Cellular and physiological consequences of opioid receptor interactions

阿片样物质可激活3种受体亚型（μ、δ和κ阿片样物质受体; MOPR、DOPR、KOPR）。多年来已经显示，不同的MOPR激动剂不一定以相同的功效激活给定的信号传导级联。事实上，G蛋白偶联受体（GPCR）不是作为拨动开关不加选择地打开或关闭预先选择的信号级联（即一种配体，一种受体和一种功效的旧教条），而是表现为调节信号模式的不同子集的通信枢纽，这些信号模式可以通过不同的效果进行特异性调节。这种新的范式被称为配体偏置信号，或者更适合本研究计划，功能选择性。我们提出，异源GPCR相互作用的调制出现作为一个有吸引力的方式来偏置给定激动剂的信号级联以及通常与受体相关的影响。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，并研究寡聚化的功能后果。更具体地说，我们将研究1）MOPR/DOPR体内相互作用的机制和2）与MOPR/DOPR寡聚体相关的信号级联。由于GPCR寡聚化作为一种选择性控制GPCR的细胞和生理反应的新方法出现，因此该研究计划具有很大的潜力，可以扩展功能选择性的概念，目前仅限于配体，GPCR相互作用和新分子的开发，以突出GPCR寡聚体的作用。

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.