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

细胞膜蛋白G蛋白偶联受体(GPCRs)参与调控多种生理功能。因此，GPCR超家族的药物在我们目前的药典中有很好的代表性，估计有40%的上市药物直接作用于GPCRs或通过其相关机制起作用。虽然最初被认为以单体状态存在并发挥作用，但多个令人信服的证据清楚地支持GPCR同聚体(和异构体)的存在。因此，GPCRs的二聚化被证明影响它们到细胞表面的运输、它们的药理、它们的信号和/或它们通过原体间的分子间通信而内化的特性。多年来，我们的研究主要集中在一个由两个内源性配体Urotensin II(UII)和Urotensin II相关肽(URP)和一个被称为UT的GPCR组成的肽能系统。尿紧张素能系统的独特性质，特别是在心血管水平，使UT成为心血管疾病治疗/管理的关键靶点。然而，虽然两种配体都有相同的受体，但最近的证据表明，UII和URP不仅发挥共同的生理作用，而且还发挥不同的生理作用；每个肽可能触发自己的第二信使集。虽然GPCR寡聚的新概念可能有助于它们的药理和信号多样性，但似乎有必要破译UII和/或URP相关UT激活的分子机制，并重新评估UT激动剂和拮抗剂的设计策略。因此，我们的研究计划将揭示UT同源/异二聚体的存在，并探索如何通过原基之间的分子间通信来控制UII/URP相关的结合和信号转导。因此，我们的研究可能会带来关于尿紧张素能系统的复杂药理学的重要见解。值得注意的是，随着新一代配体的开发，UT同/异二聚体的发现可能会对药物发现计划产生巨大影响，新一代配体同时针对复合体的两个受体原型，以重定向受体信号。因此，在整个项目中检索到的信息无疑将有助于更好地了解这一系统的复杂药理学，并有助于确定用于治疗UT相关疾病的潜在相关药理学/治疗性低聚物的特征。

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.