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G-Protein-Coupled Receptor Signaling Through Gpr176, Gz, and RGS16 Tunes Time in the Center of the Circadian Clock

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G-Protein-Coupled Receptor Signaling Through Gpr176, Gz, and RGS16 Tunes Time in the Center of the Circadian Clock 2017, 64 (1), 1-10 Advance Publication doi: 10.1507/endocrj.EJ17-0130 REVIEW G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock Kaoru Goto*, Masao Doi*, Tianyu Wang, Sumihiro Kunisue, Iori Murai and Hitoshi Okamura Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan Abstract. G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock. Key words: Circadian clock, Orphan GPCR, Gpr176, Gz, RGS16 Introduction the enormous clinical relevance of this class of recep- tors. Astonishingly, of the 356 non-olfactory GPCRs G-protein-coupled receptors (GPCRs), also known encoded in the human genome, about 38% are still as 7 transmembrane receptors, constitute the largest considered ‘orphans’ whose physiological roles and family of cell surface molecules involved in signal endogenous ligands are not known. Deciphering their transmission. They are activated by a wide range of functions therefore remains of hot interest from both stimulants, including light, odorant molecules, peptide basic sciences and drug development perspectives. and non-peptide neurotransmitters, hormones, growth A set of the central pacemaker neurons in the supra- factors and lipids, and control their corresponding chiasmatic nucleus (SCN) in the brain serves as a downstream processes, including sensory transduction, guardian of our daily life: it co-ordinates the daily cell–cell communication, neuronal transmission, and rhythms of sleep and wakefulness, as well as behav- hormonal signaling. Given the central role of GPCRs ior and physiology. Through its ability to set the pace in diverse physiological processes and diseases, it may and phase of physiological rhythms in anticipation of not come as a surprise that more than 20% of drugs in regular day/night cycles, the clock forms a highly effi- current clinical use act on specific GPCRs, attesting to cient adaptation system to the predictive changes in environment. Disturbance of this endogenous clock, Submitted Mar. 26, 2017; Accepted Mar. 29, 2017 as EJ17-0130 with, e.g., jet-lag, rotational shiftwork, and irregular Released online in J-STAGE as advance publication May 13, 2017 night-owl lifestyles in current society, therefore causes Correspondence to: Masao Doi, Ph.D., Department of Systems a range of healthcare problems. One of the most sig- Biology, Graduate School of Pharmaceutical Sciences, Kyoto nificant conceptual changes brought about by the anal- University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 6068501, Japan. ysis of circadian clock-deficient mice is that abnor- E-mail: [email protected] malities in the circadian clock are linked not only to * These authors contributed equally to this work. sleep arousal disorder but also to a wide variety of ©The Japan Endocrine Society 2 Goto et al. common diseases, including hypertension, diabetes, The SCN is the center of obesity, and cancer [1-5]. It is worth noting that drug the body clock efficacy and toxicity also change with time in a man- ner depending on the endogenous clock [6]. These The SCN is the chief orchestrator for the lines of growing evidence support the potential value rhythms generated in the body. Almost all cells in of developing drugs that target the circadian clock. the body express a set of the essential clock genes. Here, we review a recently identified role of Gpr176 Correspondingly, all major organs have their own in the SCN. Gpr176 is an SCN-enriched orphan GPCR circadian clocks and they constitute a hierarchical that sets the pace of the central clock in the SCN [7]. multi-oscillator network, in which the SCN serves as Gpr176 couples to Gz, and even in the absence of known the chief orchestrator dominating the rhythms in the ligand, it possesses an agonist-independent basal activ- peripheral clocks (Fig. 1). ity to repress cAMP signaling [7, 8]. Besides Gpr176 In searching for the anatomical structure of the and Gz, this review also emphasizes a role for the regu- master clock, lesion studies led to the identification lator of G-protein signaling 16 (RGS16) in the tempo- of a part of the brain called the “suprachiasmatic ral regulation of G-protein-cAMP signaling in the SCN nucleus” (SCN). As its name suggests, the SCN is [9, 10]. Developing drugs that specifically target the located just above (supra to) the optic chiasm, the SCN remains an unfulfilled opportunity for the circa- place where the optic nerves cross-pass beneath the dian clock therapy. In this context, this review argues brain hypothalamus. Physical lesion of this structure for the potential merit of focusing on GPCRs in the abolishes circadian behavioral rhythms, which can be SCN for the purpose of tuning the body clock. restored by transplantation of fetal SCN tissue [11]. Central clock SCN Pineal Light (retina) Melatonin secretion 024 Time (hr) SCN governs periphery via signals involving neuronal, endocrine, feeding, behavior rhythms Autonomic Adrenal Heart Liver nervous system Heart rate Cortisol secretion Detoxication activity Body temperature 024 024 024 024 Time (hr) Time (hr) Time (hr) Time (hr) Fig. 1 The SCN is the center of the body clock The SCN oscillator synchronizes peripheral clocks in organs such as liver, heart, and adrenal via direct and indirect routes. SCN neurons receive light information directly from retina. This photic entrainment corrects the phase of the endogenous SCN clock to ultimately adjust the organismal physiological rhythms to the regular geographical light/dark cycle. Endocrine Journal Advance Publication GPCR signaling in the SCN 3 In addition, SCN transplants from Tau mutant ham- The SCN-GENE PROJECT identifies sters displaying a short period phenotype restore Gpr176: Gpr176 is an SCN-enriched rhythms in SCN-lesioned wild-type hamsters with a orphan GPCR that sets the pace of period length characteristic of the mutant donor [12], circadian behavior demonstrating that the period is encoded by the SCN. Moreover, SCN transplants from wild-type mice In order to identify a new GPCR that tunes the cen- restore circadian rhythmicity in global clock-gene tral clock, we launched the SCN-orphan GPCR project knockout mice, where no functional clocks operate [7, 9], in which we (i) searched for the orphan GPCRs throughout the body [13], providing evidence that the whose expression is enriched in the SCN, (ii) generated transplanted SCN alone is sufficient to produce organ- knockout mice of candidate GPCR genes of interest, ismal rhythmicity. Recent cell-type-specific condi- and (iii) asked whether there is a defect in their circa- tional clock-gene knockout studies also support the dian rhythms in behavior. Based on this screening strat- assertion that the SCN is the central clock [14-16]. egy, Gpr176 was identified as an SCN-enriched orphan The SCN is the site of the circadian center; it is GPCR that sets the pace of circadian behavior (Fig. 2). hence logical that the SCN expresses all of known Gene ablation of Gpr176 shortens circadian period of genes that determine the circadian period of locomotor behavior. A similar short-period phenotype was also activity rhythms. Taking advantage of this nature, we observed for the clock gene Per1 transcription rhythms initiated the SCN-GENE PROJECT [17] that focuses in ex vivo organotypic SCN slice cultures. Thus, the on the genes highly expressed in the SCN. defect in the SCN mirrors the behavioral rhythm output. A B 11 PACAP DNA microarray 11 Gpr176 SCN-GPCR Project 10 receptor SCN-GPCR 10 9 Top100 9 SCN microarray Prokineticin receptor 8 V1a 8 7 Vipr2 (VPAC2) 7 In situ hybridization 6 6 5 5 Creation of KO mice 4 4 3 3 Behavioral test 2 2 Log2 GPCR mRNA levels 1 1 Identication of a new 0 0 relevant SCN-GPCR C Gpr176 D SCN In situ Behavioral microarray hybridization test Orphan GPCRs Candidates Candidates Gpr176 > 120 26 3 Fig. 2 The SCN-GENE PROJECT leading to the identification of Gpr176 (A) Experimental design of the SCN orphan GPCR project. (B) The top 100 GPCRs in SCN microarray. Note that Gpr176 was estimated to be abundant, relative to prokineticin receptor, vasopressin V1a receptor, and Vip receptor, Vipr2; all of them are known to be important in the SCN function. (C) The genes highlighted in blue in (B), which include all listed orphan GPCRs, were assessed through in situ hybridization. Arrows indicate robust positive SCN signals for Gpr176, Calcr, and Gpr19. (D) The results form behavioral tests on respective knockout mice for Gpr176, Calcr, and Gpr19 led us to prioritize Gpr176 as a target for further analysis [Adapted from Ref.
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