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Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform

Author

Listed:
  • Manel Zeghal

    (University of Ottawa)

  • Geneviève Laroche

    (University of Ottawa)

  • Julia Douglas Freitas

    (University of Ottawa)

  • Rebecca Wang

    (University of Ottawa)

  • Patrick M. Giguère

    (University of Ottawa
    University of Ottawa)

Abstract

Representing the most attractive and successful druggable receptors of the proteome, GPCRs regulate a myriad of physiological and pathophysiological functions. Although over half of present pharmaceuticals target GPCRs, the advancement of drug discovery is hampered by a lack of adequate screening tools, the majority of which are limited to probing agonist-induced G-protein and β-arrestin-2-mediated events as a measure of receptor activation. Here, we develop Tango-Trio, a comprehensive cell-based high-throughput platform comprising cumate-inducible expression of transducers, capable of the parallelized profiling of both basal and agonist-dependent GPCR activities. We capture the functional diversity of GPCRs, reporting β-arrestin-1/2 couplings, selectivities, and receptor internalization signatures across the GPCRome. Moreover, we present the construction of cumate-induced basal activation curves at approximately 200 receptors, including over 50 orphans. Overall, Tango-Trio’s robustness is well-suited for the functional characterization and screening of GPCRs, especially for parallel interrogation, and is a valuable addition to the pharmacological toolbox.

Suggested Citation

  • Manel Zeghal & Geneviève Laroche & Julia Douglas Freitas & Rebecca Wang & Patrick M. Giguère, 2023. "Profiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39132-x
    DOI: 10.1038/s41467-023-39132-x
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    References listed on IDEAS

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    1. Daniel M. Rosenbaum & Søren G. F. Rasmussen & Brian K. Kobilka, 2009. "The structure and function of G-protein-coupled receptors," Nature, Nature, vol. 459(7245), pages 356-363, May.
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