Discovery of Novel Receptors for Lipid Mediators - a study leading to the identification of receptors involved in metabolism and the immune system

Abstract: Intercellular communication is of crucial importance in regulating physiology and G-protein coupled receptors (GPCRs) have evolved as an important mechanism in this process. Of the approximately 800 human GPCRs, about 160 are still considered to be “orphan” receptors for which an endogenous ligand remains to be identified. Since an estimated 50% of all clinical drugs act on 30 known GPCRs, the remaining orphan receptors provide excellent, potential new drug targets. Orphan receptors were selected using known receptor sequences as templates and subsequently cloned into expressing plasmids that were then stably transfected into luciferase-based reporter cells. An orphan receptor was found to be the second GPCR, BLT2, activated by the pro-inflammatory molecule leukotriene B4. Through use of a library of orphan receptors, potential ligands were screened for activity by applying reversed pharmacology. This approach led to the discovery of the novel receptor (FFA1R) for medium- to long-chain free fatty acids, previously known as the orphan receptor GPR40. Significantly, this receptor was found to be expressed on e.g. pancreatic beta-cells and to mediate the fatty acid augmentation of glucose stimulated insulin secretion. The clinically used anti-diabetic drugs, thiazolidinediones, also activate FFA1R expressed on reporter cells. It was discovered that FFA2R and FFA3R (GPR43 and GPR41) are activated by short-chain fatty acids (SCFAs). Being abundantly expressed on blood leukocytes, FFA2R may act as the mediator in SCFA-induced immune suppression in the intestinal tract. A recent proposal links FFA3R to leptin secretion by adipose tissue.