The G protein-coupled receptor GPRC5C is a saccharide sensor with a novel "off" response.

GPRC5C is an orphan G protein-coupled receptor (GPCR) that belongs to the class C GPCR family. Although GPRC5C is expressed in various organs, its function and ligand are still undetermined. We found that GPRC5C is expressed in mouse taste cells, enterocytes, and pancreatic α-cells. In functional imaging assays, HEK293 cells heterologously expressing GPRC5C and the chimeric G protein α subunit Gα16-gust44 showed robust intracellular Ca increases in response to monosaccharides, disaccharides, and a sugar alcohol, but not an artificial sweetener or sweet-tasting amino acid. Notably, Ca increases occurred after washout, not during stimulation. Our findings suggest that GPRC5C has receptor properties which lead to novel "off" responses to saccharide detachment and may work as an internal or external chemosensor specifically tuned to natural sugars.