title: Identification of metals from osteoblastic ST-2 cell supernatants as novel OGR1 agonists.
abstract: Ovarian cancer G-protein-coupled receptor 1 (OGR1) is a G-protein-coupled receptor (GPCR), which has previously been identified as a receptor for protons. It has been reported in this and previous studies that OGR1 expression was markedly up-regulated during osteoclast differentiation. We predicted the possibility of other molecules activating OGR1 in neutral pH, and that osteoblasts might release OGR1 agonistic molecules and activate OGR1 expressed in osteoclasts such as RANKL. We screened for cell supernatants and organ extracts and discovered OGR1 agonistic activity in ST-2 osteoblastic cell supernatants and pancreatic tissues. Finally, we partially purified and identified essential metals, Fe, Zn, Co, Ni and Mn, as novel OGR1 agonists. These OGR1 agonistic metals induce intracellular Gq-coupled inositol phosphate signals in OGR1-expressing cells and primary osteoclasts through OGR1. We also confirmed that these OGR1 agonistic metals activated OGR1 through the same residues which act with protons. Here, we demonstrate that metals, Fe, Zn, Co, Ni and Mn are the novel OGR1 agonists, which can singly activate OGR1 in neutral pH.
authors.affiliation: a Cardiovascular-Metabolics Research Laboratories, Research Oversight Function, R&D Division , Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Rie
authors.initials: R
authors.lastname: Abe-Ohya
authors.affiliation: b Discovery Science and Technology Department, Drug Discovery and Biomedical Technology Unit , Daiichi Sankyo RD Novare Co., Ltd. , Tokyo , Japan , and.
authors.forename: Tomio
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: c Drug Metabolism & Pharmacokinetics Research Laboratories , and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shiozawa
authors.affiliation: d Frontier Research Laboratories, Research Oversight Function, R&D Division , Daiichi Sankyo Co., Ltd. , Tokyo , Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Suda
authors.affiliation: a Cardiovascular-Metabolics Research Laboratories, Research Oversight Function, R&D Division , Daiichi Sankyo Co., Ltd. , Tokyo , Japan .
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D008670:Metals / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000737:chemistry* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C525539:GPR68 protein, mouse; D008670:Metals; D043562:Receptors, G-Protein-Coupled
keywords: GPCR; OGR1; ligand; metal; osteoblast; osteoclast