title: Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour.
abstract: G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz.
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Doi
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Iori
authors.initials: I
authors.lastname: Murai
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Kunisue
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Genzui
authors.initials: G
authors.lastname: Setsu
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Uchio
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Sakurako
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimatani
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hida
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Hsu-Wen
authors.initials: HW
authors.lastname: Chao
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Hotta
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Jun-ichirou
authors.initials: J
authors.lastname: Yasunaga
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Masao
authors.identifier: http://orcid.org/0000-0002-0473-754X
authors.initials: M
authors.lastname: Matsuoka
authors.affiliation: Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.affiliation: Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.|Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamura
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: C000609262:Gpr176 protein, mouse; D043562:Receptors, G-Protein-Coupled