The MAPK signaling pathways are some of the best characterized signaling systems

ore, free fatty acids of various chain length and degree of saturation have been shown to act as agonists at both GPR120 and GPR84 as well as the group of related GPCRs named free fatty acid receptors FFA1, FFA2 and FFA3 . In a number of these cases, identification of endogenous ligands able to activate these GPCRs has not yet resulted in the identification of synthetic, small molecule ligands able to act as agonists or antagonists of these receptors. Phylogenetic analysis has clustered FFA1-3 into a branch of the rhodopsin-like, class A GPCRs that contains receptors for phospholipids, nucleotides, citric acid cycle intermediates and the protease-activated receptors, along with a number of orphan GPCRs. FFA1 has attracted considerable attention as a potential GSK-126 site therapeutic target for the treatment of diabetes, based predominantly on its expression in pancreatic b-cells and the known role of medium- and longer-chain fatty acids, that are agonists at this GPCR, in modulating glucose-dependent release of insulin. This has resulted in the identification of a number of small molecule agonist and antagonist ligands at this receptor. A considerable number of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809774 recent reviews have centred on the function and pharmacology of this receptor and whether short-term stimulation or longerterm blockade might result in the most effective therapeutic treatment. Significantly less discussion of the pharmacology and function of the related family members FFA2 and FFA3 is available and these receptors will, therefore, be the focus of the current review. Brown et al. used recombinant cell systems to demonstrate that FFA2 was activated by the carboxylic acid, acetate and related molecules. This was also noted by Le Poul et al. and Nilsson et al.. Brown et al. and Le Poul et al. also demonstrated that short-chain fatty acids were agonists at FFA3. Despite responding to the same group of endogenous agonists, FFA2 and FFA3 have distinct G protein-coupling specificities. FFA2 couples to both pertussis toxinsensitive and -insensitive G proteins while FFA3 couples selectively to pertussis toxin-sensitive Gai family G proteins. However, as with many Gai-coupled GPCRs, Le Poul et al., found that co-expression with the promiscuous G protein, Ga16, allowed activation of FFA3 to be coupled to the release of i, despite an inability to couple directly to Gaq/11. Based on these observations, Stoddart et al. employed a chimeric Gly66AspGaq-i5 variant to link activation of FFA3 to the elevation of intracellular and explore the structureactivity relationships of short-chain free fatty acids at this receptor. Furthermore, given the pleiotropic effects of short-chain free fatty acids, Stoddart et al. also employed cells able to express either FFA2 or FFA3 in an entirely inducible manner to ensure that effects of the ligands were actually mediated via the receptor. Identification, tissue distribution and physiological function of FFA2 and FFA3 The genes encoding FFA2 and FFA3 in man were first identified by Sawzdargo et al. within a tandemly encoded group of intronless genes, located at chromosome 19q13.1. This region also encompasses the genes encoding FFA1 and GPR42. The proteins predicted from these sequences contained seven British Journal of Pharmacology 158 146153 148 Pharmacology of FFA2/3 G Milligan et al FlpIN HEK293 hFFA2-eYFP FlpIN HEK293 hFFA3-eYFP no induction induction of expression with 0.5 gmL1 doxycycline putative transmembrane domains and a variety of other feature