Dataset Information

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 ?-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.

SUBMITTER: Rueda P

PROVIDER: S-EPMC4718634 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.

Rueda Patricia P Harley Elizabeth E Lu Yao Y Stewart Gregory D GD Fabb Stewart S Diepenhorst Natalie N Cremers Béatrice B Rouillon Marie-Hélène MH Wehrle Isabelle I Geant Anne A Lamarche Gwladys G Leach Katie K Charman William N WN Christopoulos Arthur A Summers Roger J RJ Sexton Patrick M PM Langmead Christopher J CJ

PloS one 20160119 1

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-sensin ...[more]

PMID: 26785252

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Project description:Background and objectivesGenetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts.Design, setting, participants, & measurementsWe conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record-linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624).ResultsOf 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all P values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study.ConclusionsWe demonstrate significant associations between an NAT8 gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.

Dataset Information

Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.

Publications

Murine GPRC6A Mediates Cellular Responses to L-Amino Acids, but Not Osteocalcin Variants.

Similar Datasets

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