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.
Highlights
Neuropeptides represent the largest and most diverse class of neuron-secreted signaling molecules
We identified a ligand for the Platynereis ortholog of vertebrate thyrotropinreleasing hormone (TRH) receptors, revealing the ancient origin of TRH-receptor signaling
Combinatorial Screening for Platynereis GPCRNeuropeptide Ligand Pairs To facilitate the rapid identification of neuropeptide G-proteincoupled receptors (GPCRs), we developed a combinatorial cell-culture-based screening strategy (Figure 1)
Summary
Neuropeptides represent the largest and most diverse class of neuron-secreted signaling molecules. These peptides can have neuromodulatory, neurotransmitter, or hormonal functions and can affect development, physiology, and the activity in neural circuits. The majority of neuropeptides signal by G-protein-coupled receptors (GPCRs), with some exceptions (Chang et al, 2009; Leung et al, 1987; Lowe et al, 1989; Rechler and Nissley, 1985). The lack of information regarding neuropeptide receptors hinders the identification of the downstream signaling mechanisms underlying neuromodulation
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