Coevolution of neuropeptidergic signaling systems: from worm to man

Despite the general knowledge and repeated predictions of peptide G protein-coupled receptors following the elucidation of the Caenorhabditis elegans genome in 1998, only a few have been deorphanized so far. This was attributed to the apparent lack of coevolution between (neuro)peptides and their cognate receptors. To resolve this issue, we have used an in silico genomic data mining tool to identify the real putative peptide GPCRs in the C. elegans genome and then made a well-considered selection of orphan peptide GPCRs. To maximize our chances of a successful deorphanization, we adopted a combined reverse pharmacology approach. At this moment, we have successfully uncovered four C. elegans neuropeptide signaling systems that support the theory of receptor-ligand coevolution. All four systems are extremely well conserved within nematodes and show a high degree of similarity with their vertebrate and arthropod counterparts. Our data indicate that these four neuropeptide signaling systems have been well conserved during the course of evolution and that they were already well established prior to the divergence of protostomes and deuterostomes.