Omega‐3 fatty acid mediated phosphorylation of the short and long human GPR120 receptor isoforms

Abstract

The orphan G protein‐coupled receptor, GPR120, has recently been thrust to the forefront of diabetes research due to its ability to stimulate release of the insulin secretagogue glucagon‐like peptide 1. While the molecular aspects involved in GPR120 signaling remain elusive, it has been shown that long chained free fatty acids, including the omega‐3 fatty acids α‐linolenic acid (ALA) and docosahexaenoic acid (DHA), are agonists of GPR120. We have recently cloned the human and rat GPR120 genes and have discovered that the human receptor can be alternatively spliced, yielding distinct short and long isoforms. Interestingly, we have identified that GPR120‐long contains an additional 16 amino acids within the third intracellular loop, and importantly, this region contains four phospho‐labile residues. Based on this distinct difference, we hypothesized that the long and short GPR120 isoforms have differing phosphorylation and desensitization profiles. Here, we present data which compares the phosphorylation of both variants upon agonism with various omega‐3 fatty acids. We also present data regarding the molecular mechanisms of GPR120 phosphorylation. Our data, taken together with the variation of the sequences encoding the third intracellular loop, suggest that the two GPR120 isoforms have distinct desensitization profiles. This project is funded by the Diabetes Action Research and Education Foundation.