Molecular basis of ligand binding and receptor activation in the oxytocin and vasopressin receptor family

Although it is now widely accepted that G-protein-coupled receptors exist i n at least two allosteric states, inactive and active, and that the spontan eous equilibrium between the two is regulated by various events including t he binding of specific agonists and antagonists, the molecular counterparts of these functionally different states are still poorly understood. In thi s paper, we review our current knowledge concerning the structure-function relationships of the oxytocin and vasopressin receptors, focusing in partic ular on the process of receptor activation. Using a combined approach of si te-directed mutagenesis and molecular modelling, we investigated the molecu lar events leading to agonist-dependent and -independent receptor activatio n in the human oxytocin receptor. Our analysis allows us to propose that th e active conformations of this receptor are characterised by similar rearra ngements of its cytosolic regions that ultimately lead to the opening of a putative docking site for the G-protein. Furthermore, the dynamics of these motions are similar to that observed in the alpha(1B)-adrenergic receptor, thus suggesting that, although activated by different ligands, the process of receptor isomerization in these two receptors is regulated by the same cluster of highly conserved residues and that common molecular events are r esponsible for receptor activation in different G-protein-coupled receptors .