Cellular and physiological consequences of opioid receptor interactions

阿片受体相互作用的细胞和生理后果

• 批准号: 341398-2013
• 负责人: Gendron, Louis
• 金额: $ 2.62万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527288
• 关键词: Cellular; physiological; consequences; opioid; receptor

Opioids can activate 3 receptor subtypes (mu, delta, and kappa opioid receptors; MOPRs, DOPRs, KOPRs). It has been shown over the years that different MOPR agonists do not necessarily activate a given signaling cascade with identical efficacy. In fact, rather than operating as toggle switches limited to turn pre-selected signalling cascades ''on'' or ''off'' indiscriminately (i.e. the old dogma of one ligand, one receptor and one efficacy), G protein-coupled receptors (GPCRs) were instead shown to behave as communication hubs that regulate different subsets of signalling modes that can be specifically modulated with distinct effects. This novel paradigm is called ligand-biased signalling or, more appropriate for this research program, functional selectivity. We propose that modulation of heterologous GPCR interactions emerges as an attractive way to bias the signaling cascades of a given agonist as well as the effects typically associated to a receptor. The long term objective of my research program is therefore to characterize the cellular mechanisms of opioid receptor interactions and to study the functional consequences of oligomerization. More specifically, we will study 1) the mechanisms involved in MOPR/DOPR interactions in vivo and 2) the signaling cascades associated with MOPR/DOPR oligomers. Since GPCR oligomerization emerges as a new way to selectively control the cellular and physiological responses of GPCRs, this research program thus has a great potential to extend the concept of functional selectivity, currently limited to ligands, to GPCR interactions and to the development of new molecules to highlight the role of GPCR oligomers.

阿片类药物可激活3种受体亚型(Mu、Delta和Kappa阿片受体；MOPR、DOPR和KOPR)。多年来的研究表明，不同的MOPR激动剂并不一定以相同的效果激活给定的信号级联反应。事实上，G蛋白偶联受体(GPCRs)并不是被限制为不分青红皂白地开启或关闭预先选择的信号级联(即一个配体、一个受体和一个功效的旧教条)的触发开关，相反，G蛋白偶联受体(GPCR)被证明扮演着通讯中枢的角色，调节不同的信号模式子集，这些信号模式可以被特定地以不同的效果进行调制。这种新的范式被称为配体偏向信号传递，或者，更适合于这个研究计划，功能选择性。我们认为，调节异源GPCR相互作用是一种有吸引力的方式，可以偏向给定激动剂的信号级联以及典型的与受体相关的影响。因此，我的研究计划的长期目标是描述阿片受体相互作用的细胞机制，并研究寡聚的功能后果。更具体地说，我们将研究1)体内MOPR/DOPR相互作用的机制和2)与MOPR/DOPR寡聚体相关的信号级联。由于GPCR寡聚是一种选择性控制GPCRs细胞和生理反应的新方法，因此该研究计划具有很大的潜力将目前仅限于配体的功能选择性的概念扩展到GPCRs的相互作用和开发新的分子来突出GPCR寡聚体的作用。