Probing the existence and the role of urotensin II receptors homo/heterodimerization

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Cell membrane proteins named G protein-coupled receptors (GPCRs) are involved in the control of a large array of physiological functions. Hence, drugs of the GPCR superfamily are well represented in our current pharmacopeia with an estimated 40% of marketed drugs acting directly on GPCRs or through their associated mechanisms. While originally believed to exist and to function in a monomeric state, multiple compelling evidence clearly support the existence of GPCR homomers (and heteromers). Dimerization of GPCRs was thus shown to affect their trafficking to the cell surface, their pharmacology, their signaling and/or their internalization properties through intermolecular communication between protomers. Over the years, our research has focused on a peptidergic system composed of two endogenous ligands, urotensin II (UII) and urotensin II-related peptide (URP), and one GPCR termed UT. The unique nature of the urotensinergic system, especially at the cardiovascular level, identifies UT as a key target for the treatment/management of cardiovascular diseases. However, while both ligands share the same receptor, recent evidence has shown that UII and URP exert not only common but also divergent physiological actions; each peptide probably triggering its own set of second messengers. While the emerging concept of GPCR oligomerization could contribute to their pharmacological and signaling diversity, it appears mandatory to decipher the molecular mechanism involved in UII and/or URP-associated UT activation and to reassess the strategy for the design of UT agonists and antagonists. Our research program will therefore uncover the existence of UT homo/heterodimer and explore how we can control UII/URP-associated binding and signaling through intermolecular communication between protomers. Our studies could thus bring important insights regarding the complex pharmacology of the urotensinergic system. Notably, discovery of UT homo/heterodimer could have a tremendous impact on drug discovery program with the development of a new generation of ligand concomitantly targeting both receptor protomers of the complex in order to redirect receptors signaling. The information retrieved throughout this project will therefore undoubtedly lead to a better understanding of the complex pharmacology of this system and to the characterization of potentially relevant pharmacologic/therapeutic oligomers for the treatment of UT-associated diseases.