Neuropeptides are key modulators of adaptive behaviors and represent one of the largest groups of neural messengers, with over 250 bioactive peptides predicted in C. elegans. Most of them are thought to act by binding of G protein-coupled receptors (GPCRs). Despite the broad diversity of neuropeptides and their physiological effects, a handful of neuropeptide-specific receptors have been characterized and the majority of peptide GPCRs remain orphan receptors, i.e. have no known ligand.We are therefore undertaking a large-scale deorphanization initiative - the Peptide-GPCR project - that aims to match all predicted peptide GPCRs of C. elegans to their cognate neuropeptide ligand(s). Using an in vitro reverse pharmacology approach, more than 150 peptide GPCR candidates are expressed in a heterologous cellular system and screened with a library of all known and predicted C. elegans peptides of the established NLP and FLP families. Activation of each receptor is measured by a calcium reporter read out. We have found several novel and evolutionary conserved neuropeptidergic systems including signaling pathways related to mammalian neuromedin, neuropeptide FF, and neuropeptide Y systems. Our results provide insight into neuropeptide signaling networks, and present a scaffold for further unravelling how neuropeptidergic states modulate adaptive behaviors and physiology. Peptide GPCRs are screened randomly, but community members are invited to help us prioritize candidates and steer the project's progression via
http://worm.peptide-gpcr.org.