Cellular and physiological consequences of opioid receptor interactions

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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.