Identification and Application of Drosophila Novel Bioactive Peptides dRYamides

Abstract

The ligands of many orphan G protein-coupled receptors (GPCRs) remain to be identified, in both vertebrates and invertebrates, such as Drosophila melanogaster. Identification of their cognate ligands is critical for understanding the function and regulation of such GPCRs. Indeed, the discovery of bioactive peptides that bind GPCRs has enhanced our understanding of the mechanisms underlying many physiological processes. Here, we identified five endogenous ligands of the Drosophila orphan GPCRs, using functional assays and reverse pharmacological techniques. dRYamide-1 and -2 were found to be paired with the Drosophila neuropeptide Y (NPY)-like receptor (CG5811). Both dRYamide-1 and -2 contain a C-terminal RYamide. In vertebrates, RYamide motifs are found in NPY-family peptides. dRYamides were found to modulate feeding motivation in flies. These results suggest that deorphanizing the Drosophila orphan GPCRs might facilitate the elucidation of various physiological functions and identification of the ligands of orphan GPCRs in mammals.