes [43]. The mRNA for L-PGDS wasfound to be down-regulated in hypothyroid rats[44,45], similar to the transcripts for several myelin-associated proteins [46]. The thyroid hormone re-sponse element was then identi¢ed in the promoterregion of the rat [47] and human [48] genes ofL-PGDS.

A homology search in data bases of protein pri-mary structure and comparison of the gene structurerevealed that PGD synthase is a member of the lipo-calin superfamily [49], which is composed of varioussecretory lipid-transporter proteins, such as L-lacto-globulin, plasma retinol-binding protein, major uri-nary protein, and epididymal retinoic acid-bindingprotein. All these proteins are small secretory pro-teins sharing a common feature of binding and trans-porting small lipophilic molecules [50,51]. The onlyexception to this rule is L-PGDS [30,52], which hasbeen isolated as an enzyme rather than as a lipidtransporter. Because of the high evolutionary diver-gence of the lipocalin superfamily, the homology ofthe amino acid sequences of the members is ratherweak [49^51]. However, the tertiary structure is wellconserved to form a remarkably similar L-barrel

structure, as revealed by X-ray crystallographic stud-ies of members of this family, such as L-lactoglobulin[53], plasma retinol-binding protein [54], major uri-nary protein [55], epididymal retinoic acid-bindingprotein [56], and nitrophorin 1 [57].

When the tertiary structure of rat L-PGDS wasconstructed by homology modeling based on thecrystal structure of the above lipocalins, one freeSH group due to cysteine residue 65 was found tobe located in the hydrophobic pocket of the modelstructure [49,58]. This residue is conserved in themammalian and amphibian L-PGDS thus far identi-¢ed, but never found, in other lipocalins [49]. Whencysteine-65 of L-PGDS was chemically modi¢ed orreplaced with serine or alanine by site-directed muta-genesis, the enzyme activity disappeared completely[58]. Therefore, this residue is considered to be a keyone for the catalytic function of L-PGDS. Quadra-valent selenium compounds are predicted to interactwith this free sulfhydryl group in the active centerand thus inhibit L-PGDS.

By immunoperoxidase staining with speci¢c poly-clonal or monoclonal antibodies and by in situ hy-bridization with the antisense RNA, L-PGDS in therat [57] and human [60,61] brain was shown to bemainly produced in the leptomeninges (pia-arachnoidmembrane) and choroid plexus, rather than in theoligodendrocytes of the parenchyma. Moreover,L-PGDS was demonstrated to be secreted into theCSF as L-trace [62^65]. L-Trace was originally dis-covered in the early 1960s as a protein speci¢c to thehuman CSF [66,67], but its structure, sites of syn-thesis, and function were not elucidated until re-cently. From 1991 to 1993, several groups of inves-tigators reported independently and almostconcurrently that the N-terminal partial amino acidsequence of L-trace is highly homologous to that ofrat and human L-PGDS enzymes except that L-tracehas no signal peptide [62,63]. Finally, the full amino-acid sequence of L-trace was determined to be essen-tially identical to that of human L-PGDS except forthe absence of the signal peptide in L-trace [64]. Wealso con¢rmed that L-PGDS puri¢ed from humanCSF and L-trace are structurally, enzymatically,and immunologically identical [65].

Although L-PGDS is considered to have evolvedfrom lipophilic-ligand carrier proteins, it retains theancestral characteristic of binding lipophilic ligands.

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Rat [68] and Xenopus [36] L-PGDS bind retinoidsand thyroids with a high a¤nity comparable tothat of other lipocalins. In the brain and eye[69,70], L-PGDS (L-trace) is produced at the sitesof blood^CSF and blood^retinal barriers, respec-tively, and is secreted into a closed compartmentseparated from the systemic circulation. In the retina,L-PGDS is produced in pigmented epithelial cellsand accumulates within the interphotoreceptor ma-trix [69], a compartment possessing the most activeretinoid-transporting system in the body. These re-sults, taken together, indicate that L-PGDS (L-trace)may also act as a novel extracellular retinoid trans-porter in those compartments.

3.2. Hematopoietic prostaglandin D synthase

PGD2 is also actively produced in a variety ofperipheral tissues [71], in which it prevents plateletaggregation and induces vasodilation and broncho-constriction [72]. PGD2 is also released from mastcells upon stimulation with various immunologicalstimuli and functions as a lipid mediator in allergyand in£ammation [73]. PGD2 is further converted tothe J series of PGs, such as PGJ2, v12-PGJ2, and 15-deoxy-v12,14-PGJ2, the last of which has been re-cently identi¢ed to be an endogenous ligand for anuclear receptor, the peroxisome proliferator-acti-vated receptor (PPAR) Q [74,75]. The ligand activa-tion of PPARQ was found to regulate macrophageand monocyte functions [76^80].

Production of PGD2 in the peripheral tissues ismainly catalyzed by hematopoietic PGDS (H-PGDS), which was originally puri¢ed from rat spleenas a cytosolic, GSH-requiring enzyme with a molec-ular weight of approximately 26 000 [81,82]. H-PGDS was immunohistochemically localized in anti-gen-presenting cells [83,84] and mast cells [85]. Theinduction of H-PGDS is involved in mast cell acti-vation [86^88] and also in megakaryocytic di¡eren-tiation [89,90]. The enzyme is considered to be in-volved in deep sleep of mastcytotic patients asdescribed above. The immunoreactivity of H-PGDSwas localized to be satellite and Schwann cells ofchick dorsal root ganglia [91]. However, the existenceof H-PGDS in the CNS and its cellular localizationthere, if any, remain to be elucidated.

The cDNA for H-PGDS has been cloned from rats

[92] and chicken [93]. A homology search in databases of protein primary structure revealed that H-PGDS is a member of the GSH S-transferase (GST)family, as previously predicted by the results of par-tial amino acid sequence analyses [84,94]. However,H-PGDS showed a weak homology against mamma-lian GST isozymes of the previously known fourclasses (K, W, Z, and a) and yet revealed a relativelyhigh homology with GST isozymes of the c-class,which had been observed only in invertebrates. Fi-nally, the enzyme was demonstrated to be the ¢rstrecognized vertebrate homolog of the c-class of theGST family [92^94].

The recombinant rat H-PGDS was then crystal-lized, and the tertiary structure of the enzyme com-plexed with GSH was determined with a resolutionof 2.3 Aî by X-ray di¡raction analysis [92]. This wasthe ¢rst report of the tertiary structure of an enzymethat utilizes PGH2 as a substrate. The X-ray crystal-lographic analysis revealed that H-PGDS possesses aprominent cleft as the active site, which feature hasnever seen among other members of the GST family.This ¢nding is in agreement with the fact that otherGST isozymes catalyze the conversion of PGH2 toproduce PGE2 and PGF2K [95,96] whereas H-PGDSselectively forms PGD2.

4. Prostanoid DP receptor

The actions of PGD2 are mediated by a prostanoidreceptor speci¢c for PGD2, i.e. the DP receptor[97,98]. The cDNA for this receptor was clonedfrom mice [99], humans [100], and rats [101]. TheDP receptor contains seven hydrophobic transmem-brane domains and is a member of the G-protein-coupled, rhodopsin-type receptor family. The activa-tion of this DP receptor results in an elevation ofintracellular cAMP and mobilization of Ca2�

[99,100].As examined by Northern blot analysis, the tissue

distribution pro¢le of the mRNA for the DP recep-tor varied signi¢cantly among mice, rats, and hu-mans [99^101], which variation is consistent withthe highly species-speci¢c pharmacological activitiesof PGD2 [102]. In the same species, for example inrats, the tissue distribution pro¢le of the mRNA forthe DP receptor overlaps those pro¢les of L-PGDS

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and H-PGDS [101]. In situ hybridization utilizingmouse [103] and rat [101] brain revealed that themRNA for the DP receptor was dominantly ex-pressed in the leptomeninges rather than in the pa-renchyma, similar to the case of L-PGDS [59,61].These results are in agreement with the classicalidea that PGD2 acts as a local mediator in an auto-crine or paracrine fashion.

5. Signal transduction of PGD2 to promote sleep

Dominant localization of the DP receptor in theleptomeninges, and not in the brain parenchyma, in-dicates that the initial event to promote sleep afterPGD2 administration probably occurs at the surfaceof the brain. This idea was con¢rmed by our phar-macological study to identify the site of action ofPGD2 to induce sleep. When PGD2 was continu-ously infused into a variety of regions of the ratbrain through an implanted microdialysis probe, itpromoted sleep the most e¡ectively by infusion intothe subarachnoidal space at the ventral surface of therostral basal forebrain [104]. Interestingly, the PGD2

infusion into the subarachnoidal space preferentiallyinduced slow-wave sleep (SWS), but not rapid eyemovement (REM) sleep (paradoxical sleep), whereasthe cerebroventricular infusion of PGD2 inducedboth SWS and REM sleep [18,19]. The SWS levelduring the PGD2 infusion into the subarachnoidalspace was comparable to the level of the daytimeSWS of rats, i.e. PGD2 induced the maximum, satu-ration amount of sleep with the minimum awakingtime in rats [104].

We then attempted to identify the chemical trans-mitter(s) that sends the PGD2-produced signal to theneural circuits responsible for the sleep promotionand found that an adenosine A2A-receptor antago-nist, KF17837, attenuated the PGD2-induced sleep[105]. Furthermore, when adenosine A2A-receptor ag-onists, such as 2-(4-(2-carboxyethyl)phenylethylami-no)-5P-N-ethylcarboxamidoadenosine (CGS21680)and 2-(4-(2-(2-aminoethylaminocarbonyl)ethyl)phe-nylethylamino)-5P-N-ethylcarboxamido-adenosine(APEC), were infused into the subarachnoidal spaceof the rostral basal forebrain, these compounds alsoinduced a remarkable SWS and REM sleep[105,106]. These results, taken together, indicate

that the signal of PGD2 to induce sleep is mediatedby the adenosine A2A-receptive neurons [107,108].

We then used Fos immunohistochemistry to iden-tify neuroanatomically the neurons activated by in-fusion of PGD2 into the subarachnoid space of therostral basal forebrain [109]. PGD2 increased SWS(non-REM sleep) and induced striking expressionof Fos in neurons within the ventrolateral preopticarea (VLPO), which was recently proposed to play acritical role in the generation of sleep [110]. TheVLPO sends speci¢c GABAergic and galaninergice¡erents to the core of the tuberomammillary nu-cleus (TMN) [111], the source of the ascending his-taminergic arousal system and receives a¡erents fromthe suprachiasmatic nucleus and retina. Fos expres-sion in the VLPO after the PGD2 infusion was pos-itively correlated with the preceding amount of sleepand negatively correlated with Fos expression in theTMN [109]. These observations indicate that PGD2

may induce sleep through activation of the VLPOand inhibition of the TMN. PGD2 also increasedFos-immunoreactivity in the basal leptomeninges[109], which ¢nding is in good agreement with thefact that the DP receptor is localized in the leptome-ninges [101]. These results also suggest that the lep-tomeninges may be the site for transmission of thesignal of PGD2 to the next substance (adenosine?) toinduce sleep.

6. Future studies

PGD2 is, therefore, not a typical neurotransmitter,but rather a `neurohormone' or an `informationalsubstance' that circulates through the CSF and trans-mits certain chemical messages to promote sleep. Themode of communication through the CSF in theventricular system and the extracellular space hasadvantages for global regulation of the brain to in-duce sleep or to increase the propensity for sleep.Studies are still in progress in our own and otherlaboratories concerning the regulatory mechanismsof PGD2 biosynthesis and the molecular mechanismsinvolved in the transmission of the message initiatedby PGD2 to induce sleep. We recently crystallizedrecombinant mouse L-PGDS and human H-PGDSand have started the X-ray di¡raction analyses.The three-dimensional coordinates of these enzymes

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will be useful for designing selective and non-selec-tive inhibitors for each enzyme. Gene-knockout ortransgenic mice for L-PGDS, H-PGDS, DP receptor,and adenosine A2A receptor have also been generatedby our group and by others. Further investigation toexamine the functional abnormality of sleep^wakeregulation in such genetically engineered mutantmice should provide us with new insight into themolecular mechanism of sleep^wake regulation.

7. Concluding remarks

The PGD2 concentration in rat CSF was higher inthe sleeping period than in the waking period andincreased during sleep deprivation in parallel withan increase in sleep propensity. L-PGDS catalyzesproduction of PGD2 in the CNS and is likely to bethe key enzyme for the regulation of physiologicalsleep. L-PGDS is present mainly in the membranesystem surrounding the brain rather than in the brainparenchyma, and is secreted into the CSF to becomeL-trace, a major protein component of the CSF.L-PGDS as well as the PGD2 thus produced circu-

lates in the ventricular system, subarachnoidal space,and extracellular space in the brain system. PGD2

then interacts with DP receptors in the chemosensoryregion of the ventromedial surface of the rostralbasal forebrain to initiate the signal to promote sleepprobably via the activation of adenosine A2A recep-tive neurons. The activation of DP receptors in thePGD2-sensitive chemosensory region of the rostralbasal forebrain results in activation of a cluster ofneurons within the VLPO, which may promote sleepby inhibiting TMN, the source of the ascending his-taminergic arousal system. The proposed mechanismof PGD2 to promote sleep is schematically summar-ized 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. Wealso thank D. Irikura, Y. Kuwahata, Shigeko Mat-sumoto, S. Ueta, and Shuko Matsumoto for techni-cal and secretarial assistance. This work was sup-ported in part by grants from the program Grants-in-Aid for Scienti¢c Research of the Ministry ofEducation, Science, Sports, and Culture of Japan(07558108, 07457033 and 09044352 to Y.U. and06508003 to O.H.), a grant from the program forCore Research for Evolutional Science and Technol-ogy from Japan Science and Technology Corpora-tion (to Y.U.), and by grants from the Ministry ofHealth and Welfare of Japan (100107 to O.H.), theSuntory Institute for Bioorganic Research (to Y.U.),and the Japan Foundation for Applied Enzymology(to Y.U.).

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Fig. 2. Possible mechanisms for sleep induction by PGD2.L-PGDS is present mainly in the membrane system surroundingthe brain (arachnoid membrane) and within the ventricles (cho-roid plexus), and is secreted into the CSF. L-PGDS as well asthe PGD2 thus produced circulates in the ventricular system,subarachnoidal space, and extracellular space in the brain sys-tem. PGD2 then interacts with DP receptors in the chemosen-sory region of the surface of the basal forebrain. The activationof these receptors initiates the signal to activate adenosine A2A

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Prostaglandin D2 and Sleep Regulation