title: Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.
abstract: Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the concept of a bone-energy-metabolism-reproduction functional crosstalk mediated by GPRC6A. However, whilst the calcium and L-amino acid-sensing properties of GPRC6A are well established, verification of activity of osteocalcin at both human and mouse GPRC6A in vitro has proven somewhat elusive. This study characterises the in vitro pharmacology of mouse GPRC6A in response to its putative ligands in both recombinant and endogenous GPRC6A-expressing cells. Using cell signalling, and glucagon-like peptide (GLP)-1 and insulin release assays, our results confirm that basic L-amino acids act as agonists of the murine GPRC6A receptor in both recombinant cells and immortalised entero-endocrine and pancreatic β-cells. In contrast, our studies do not support a role for OCN as a direct ligand for mouse GPRC6A, suggesting that the reported in vivo effects of OCN that require GPRC6A may be indirect, rather than via direct activation of the receptor.
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rueda
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harley
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Stewart
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Stewart
authors.initials: S
authors.lastname: Fabb
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Diepenhorst
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Cremers
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Rouillon
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Wehrle
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Geant
authors.affiliation: Institut de Recherches Servier, Suresnes, France.
authors.forename: Gwladys
authors.initials: G
authors.lastname: Lamarche
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Katie
authors.initials: K
authors.lastname: Leach
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: William N
authors.initials: WN
authors.lastname: Charman
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015675:Osteocalcin / Q000494:pharmacology*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D000596:Amino Acids; C515750:GPRC6A protein, mouse; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D015675:Osteocalcin; D052216:Glucagon-Like Peptide 1