The Orphan G Protein-coupled Receptors GPR41 and GPR43 Are Activated by Propionate and Other Short Chain Carboxylic Acids

Abstract

GPR41 and GPR43 are related members of a homologous family of orphan G protein-coupled receptors that are tandemly encoded at a single chromosomal locus in both humans and mice. We identified the acetate anion as an agonist of human GPR43 during routine ligand bank screening in yeast. This activity was confirmed after transient transfection of GPR43 into mammalian cells using Ca 2؉ mobilization and [ 35 S]guanosine 5-O-(3-thiotriphosphate) binding assays and by coexpression with GIRK G protein-regulated potassium channels in Xenopus laevis oocytes. Other short chain carboxylic acid anions such as formate, propionate, butyrate, and pentanoate also had agonist activity. GPR41 is related to GPR43 (52% similarity; 43% identity) and was activated by similar ligands but with differing specificity for carbon chain length, with pentanoate being the most potent agonist. A third family member, GPR42, is most likely a recent gene duplication of GPR41 and may be a pseudogene. GPR41 was expressed primarily in adipose tissue, whereas the highest levels of GPR43 were found in immune cells. The identity of the cognate physiological ligands for these receptors is not clear, although propionate is known to occur in vivo at high concentrations under certain pathophysiological conditions.Within family A of the G protein-coupled receptor (GPCR) 1 gene superfamily (also classified as family 1), there is a phylogenetically related group of ϳ90 receptors that respond to an unusually wide variety of ligand types, considering the relatively close similarity of their primary sequences (1). The group includes receptors that respond to purinergic or pyrimidinergic nucleotides (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , and P2Y 13 ), modified nucleotides (UDP-glucose), lipids (plateletactivating factor receptor), leukotrienes (BLT 1 and BLT 2 and CysLT 1 and CysLT 2 ), proteases (protease-activated receptor-1-4), chemoattractants (FPR1), and chemokines. To date, these receptors have no clear homologs in invertebrates, unlike the monoamine or neuropeptide receptors, suggesting a relatively recent evolutionary origin (2, 3). At least 50 GPCRs whose cognate ligands are unknown (orphans) (4) are categorized within this group on the basis of sequence homology. Often, these orphans fall into subsets, being more related to each other than to receptors with known ligands; and this, combined with the ligand diversity noted above, makes it difficult to predict the chemical nature of their ligands. One subset comprises GPR40 -43, which were identified as tandemly encoded genes present on cosmids isolated from human chromosomal locus 19q13.1 (5). GPR42 differs from GPR41 at only six amino acid positions; otherwise, the four members of this subfamily share ϳ30% minimum identity. BLAST searches have identified the next most closely related receptors as the proteaseactivated receptors. However, the long N-terminal extracellular domains that serve as protease substrates and that are characteristic of protease-activated receptors are absent in the GPR...

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