{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T05:25:06Z","timestamp":1784957106472,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T00:00:00Z","timestamp":1594944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["17H01524"],"award-info":[{"award-number":["17H01524"]}]},{"name":"The Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["15H05933"],"award-info":[{"award-number":["15H05933"]}]},{"name":"The Project for Elucidating and Controlling Mechanisms of Ageing and Longevity of the Japan Agency for Medical Research and Development","award":["JP19gm5010002"],"award-info":[{"award-number":["JP19gm5010002"]}]},{"name":"The Basis for Supporting Innovative Drug Discovery and Life Science Research program of the Japan Agency for Medical Research and Development","award":["JP19am0101092"],"award-info":[{"award-number":["JP19am0101092"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>G-protein-coupled receptors (GPCRs) are an important source of drug targets with diverse therapeutic applications. However, there are still more than one hundred orphan GPCRs, whose ligands and functions remain unidentified. The suprachiasmatic nucleus (SCN) is the central circadian clock of the brain, directing daily rhythms in activity\u2013rest behavior and physiology. Malfunction of the circadian clock has been linked to a wide variety of diseases, including sleep\u2013wake disorders, obesity, diabetes, cancer, and hypertension, making the circadian clock an intriguing target for drug development. The orphan receptor GPR176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock. GPR176 undergoes asparagine (N)-linked glycosylation, a post-translational modification required for its proper cell-surface expression. Although its ligand remains unknown, this orphan receptor shows agonist-independent basal activity. GPR176 couples to the unique G-protein subclass Gz (or Gx) and participates in reducing cAMP production during the night. The regulator of G-protein signaling 16 (RGS16) is equally important for the regulation of circadian cAMP synthesis in the SCN. Genome-wide association studies, employing questionnaire-based evaluations of individual chronotypes, revealed loci near clock genes and in the regions containing RGS16 and ALG10B, a gene encoding an enzyme involved in protein N-glycosylation. Therefore, increasing evidence suggests that N-glycosylation of GPR176 and its downstream G-protein signal regulation may be involved in pathways characterizing human chronotypes. This review argues for the potential impact of focusing on GPCR signaling in the SCN for the purpose of fine-tuning the entire body clock.<\/jats:p>","DOI":"10.3390\/ijms21145055","type":"journal-article","created":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T10:22:02Z","timestamp":1594981322000},"page":"5055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus"],"prefix":"10.3390","volume":"21","author":[{"given":"Shumpei","family":"Nakagawa","sequence":"first","affiliation":[{"name":"Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Saky\u014d-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh Tien","family":"Nguyen Pham","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Saky\u014d-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Saky\u014d-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6264-9217","authenticated-orcid":false,"given":"Masao","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Saky\u014d-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. 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