Robust GLP‐1 secretion by basic L‐amino acids does not require the GPRC6A receptor

Abstract

The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo.

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

“…Because of a lack of potent and selective ligands, these suggested functions have mainly been investigated by phenotyping of knock-out mice where the gene function has been destroyed by deletion of exon 6 (Bräuner-Osborne group (17)), exon 2 (Quarles (18) and Karsenty (14) groups), or the full gene (Murphy (19) and Bräuner-Osborne groups (20)). Under normal physiological conditions, these mouse strains have shown very different phenotypes.…”

Pharmacology and physiological function of the orphan GPRC6A receptor

“…To test whether this translates to the in vivo state, we have administered L‐ornithine and L‐arginine orally to the full locus and exon VI GPRC6A KO mouse models. We observed robust GLP‐1 release, but while the GLP‐1 secretion was attenuated at later time‐points, there were no overall differences between KOs and WTs, demonstrating that functional GPRC6A is not required for robust secretion of GLP‐1 in vivo by basic L‐amino acids . This suggests that other receptors or mechanisms than GPRC6A are mediating at least some of the effects of L‐arginine and L‐ornithine in vivo.…”

“…The most recently obtained data using the full locus GPRC6A KO model have supported the lack of abnormalities of the exon VI KO model with respect to bones and metabolism and demonstrated that GPRC6A is not required for robust L‐amino acid‐induced GLP‐1 release in vivo . Other studies indicate a role of GPRC6A in male reproduction, prostate cancer and inflammation, and will be important to validate in other groups/mouse models before firm conclusions can be drawn.…”

l‐Glutamate stimulates cholecystokinin secretion via the T1R1/T1R3 mediated PLC/TRPM5 transduction pathway

“…25 Accumulating evidence has indicated that amino acids are potent stimulators of gut hormone secretion. 26,27 Less understood is the mechanism by which amino acids exert this effect. Among 20 proteogenic amino acids, although both Asp and Glu belong to acidic amino acids, they show different patterns of CCK secretion in pig duodenum.…”