The G Protein-coupled Receptor P2Y14 Influences Insulin Release and Smooth Muscle Function in Mice

Background: The relevance of the widely expressed GPCR P2Y(14) is only partially understood. Results: Analysis of P2Y(14)-KO mice revealed decreased gastrointestinal emptying, reduced glucose tolerance, and insulin release. Conclusion: P2Y(14) function is required for proper intestine emptying and adequate glucose response. Significance: P2Y(14) plays a role in smooth muscle function and maintaining energy homeostasis by influencing insulin release. 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 P2Y(14) (GPR105) was found to bind extracellular UDP and UDP sugars. Little is known about the physiological functions of this G protein-coupled receptor. To study its physiological role, we used a gene-deficient mouse strain expressing the bacterial LacZ reporter gene to monitor the physiological expression pattern of P2Y(14). We found that P2Y(14) is mainly expressed in pancreas and salivary glands and in subpopulations of smooth muscle cells of the gastrointestinal tract, blood vessels, lung, and uterus. Among other phenotypical differences, knock-out mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. An unchanged insulin tolerance suggested altered pancreatic islet function. Transcriptome analysis of pancreatic islets showed that P2Y(14) deficiency significantly changed expression of components involved in insulin secretion. Insulin secretion tests revealed a reduced insulin release from P2Y(14)-deficient islets, highlighting P2Y(14) as a new modulator of proper insulin secretion.