TY - JOUR
T1 - Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour
AU - Doi, Masao
AU - Murai, Iori
AU - Kunisue, Sumihiro
AU - Setsu, Genzui
AU - Uchio, Naohiro
AU - Tanaka, Rina
AU - Kobayashi, Sakurako
AU - Shimatani, Hiroyuki
AU - Hayashi, Hida
AU - Chao, Hsu Wen
AU - Nakagawa, Yuuki
AU - Takahashi, Yukari
AU - Hotta, Yunhong
AU - Yasunaga, Jun Ichirou
AU - Matsuoka, Masao
AU - Hastings, Michael H.
AU - Kiyonari, Hiroshi
AU - Okamura, Hitoshi
N1 - Funding Information:
We thank members of the H.O. laboratory, Drs Akira Hirasawa, and Masahiro Matsuo for technical assistance and discussion. We also thank Dr William J. Schwartz (University of Massachusetts Medical School) for stimulating discussions and kind reading of this manuscript. We are grateful to Dr David R. Manning (University of Pennsylvania) for providing an antiserum against Gz (2919) and to Dr Mitsuo Tagaya (Tokyo University of Pharmacy and Life Science) for providing a DN-Gz expression plasmid. This research was supported by Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (to H.O.), and the Ministry of Education, Culture, Sports, Science and Technology of Japan through a Funding Program for Next Generation World-Leading Researchers (to M.D.), and grants from Takeda Science Foundation and Kobayashi International Scholarship Foundation (to H.O.), Senri Life Science Foundation, Daiichi Sankyo Foundation of Life Science, Inoue Foundation for Science, Brain Science Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Kanae Foundation for the Promotion of Medical Science (to M.D.). M.H.H. is supported by Medical Research Council, UK.
PY - 2016/2/17
Y1 - 2016/2/17
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms10583
DO - 10.1038/ncomms10583
M3 - Article
AN - SCOPUS:84958567860
SN - 2041-1723
VL - 7
JO - Nature Communications
JF - Nature Communications
M1 - 10583
ER -