G protein-coupled receptors (GPCRs) are divided into Group A, B and C receptors based on phylogenetics. The majority of Group C GPCRs consist of a large extracellular ‘Venus Flytrap’ domain and Cystein-rich domain followed by a 7-transmembrane domain. The ‘Venus Flytrap’ domain is homologous to periplasmic binding proteins which act as amino acid and nutrient transporters in bacteria. Likewise, human Group C GPCRs have been shown to binds amino acids, cations and sugars and thus potentially act as nutrient sensors in mammals [1]. We have paid particular interest to the Group C receptor entitled GPRC6A, which will be the focus of the present talk. In 2004 we reported the cloning and tissue expression of the GPRC6A receptor [2]. Using a variety of pharmacological assays at the human, mouse and rat receptor orthologs expressed in Xenopus laevis oocytes and mammalian cell lines, we have shown that the receptor is Gq coupled and promiscuously activated by L-amino acids of which the basic L-amino acids L-Arg, L-Lys and L-ornithine are the most potent [3-4]. In addition, we have shown that the receptor is co-activated by divalent cations such as calcium [4-5]. Unfortunately, these endogenous agonists also act on a range of other targets, which decreases their use as pharmacological tool compounds. Novel tools are thus warranted to study the physiological function of the receptor including its potential role as nutrien sensor. To this end, we recently reported the first GPRC6A selective negative allosteric modulators (NAMs). The NAMs, based on so-called privileged structures containing a 2-phenyl-indole scaffold, were inferred from family A receptors using chemogenomics [6]. Another strategy has been to develop a GPRC6A knockout mouse where exon 6 containing the entire 7TM domain was removed. We have shown that the GPRC6A knockout mice had wild-type-like growth rate [7] body composition and glucose metabolism [8] when fed a regular chow diet. However, when the mice are fed a 60% high fat diet the knockout mice become more obese than their wild-type littermates and show impaired glucose metabolism [9]. Given that the GPRC6A receptor is expressed in the islets of Langerhans and that L-amino acids such as L-Arg are known to increase insulin secretion, we hypothesized that the impaired glucose metabolism could be caused by decreased L-amino acid insulin secretion. However, both ex vivo experiments on isolated islets and in vivo experiments demonstrate that the GPRC6A knockout mice demonstrate wild-type-like L-Arg mediate insulin release [8]. Collectively, these studies of our GPRC6A knockout mice indicate a role as nutrient sensor. However, further studies are needed to delineate the precise mechanisms of the observed phenotype. References: 1. Wellendorph et al. Mol. Pharmacol. 2009; 76: 453-465. 2. Wellendorph and Bräuner-Osborne, Gene 2004; 335: 37-46. 3. Wellendorph et al. Mol. Pharmacol. 2005; 67: 589-597. 4. Wellendorph et al. Gene 2007; 396: 257-267. 5. Christiansen et al. Br. J. Pharmacol. 2007; 150: 798-807. 6. Gloriam, Wellendorph, Johansen et al. Chem. Biol. 2011; 18: 1489-1498. 7. Wellendorph et al. J. Mol. Endocrinol. 2009; 42: 215-223. 8. Smajilovic et al. Amino Acids. 2013; 383-390. 9. Clemmensen, Smajilovic et al. Submitted.