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Abstract

Neuropeptides, representing the largest class of neuromodulators, commonly signal by G-protein-coupled receptors (GPCRs). While the neuropeptide repertoire of several metazoans has been characterized, many GPCRs are orphans. Here, we develop a strategy to identify GPCR-peptide pairs using combinatorial screening with complex peptide mixtures. We screened 126 neuropeptides against 87 GPCRs of the annelid Platynereis and identified ligands for 19 receptors. We assigned many GPCRs to known families and identified conserved families of achatin, FMRFamide, RGWamide, FLamide, and elevenin receptors. We also identified a ligand for the Platynereis ortholog of vertebrate thyrotropin-releasing hormone (TRH) receptors, revealing the ancient origin of TRH-receptor signaling. We predicted ligands for several metazoan GPCRs and tested predicted achatin receptors. These receptors were specifically activated by an achatin D-peptide, revealing a conserved mode of activation. Our work establishes an important resource and provides information about the complexity of peptidergic signaling in the urbilaterian.