Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

Avet, C.; Mancini, A.; Breton, B.; Le Gouill, C.; Hauser, A. S.; Normand, C.; Kobayashi, H.; Gross, F.; Hogue, M.; Lukasheva, V.; Morissette, S.; Fauman, E.; Fortin, J.-P.; Schann, S.; Leroy, X.; Gloriam, D. E.; Bouvier, M.

doi:10.1101/2020.04.20.052027

bioRxiv · 10.1101/2020.04.20.052027

Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

Avet, C.·Mancini, A.·Breton, B.·Le Gouill, C.·Hauser, A. S.·Normand, C.·Kobayashi, H.·Gross, F.·Hogue, M.·Lukasheva, V.·Morissette, S.·Fauman, E.·Fortin, J.-P.·Schann, S.·Leroy, X.·Gloriam, D. E.·Bouvier, M.

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Abstract

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 {beta}arrestins 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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Avet, C., Mancini, A., Breton, B., Le Gouill, C., Hauser, A. S., Normand, C., Kobayashi, H., Gross, F., Hogue, M., Lukasheva, V., Morissette, S., Fauman, E., Fortin, J.-P., Schann, S., Leroy, X., Gloriam, D. E., Bouvier, M.. 2020-04-24. Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform. https://doi.org/10.1101/2020.04.20.052027

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