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

探讨尾加压素 II 受体同/异二聚化的存在及其作用

• 批准号: RGPIN-2015-04848
• 负责人: Chatenet, David
• 金额: $ 2.33万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=647265
• 关键词: Probing; existence; role; urotensin; II

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.**

被称为G蛋白偶联受体（GPCRs）的细胞膜蛋白参与控制大量生理功能。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%的市售药物直接作用于GPCR或通过其相关机制作用。虽然最初认为GPCR存在并以单体状态发挥作用，但多个令人信服的证据清楚地支持GPCR同聚体（和异聚体）的存在。因此，GPCR的二聚化显示通过原聚体之间的分子间通讯影响它们向细胞表面的运输、它们的药理学、它们的信号传导和/或它们的内化性质。多年来，我们的研究集中在由两个内源性配体，尾加压素II（UII）和尾加压素II相关肽（URP），和一个GPCR称为UT组成的肽能系统。特别是在心血管水平上，Urotensinergic系统的独特性质将UT确定为心血管疾病治疗/管理的关键靶标。然而，虽然这两种配体共享相同的受体，但最近的证据表明，UII和URP不仅发挥共同的生理作用，而且发挥不同的生理作用;每种肽可能会触发自己的第二信使。虽然GPCR寡聚化的新概念可能有助于其药理学和信号转导的多样性，但似乎必须破译UII和/或URP相关UT激活中涉及的分子机制，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/异源二聚体的存在，并探索我们如何通过原聚体之间的分子间通讯来控制UII/URP相关的结合和信号传导。因此，我们的研究可以带来重要的见解，关于复杂的药理学的尿加压素系统。值得注意的是，UT同源/异源二聚体的发现可能对药物发现计划产生巨大影响，开发了新一代配体，同时靶向复合物的两种受体原聚体，以重定向受体信号传导。因此，在整个项目中检索到的信息无疑将有助于更好地理解该系统的复杂药理学，并表征用于治疗UT相关疾病的潜在相关药理学/治疗性寡聚体。