Orphan GPCRs in the regulation of sleep and circadian rhythm

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<ul><li><p>MINIREVIEW SERIES</p><p>Orphan GPCRs in the regulation of sleep and circadianrhythmOlivier Civelli</p><p>Department of Pharmacology and Department of Developmental and Cell Biology, University of California, Irvine, CA, USA</p><p>The hypothalamus is the brain center that is most</p><p>important in regulating sleep duration and circadian</p><p>rhythm. Some 75 years ago, it was predicted that the</p><p>rostral hypothalamus contains the sleep-promoting</p><p>neurons, while the posterior hypothalamus contains</p><p>wakefulness-promoting neurons [1]. Sleep is controlled</p><p>by two processes, a homeostatic and a circadian timing</p><p>process, which together determine the propensity,</p><p>length, and incidence of episodes and intensity of sleep</p><p>[2]. Sleep itself is divided into two major phases, non-</p><p>rapid eye movement (NREM) and rapid eye movement</p><p>(REM) sleep [3]. Modulation of these phases and of</p><p>the circadian rhythms relies on several transmitters</p><p>which together generate and maintain sleep [4].</p><p>The sleep-producing neurons are c-aminobuty-rate(GABA)-ergic cells [3,4]. They induce sleep by</p><p>inhibiting cells that are involved in arousal functions.</p><p>The wakefulness-promoting neurons on the other hand,</p><p>rely on several transmitters (Fig. 1). The peduncolo-</p><p>pontine and laterodorsal tegmental (PPTLDT) nuclei</p><p>rely on acetylcholine and re rapidly during wakeful-</p><p>ness and REM sleep but become inactive during</p><p>NREM sleep. It projects to the thalamus, in particular</p><p>to the reticular nucleus, which is thought to be critical</p><p>in activating thalamocortical transmission. Three other</p><p>distinct nuclei exhibit similar activity during the wake-</p><p>sleep phases. The tuberomammilary nucleus (TMN) is</p><p>a histaminergic nucleus and plays a major role in the</p><p>maintenance of wakefulness. Inhibition of their activity</p><p>by GABAergic cells appears to be closely linked to slee-</p><p>piness, as evidenced by the drowsiness elicited by anti-</p><p>histamine drugs. The locus coeruleus (LC), center of</p><p>norepinephrine production, is active during wakeful-</p><p>ness, displays low activity during NREM sleep and is</p><p>inactive during REM sleep. The raphe nucleus, which</p><p>relies on serotonin as transmitter, is also inactive dur-</p><p>ing sleep, in particular during REM sleep. Its inactivity</p><p>allows electrical activity to propagate from the pons to</p><p>the thalamus and cortex inducing eye movement and</p><p>twitches. Neurons from the TMN, LC and dorsal raphe</p><p>re fastest during wakefulness, slow down during</p><p>NREM and nearly stop ring during REM sleep.</p><p>While most sleep research has focused on the actions</p><p>of neurotransmitters, an increasing amount of data</p><p>point at neuropeptides as being important in modula-</p><p>ting the sleep-wake cycle. Neuropeptides exert their</p><p>actions by activating G-protein coupled receptors</p><p>(GPCRs). Interestingly, most of these sleep-regulating</p><p>neuropeptides were discovered recently, not for their</p><p>activities at regulating sleep, but as the natural ligands</p><p>of orphan GPCRs.</p><p>The human genome expresses some 800 GPCRs of</p><p>which some 360 are activated by transmitters. Ten years</p><p>ago, half of these GPCRs had not been matched to any</p><p>known transmitters; they became to be known as</p><p>orphan GPCRs [5]. Because of their intrinsic receptor</p><p>nature, a strategy was developed to use the orphan</p><p>GPCRs as targets in the discovery of novel transmitters.</p><p>In short, orphan GPCRs are heterologously expressed</p><p>in cells in culture and subjected to tissue extracts expec-</p><p>ted to contain their natural transmitters. Activation of</p><p>the orphan GPCRs are monitored through their second</p><p>messenger responses. This strategy, rst reported in</p><p>1995, has led to the discovery of 10 novel neuropeptides.</p><p>It has also allowed matching of several orphan GPCRs</p><p>to neuropeptides that had been described previously [5].</p><p>Novel neuropeptides discovered as ligands of orphan</p><p>GPCRs have unknown functions. Finding these requires</p><p>experimental studies that are predominantly directed by</p><p>the anatomical localization analyses of the sites of syn-</p><p>thesis and the sites of action of the novel neuropeptides</p><p>in the central nervous system (CNS). But ultimately, it</p><p>is the administration of the novel neuropeptide to ani-</p><p>mals and or the engineering of knockout mouse strainsthat reveals the function of the novel neuropeptide sys-</p><p>tem. Surprisingly a series of novel neuropeptide systems</p><p>were found to be implicated in sleep and wakefulness.</p><p>The rst deorphanized GPCR system to be shown to</p><p>modulate sleep was the hypocretin orexin (Hcrt orx)system. This system relies on the action of two closely</p><p>related neuropeptides at two sequentially similar</p><p>GPCRs. This system originates in the lateral hypothala-</p><p>mus and projects to throughout the whole brain but in</p><p>particular to the LC, dorsal raphe and PPTLDT. That</p><p>doi:10.1111/j.1742-4658.2005.04867.x</p><p>FEBS Journal 272 (2005) 56735674 2005 FEBS 5673</p></li><li><p>the Hcrt orx system is a major modulator of sleep hasbeen demonstrated by the discovery that animals, in</p><p>which one of the Hcrt receptors is inactive (Hcrt2), are</p><p>narcoleptic and that most human narcoleptic patients</p><p>have no detectable circulating Hcrt and exhibit a</p><p>reduced number of Hcrt neurons. This system is</p><p>reviewed in this series by de Lecea &amp; Sutcliffe.</p><p>Another novel neuropeptide system that modulates</p><p>sleep is the neuropeptide S (NPS) system. NPS is syn-</p><p>thesized in several parts of the CNS but in particular</p><p>in a nucleus anatomically associated with the LC. Acti-</p><p>vation of the NPS system promotes wakefullness by</p><p>decreasing the NREM and REM stages of sleep. This</p><p>system is reviewed in this series by Reinscheid &amp; Xu.</p><p>The urotensin II (UII) receptor, a GPCR deorphanized</p><p>in 1999, has been shown to be selectively expressed in the</p><p>cholinergic LDTPPT neurons in the CNS. These neu-</p><p>rons re during REM sleep. The UII receptor acts as a</p><p>presynaptic receptor in the LDTPPT and consequently</p><p>activation of this system has been shown to increase REM</p><p>sleep. This system is reviewed by Nothacker &amp; Clark.</p><p>However, there are other orphan GPCR systems that</p><p>impact sleep. The prolactin-releasing peptide (PrRP)</p><p>system is one of these. In the CNS, the PrRP receptor is</p><p>predominantly expressed in the reticular nucleus of the</p><p>thalamus. This is the thalamic relay nucleus of the choli-</p><p>nergic LDTPPT and it has been shown that activation</p><p>of this system induces sleep [6].</p><p>Sleep regulation is directly linked to the circadian</p><p>rhythm. The circadian rhythm is orchestrated in the</p><p>suprachiasmatic nucleus (SCN) which provides the</p><p>genetically based clock. The SCN clock relies on posit-</p><p>ive and negative feedback loops involving the time-</p><p>dependent transcription of a series of genes [7]. The</p><p>factors responsible for the output of the SCN clock</p><p>however, were unknown until recently when prokineti-</p><p>cin 2 (PK2) was shown to be such a factor. PK2 was</p><p>discovered as the natural ligand of an orphan GPCR</p><p>and is reviewed in this series by Zhou.</p><p>This minireview series is intended to present the</p><p>impact that novel neuropeptides have on our under-</p><p>standing of the sleep-wake cycle. This is not the only</p><p>eld on which novel neuropeptides have had an</p><p>impact. Most notably, our understanding of the regu-</p><p>lation of feeding has greatly gained from the discover-</p><p>ies of novel neuropeptides. These reviews therefore</p><p>serve as examples of the importance of the emerging</p><p>eld of the natural ligands of orphan GPCRs.</p><p>References</p><p>1 Von Economo C (1930) Sleep as a problem of localiza-</p><p>tion. J Nerv Ment Dis 71, 249259.</p><p>2 Borbely AA (1982) A two process model of sleep regula-</p><p>tion. Hum Neurobiol 1, 195204.</p><p>3 Saper CB, Chou TC &amp; Scammell TE (2001) The sleep</p><p>switch: hypothalamic control of sleep and wakefulness.</p><p>Trends Neurosci 24, 726731.</p><p>4 Siegel JM (2004) The neurotransmitters of sleep. J Clin</p><p>Psych 65, 47.</p><p>5 Civelli O, Nothacker HP, Saito Y, Wang Z, Lin S &amp;</p><p>Reinscheid RK (2001) Discovery of novel neurotransmit-</p><p>ters as natural ligands of orphan G protein-coupled</p><p>receptors. Trends Neurosci 24, 230237.</p><p>6 Lin SHS, Arai A, Espana RA, Berridge CW, Leslie F,</p><p>Huguenard J, Vergnes M &amp; Civelli O (2002) Prolactin-</p><p>releasing peptide (PrRP) promotes awakening and sup-</p><p>presses absence seizures. Neurosci 114, 229238.</p><p>7 Reppert SM &amp; Weaver DR (2002) Coordination of circa-</p><p>dian timing in mammals. Nature 418, 935941.</p><p>Fig. 1. Sleep architecture and its transmitters. In green are the tra-</p><p>ditional transmitters: GABA, 4-aminobutyrate; Hist, histamine; NA,</p><p>norepinephrine; Ach, acetylcholine. The new tranmitters and their</p><p>sleep-related sites of synthesis: TMN, tuberomammilary nucleus;</p><p>Raphe, raphe nucleus; LC, locus coeruleus; PPT LTD, peduncolo-pontine and laterodorsal tegmental. The novel transmitters are in</p><p>red: HCRT, hypocretin orexin; PK2, prokineticin 2; NPS, neuropep-tide S; UII, urotensin II. - - - - - , sleep-producing pathways; ,</p><p>wakefulness-producing pathway.</p><p>Olivier Civelli, PhD, is Professor of Pharmacology and the Eric L. and Lila D. Nelson Chair of Neuropharmacology at</p><p>University of California, Irvine. He is one of the pioneers who devised molecular strategies for understanding the</p><p>structure and function of drug receptors. He was first to clone a dopamine receptor, and deciphered their complexity.</p><p>He also devised and successfully applied the strategy that uses orphan GPCRs to discover novel neurotransmitters.</p><p>His present research aims at discovering new neuropeptides and at finding their biological significance. His discover-</p><p>ies continue to have important implications for the development of new therapeutic targets.</p><p>Sleep and circadian rhythm regulation by novel neuropeptides O. Civelli</p><p>5674 FEBS Journal 272 (2005) 56735674 2005 FEBS</p></li></ul>


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