The physiological relevance of the G protein-coupled receptor P2Y14

UDP-sugars were identified as extracellular signaling molecules, assigning a new function to these compounds in addition to their well-defined role in intracellular substrate metabolism and storage. Previously regarded as an orphan receptor, the G protein-coupled receptor (GPCR) P2Y14 (GPR105) was found to bind extracellular UDP and UDP-sugars. Little is known about the physiological functions of this GPCR. To study its physiological role a gene-deficient (KO) mouse strain expressing the bacterial LacZ reporter gene was used to monitor the physiological expression pattern of P2Y14. P2Y14 is mainly expressed in pancreas and salivary glands and in subpopulations of smooth muscle cells of the gastrointestinal tract, bronchioles, blood vessels and uterus. Among other phenotypical differences KO mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. An unchanged insulin tolerance points towards an altered pancreatic islet function. Transcriptome analysis of pancreatic islets showed that P2Y14 deficiency significantly changed expression of components involved in insulin secretion. Insulin secretion tests revealed a reduced insulin release from P2Y14-deficient islets highlighting P2Y14 as a previously unappreciated modulator of proper insulin secretion