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Biased Signaling of the Mu Opioid Receptor Revealed in Native Neurons.

Ehrlich AT, Semache M, Gross F, Da Fonte DF, Runtz L, Colley C, Mezni A, Le Gouill C, Lukasheva V, Hogue M, Darcq E, Bouvier M, Kieffer BL

Department of Psychiatry, McGill University, Douglas Hospital Research Center, Perry Pavilion Room E-3317.1, 6875 Boulevard LaSalle, Montréal, QC H4H 1R3, Canada; Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch-Graffenstaden, France.

G protein-coupled receptors are key signaling molecules and major targets for pharmaceuticals. The concept of ligand-dependent biased signaling raises the possibility of developing drugs with improved efficacy and safety profiles, yet translating this concept to native tissues remains a major challenge. Whether drug activity profiling in recombinant cell-based assays, traditionally used for drug discovery, has any relevance to physiology is unknown. Here we focused on the mu opioid receptor, the unrivalled target for pain treatment and also the key driver for the current opioid crisis. We selected a set of clinical and novel mu agonists, and profiled their activities in transfected cell assays using advanced biosensors and in native neurons from knock-in mice expressing traceable receptors endogenously. Our data identify Gi-biased agonists, including buprenorphine, and further show highly correlated drug activities in the two otherwise very distinct experimental systems, supporting in vivo translatability of biased signaling for mu opioid drugs.

iScience 2019;14:47-57.

Pubmed ID: 30925410

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