Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs
Autor: | Madeleine Héroux, Hiroyuki Kobayashi, Christian Le Gouill, Arturo Mancini, Stephan Schann, Alexander S. Hauser, Stéphane St-Onge, Florence Gross, Marilyn Carrier, David E. Gloriam, Billy Breton, Sandra Morissette, Charlotte Avet, Viktoriya Lukasheva, Michel Bouvier, Claire Normand, Jean-Philippe Fortin, Eric B. Fauman, Mireille Hogue, Xavier Leroy |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
G protein
Membrane translocation chemical biology Computational biology Biosensing Techniques biosensor General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled 03 medical and health sciences 0302 clinical medicine GTP-Binding Proteins G protein activation effector membrane translocation assay Humans biochemistry human Receptor beta-Arrestins 030304 developmental biology G protein-coupled receptor 0303 health sciences General Immunology and Microbiology high-throughput assay Chemistry Effector General Neuroscience General Medicine g protein-coupled receptor Coupling (electronics) HEK293 Cells beta-Arrestin 1 Signal transduction enhanced bystander bioluminescence resonance energy transfer Biosensor 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Avet, C, Mancini, A, Breton, B, Le Gouill, C, Hauser, A S, Normand, C, Kobayashi, H, Gross, F, Hogue, M, Lukasheva, V, St-Onge, S, Carrier, M, Héroux, M, Morissette, S, Fauman, E B, Fortin, J P, Schann, S, Leroy, X, Gloriam, D E & Bouvier, M 2022, ' Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs ', eLife, vol. 11, e74101 . https://doi.org/10.7554/eLife.74101 |
DOI: | 10.7554/eLife.74101 |
Popis: | 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. |
Databáze: | OpenAIRE |
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