COEVOLUTION OF LIGAND-RECEPTOR PAIRS IN THE VASOPRESSIN OXYTOCIN SUPERFAMILY OF BIOACTIVE PEPTIDES

In order to understand the molecular mechanisms that underlie the co-e volution of related yet functionally distinct peptide-receptor pairs, we study receptors for the vasopressin-related peptide Lys-conopressin in the mollusc Lymnaea stagnalis, In addition to a previously cloned Lys-conopressin receptor (LSCPR1), we have now identified a novel Lys- conopressin receptor subtype, named LSCPR2. The two receptors have a d ifferential distribution in the reproductive organs and the brain, whi ch suggests that they are involved in the control of distinct aspects of reproduction and mediate transmitter-like and/or modulatory effects of Lys-conopressin on different types of central neurons. In contrast to LSCPR1, LSCPR2 is maximally activated by both Lys-conopressin and Ile-conopressin, an oxytocin-like synthetic analog of Lys-conopressin. Together with a study of the phylogenetic relationships of Lys-conopr essin receptors and their vertebrate counterparts, these data suggest that LSCPR2 represents an ancestral receptor to the vasopressin/oxytoc in receptor family in the vertebrates, Based on our findings, we provi de a theory of the molecular co-evolution of the functionally distinct ligand-receptor pairs of the vasopressin/oxytocin superfamily of bioa ctive peptides.