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 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-conopressin 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.
Highlights
Peptide receptors form an important subclass of the otherwise diverse superfamily of G protein-coupled1 receptors that
Lys-conopressin serves vasopressin-like functions in the control of carbohydrate metabolism [26]. These observations suggest that functionally distinct vasopressin and oxytocin receptors may have evolved from a nondiscriminative Lys-conopressin receptor-like receptor by gene duplication and subsequent introduction of specificity determinants that enable discriminative binding of vasopressin and oxytocin on the basis of the chemical nature of amino acid residue 8
We show that vasopressin and oxytocin receptors may have evolved from an L. stagnalis conopressin receptor 2 (LSCPR2)-like ancestral receptor, and propose a mechanism for the molecular evolution of specificity in the peptide-receptor pairs of the vasopressin/oxytocin superfamily
Summary
Peptide receptors form an important subclass of the otherwise diverse superfamily of G protein-coupled receptors that. In Lys-conopressin, the chemical nature of the amino acid residue at position 8 is not important for peptide function, since replacement of this basic residue (lysine) by an aliphatic one (isoleucine) does not affect the potency of binding of the peptide to its receptor [9] These studies show that Lys-conopressin, structurally related to vasopressin, controls reproductive functions that are clearly analogous to the central and myoregulatory functions of oxytocin in vertebrate reproduction. Lys-conopressin serves vasopressin-like functions in the control of carbohydrate metabolism [26] Together, these observations suggest that functionally distinct vasopressin and oxytocin receptors may have evolved from a nondiscriminative Lys-conopressin receptor-like receptor by gene duplication and subsequent introduction of specificity determinants that enable discriminative binding of vasopressin and oxytocin on the basis of the chemical nature of amino acid residue 8
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