University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
University of Montreal - Institute for Research in Immunology and Cancer (IRIC); University of Montreal - Department of Biochemistry and Molecular Medicine
The ability of individual G protein-coupled receptors (GPCR) to engage multiple signaling pathways opens opportunities for the development of better drugs. This requires new knowledge and tools to determine the G protein subtypes and barrestins engaged by a given receptor. Here, we used a new BRET-based effector membrane translocation assay (EMTA) that monitors activation of each Gα protein through the recruitment of selective G protein effectors and βarrestins to the plasma membrane. Profiling of 100 therapeutically relevant GPCR revealed a great diversity of coupling profiles with some receptors displaying exquisite selectivity, whereas others promiscuitely engage all four G protein families. Comparison with existing datasets points to commonalities but also to critical differences between studies. Combining a biosensor subset allowed detecting activity of nearly all GPCR thus providing a new tool for safety screens and systems pharmacology. Overall, this work describes unique resources for studying GPCR function and drug discovery.
Avet, Charlotte and Mancini, Arturo and Breton, Billy and Le Gouill, Christian and Hauser, Alexander and Normand, Claire and Kobayashi, Hiroyuki and Gross, Florence and Hogue, Mireille and Lukasheva, Viktoriya and Morissette, Sandra and Fauman, Eric and Fortin, Jean-Philippe and Schann, Stéphane and Leroy, Xavier and Gloriam, David E. and Bouvier, Michel, Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform. Available at SSRN: https://ssrn.com/abstract=3586569 or http://dx.doi.org/10.2139/ssrn.3586569
This version of the paper has not been formally peer reviewed.
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