Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

Clemmensen, Christoffer; Smajilovic, Sanela; Madsen, Andreas Nygaard; Klein, Anders Bue; Holst, Birgitte; Bräuner‐Osborne, Hans

doi:10.1530/joe-12-0550

Cited by 35 publications

(19 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other ligands as well as pathways like G s and G i have been proposed [12,34,35,39,40,41,42], however we have been unable to confirm this [20]. The physiological function of the receptor has so far only been characterized via knockout mice, which have shown interesting phenotypes like diet‐induced obesity, feminization, glucose intolerance, and insulin resistance identifying this receptor as a potential drug target in metabolic disorders [6,7,38].…”

Section: Introductionmentioning

confidence: 78%

N‐glycosylation and disulfide bonding affects GPRC6A receptor expression, function, and dimerization

2015

Self Cite

View full text Add to dashboard Cite

a b s t r a c tInvestigation of post-translational modifications of receptor proteins is important for our understanding of receptor pharmacology and disease physiology. However, our knowledge about posttranslational modifications of class C G protein-coupled receptors and how these modifications regulate expression and function is very limited. Herein, we show that the nutrient-sensing class C G protein-coupled receptor GPRC6A carries seven N-glycans and that one of these sites modulates surface expression whereas mutation of another site affects receptor function. GPRC6A has been speculated to form covalently linked dimers through cysteine disulfide linkage in the extracellular amino-terminal domain and here we show that GPRC6A indeed is a homodimer and that a disulfide bridge between the C131 residues is formed.

show abstract

Section: Introductionmentioning

confidence: 78%

N‐glycosylation and disulfide bonding affects GPRC6A receptor expression, function, and dimerization

2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…As outlined in the introduction, exon 2 GPRC6A knock-out mice have shown complex metabolic and testicular phenotypes under normal physiological conditions (13, 14, 18, 24 -26), which, however, are not observed in exon 6 and whole gene knock-out mice under normal physiological conditions (17, 19 -23) with the exception of a mild metabolic phenotype observed in exon 6 knock-out mice on high fat diet for several months (22).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

Jørgensen

Have

Underwood

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Henrik G. DohlmanGPRC6A is a G protein-coupled receptor activated by Lamino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are G q -coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers.Communication between the exterior and interior of cells is essential for cellular survival. A pivotal class of proteins, specialized to carry out such signal transduction, is the G proteincoupled receptors (GPCRs), 2 a family that includes ϳ800 subtypes in humans. The GPCR class C, group 6, member A (GPRC6A) belongs to the non-olfactory GPCRs as part of the class C receptors. Human GPRC6A (h6A) was cloned from a human kidney cDNA library in 2004 (1). Cloning and deorphanization of the mouse (2, 3) and rat (4) GPRC6A orthologs rapidly followed. These studies, together with recent evidence (5) support the existence of GPRC6A as a dimer on the cell surface. However, surprisingly, h6A has been shown to be retained intracellularly and thus does not respond to agonists, which contrasts findings for the mouse, rat, and goldfish orthologs (2, 3, 6). To deorphanize h6A, we generated chimeras between the human and goldfish GPRC6A orthologs. We found that a fusion of the human large extracellular amino-terminal domain (ATD) to the 7-transmembrane (7TM) and C-terminal domains of the orthologous goldfish 5.24 receptor allowed efficient surface expression of the chimera and thereby a way to

show abstract

“…This is underscored by the fact that parameters such as food intake, oxygen consumption and substrate metabolism are similar between GPRC6A KO and WT control mice (Clemmensen et al ., 2013a). Noteworthy, whereas we repeatedly have failed to identify any differences in body composition between chow fed KO and WT mice (Smajilovic et al ., ; Clemmensen et al ., 2013a,b), Pi et al . found increased adiposity in GPRC6A deficient mice on a chow diet (Pi et al ., ).…”

Section: Physiology and Pathophysiologymentioning

confidence: 99%

The GPCR, class C, group 6, subtype A (GPRC6A) receptor: from cloning to physiological function

Clemmensen

Smajilovic

Wellendorph

et al. 2014

British J Pharmacology

View full text Add to dashboard Cite

GPRC6A (GPCR, class C, group 6, subtype A) is a class C GPCR that has been cloned from human, mouse and rat. Several groups have shown that the receptor is activated by a range of basic and small aliphatic L-α-amino acids of which L-arginine, L-lysine and L-ornithine are the most potent compounds with EC50 values in the mid-micromolar range. In addition, several groups have shown that the receptor is either directly activated or positively modulated by divalent cations such as Ca 2+ albeit in concentrations above 5 mM, which is above the physiological concentration in most tissues. More recently, the peptide osteocalcin and the steroid testosterone have also been suggested to be endogenous GPRC6A agonists. The receptor is widely expressed in all three species which, along with the omnipresence of the amino acids and divalent cation ligands, suggest that the receptor could be involved in a broad range of physiological functions. So far, this has mainly been addressed by analyses of genetically modified mice where the GPRC6A receptor has been ablated. Although there has been some discrepancies among results reported from different groups, there is increasing evidence that the receptor is involved in regulation of inflammation, metabolism and endocrine functions. GPRC6A could thus be an interesting target for new drugs in these therapeutic areas. LINKED ARTICLESThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx

show abstract

Increased susceptibility to diet-induced obesity in GPRC6A receptor knockout mice

Cited by 35 publications

References 34 publications

N‐glycosylation and disulfide bonding affects GPRC6A receptor expression, function, and dimerization

N‐glycosylation and disulfide bonding affects GPRC6A receptor expression, function, and dimerization

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

The GPCR, class C, group 6, subtype A (GPRC6A) receptor: from cloning to physiological function

Contact Info

Product

Resources

About