IRIC - Institute for Research in Immunology and Cancer

Published on April 12, 2022

Two-thirds of human hormones and one-third of clinical drugs target and activates the G protein-coupled receptors. For a given receptor, different ligands can selectively engage different subsets of signaling pathways. Mapping the effectors that can be engaged by a given receptor is essential for understanding physiological processes as well as for designing safer drugs. The team of Professor Michel Bouvier, Director of the Molecular Pharmacology Research Unit and Chief Executive Officer of IRIC, worked on characterizing the coupling selectivity of GPCRs. Research advisor Charlotte Avet played a central role in this colossal work which also involved scientists from Domain Therapeutics and several members of the Bouvier lab, including Billy Breton and Christian Le Gouill, who developed the technological platform used. The work is the subject of two publications in the journal eLife.

A new and unique platform to study GPCR signaling and pharmacology

Activation of a GPCR by a ligand leads to the recruitment of a G protein, which in turn transmits the signal to cellular effectors. The activated signaling pathways are involved in various biological processes, ranging from cell growth, vision, and the immune response. Individual receptors, depending on the activating ligand, can engage different effectors, leading to different cellular responses. This is called ligand-biased signaling. This phenomenon could be exploited to develop drugs that selectively target the effector pathways of a GPCR that are relevant for a given pathology. To achieve this, it is essential to map the different G proteins that can be engaged by individual receptors.

The team from the Bouvier lab has developed a new methodological platform for characterizing the signaling profiles of 100 therapeutically relevant human GPCRs. The platform, named Effector Membrane Translocation Assay (EMTA), enables the measuring of the activation of G proteins in living cells. Sensitive and versatile, the EMTA platform offers a set of tools enabling high-throughput screening of small molecules and biological products on a wide range of signaling pathways. It allows unprecedented analyzes of the functional selectivity of GPCRs, paving the way for the discovery of new functionally selective molecules with therapeutic potential.

Mapping of couplings: to identify exploitable biases

The previous study expands the number of known interactions between GPCRs and G proteins – which form the couplome. It adds to two other datasets available on GPCR couplings. These independently generated datasets differ in their scope and reported couplings. To facilitate their interpretation and use, Michel Bouvier’s team collaborated with David Gloriam’s team in Denmark to establish a protocol for standardizing G protein coupling data generated by the different studies.

The team’s analysis combines the three datasets to establish high-confidence couplings supported by at least two studies. It therefore provides the first mapping unifying GPCR – G protein couplings in a quantitative way, for an unprecedented total of 256 receptors. This new common map will facilitate advances in the understanding of GPCRs and their cellular signaling, as well as the exploitation of ligand-biased signaling in the design of safer drugs.

Cited studies

Avet C, Mancini A, Breton B, Le Gouill C, Hauser AS, Normand C, Kobayashi H, Gross F, Hogue M, Lukasheva V, St-Onge S, Carrier M, Héroux M, Morissette S, Fauman EB, Fortin JP, Schann S, Leroy X, Gloriam DE, Bouvier M. Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs. Elife. 2022 Mar 18;11:e74101. doi: 10.7554/eLife.74101. Epub ahead of print. PMID: 35302493

Hauser AS, Avet C, Normand C, Mancini A, Inoue A, Bouvier M, Gloriam DE. Common coupling map advances GPCR-G protein selectivity. Elife. 2022 Mar 18;11:e74107. doi: 10.7554/eLife.74107. Epub ahead of print. PMID: 35302494.