Co-evolution of Ligand-Receptor Pairs in the Vasopressin/Oxytocin Superfamily of Bioactive Peptides

Abstract

In order to understand the molecular mechanisms that underlie the co-evolution 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 differential distribution in the reproductive organs and the brain, which suggests that they are involved in the control of distinct aspects of reproduction and mediate transmitter-like and/or modulatory effects of Lysconopressin on different types of central neurons. In contrast to LSCPR1, LSCPR2 is maximally activated by both Lys-conopressin and Ile-conopressin, an oxytocinlike synthetic analog of Lys-conopressin. Together with a study of the phylogenetic relationships of Lysconopressin receptors and their vertebrate counterparts, these data suggest that LSCPR2 represents an ancestral receptor to the vasopressin/oxytocin receptor family in the vertebrates. Based on our findings, we provide a theory of the molecular co-evolution of the functionally distinct ligand-receptor pairs of the vasopressin/oxytocin superfamily of bioactive peptides.Peptide receptors form an important subclass of the otherwise diverse superfamily of G protein-coupled 1 receptors that all have a seven-transmembrane segment topology in common (for review, see Ref. 1). This receptor type forms a component of a modular system for the transduction of extracellular signals across the cell membrane and the subsequent conversion of these signals to an intracellular second messenger pathway via the activation of heterotrimeric G proteins (for review, see Ref.2). Molecular evolutionary mechanisms such as gene duplication and subsequent mutation of the resulting genes have resulted in the formation of families of related yet distinct peptides (3) and peptide receptors (4). In the nervous and endocrine systems, many peptide isoforms bind to distinct receptor subtypes that mediate the specific cellular actions that underlie a large variety of behavioral and physiological processes. Peptide-receptor and receptor-effector interactions are of critical importance for peptide function, and many diseases are linked to malfunctions of these interactions (5). However, the great variety in structure of both peptides and receptors has hampered the development of a coherent theory explaining the molecular basis of co-evolution of specifically interacting peptide-receptor pairs. The vasopressin/oxytocin superfamily of peptides and their cognate receptors offer an attractive model for the study of specificity of peptide-receptor interactions and the co-evolution of related peptide-receptor pairs (6). These peptides and receptors occur throughout the entire animal kingdom (for review, see Ref. 7), allowing detailed comparison of their structural features and experimental testing of putative specificity determinants. The peptides of the superfamily are s...

Cloning of Octopus cephalotocin receptor, a member of the oxytocin/vasopressin superfamily

“…3C). This value is comparable to those for OT at the human OT receptor and Lys-conopressin at the LSCPR1, which are also expressed in Xenopus oocytes (Kimura et al 1992, van Kesteren et al 1995, 1996.…”

“…These receptors couple to the inositol phosphate/Ca 2+ signal transduction pathway. In invertebrates, the cloning of two Lys-conopressin receptors, LSCPR1 and LSCPR2, from Lymnaea has been reported (van Kesteren et al 1995(van Kesteren et al , 1996. These receptors are expressed in different tissues and mediate both functions of OT-like reproduction and VP-like glycogenolysis of Lys-conopressin in Lymnaea.…”

Molecular identification of the insect adipokinetic hormone receptors

“…The mammalian oxytocin receptors are often involved in various aspects of reproduction (estrous cycle length, partner bond, sexual behavior, birth, milk ejection during lactation, and offspring care) (33). Similar functions of these receptors can be found in other vertebrates and even in invertebrates, such as snails (33)(34)(35). The involvement of the oxytocin/vasopressin receptors with reproductive processes, has thus been conserved during a very long period of animal evolution.…”

“…Another example is that of the oxytocin/ vasopressin receptor family, where the ligands have remained relatively similar during evolution (five of nine residues and a disulfide ring structure have been conserved) (33). These receptors have been cloned from mammals (there exists one oxytocin and three vasopressin receptors in humans), lower vertebrates, and invertebrates and they are structurally and evolutionarily clearly related to each other (both within a mammalian species and across the different animal classes and phyla) (33)(34)(35). The mammalian oxytocin receptors are often involved in various aspects of reproduction (estrous cycle length, partner bond, sexual behavior, birth, milk ejection during lactation, and offspring care) (33).…”

Computational Approaches to Elucidating Transient Protein-Protein Interactions, Predicting Receptor-Ligand Pairings

“…Many examples of interaction between proteins have presented signs of co-evolution in such a way that members of different interacting protein families present similarity between their phylogenetic trees [Fryxell 1996, Goh et al 2000, van Kesteren et al 1996, Moyle et al 1994, Pazos and Valencia 2001. The core of co-evolutionary methods is based on measures of similarity for the phylogenetic trees of interacting protein partners.…”