Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 3 therapeutically relevant GPCRs

Elife. 2022 Mar 18;11:e74101. PMID: 35302493 DOI: 10.7554/eLife.74101

Charlotte Avet 1, Arturo Mancini 2, Billy Breton 2, Christian Le Gouill 1, Alexander Sebastian Hauser 3, Claire Normand 2, Hiroyuki Kobayashi 1, Florence Gross 2, Mireille Hogue 1, Viktoriya Lukasheva 1, Stéphane St-Onge 1, Marilyn Carrier 1, Madeleine Héroux 1, Sandra Morissette 2, Eric B Fauman 4, Jean-Philippe Fortin 5, Stephan Schann 6, Xavier Leroy 7, David E Gloriam 3, Michel Bouvier 1

1. Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, Canada.
2. Domain Therapeutics North America, Montréal, Canada.
3. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
4. Internal Medicine Research Unit, Pfizer Worldwide Research, Cambridge, United States.
5. Pfizer Global R&D, Cambridge, United States.
6. Domain Therapeutics, Illkirch-Strasbourg, France.
7. Domain Therapeutics, llkirch-Strasbourg, France.


The recognition that individual GPCRs can activate multiple signaling pathways has raised the possibility of developing drugs selectively targeting therapeutically relevant ones. This requires tools to determine which G proteins and βarrestins are activated by a given receptor. Here, we present a set of BRET sensors monitoring the activation of the 12 G protein subtypes based on the translocation of their effectors to the plasma membrane (EMTA). Unlike most of the existing detection systems, EMTA does not require modification of receptors or G proteins (except for Gs). EMTA was found to be suitable for the detection of constitutive activity, inverse agonism, biased signaling and polypharmacology. Profiling of 100 therapeutically relevant human GPCRs resulted in 1,500 pathway-specific concentration-response curves and revealed a great diversity of coupling profiles ranging from exquisite selectivity to broad promiscuity. Overall, this work describes unique resources for studying the complexities underlying GPCR signaling and pharmacology.


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