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Molecular Pharmacology

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Michaelis-Menten quantification of ligand signalling bias applied to the promiscuous Vasopressin V2 receptor

Franziska Marie Heydenreich, Bianca Plouffe, Aurelien Rizk, Dalibor Milic, Joris Zhou, Billy Breton, Christian Le Gouill, Asuka Inoue, Michel Bouvier and Dmitry Veprintsev
Molecular Pharmacology July 2, 2022, MOLPHARM-AR-2022-000497; DOI: https://doi.org/10.1124/molpharm.122.000497
Franziska Marie Heydenreich
1Structural Studies, MRC Laboratory of Molecular Biology, United Kingdom
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  • ORCID record for Franziska Marie Heydenreich
  • For correspondence: dmitry.veprintsev@nottingham.ac.uk
Bianca Plouffe
2Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, United Kingdom
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Aurelien Rizk
3InterAx Biotech AG, Switzerland
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Dalibor Milic
4Department of Structural and Computational Biology, University of Vienna, Austria
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Joris Zhou
5Institute for Research in Immunology and Cancer, University of Montreal, Canada
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Billy Breton
5Institute for Research in Immunology and Cancer, University of Montreal, Canada
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Christian Le Gouill
6University of Montreal, Canada
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Asuka Inoue
7Tohoku University, Japan
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Michel Bouvier
8Department of Biochemistry and Molec ular Medicine, University of Montreal, Canada
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  • For correspondence: dmitry.veprintsev@nottingham.ac.uk
Dmitry Veprintsev
9School of Life Sciences, University of Nottingham, United Kingdom
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  • For correspondence: dmitry.veprintsev@nottingham.ac.uk
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Abstract

Activation of the G protein-coupled receptors by agonists may result in the activation of one or more G proteins and recruitment of arrestins. The extent of the activation of each of these pathways depends on the intrinsic efficacy of the ligand. Quantification of intrinsic efficacy relative to a reference compound is essential for the development of novel compounds. In the operational model, changes in efficacy can be compensated by changes in the "functional" affinity, resulting in poorly defined values. To separate the effects of ligand affinity from the intrinsic activity of the receptor, we developed a Michaelis-Menten based quantification of G protein activation bias that uses experimentally measured ligand affinities and provides a single measure of ligand efficacy. We used it to evaluate the signalling of a promiscuous model receptor, the Vasopressin V2 receptor (V2R). Using BRET-based biosensors, we show that the V2R engages many different G proteins across all G protein subfamilies in response to its primary endogenous agonist, arginine vasopressin (AVP), including Gs and members of the Gi/o and G12/13 families. These signaling pathways are also activated by the synthetic peptide desmopressin, oxytocin, and the non-mammalian hormone vasotocin. We compared bias quantification using the operational model with Michaelis-Menten based quantification, the latter accurately quantified ligand efficacies despite large difference in ligand affinities. Together, these results showed that V2R is promiscuous in its ability to engage several G proteins and that its' signaling profile is biased by small structural changes in the ligand.

Significance Statement By modelling the G protein activation as Michaelis-Menten reaction, we developed a novel way of quantifying signalling bias. V2R activates or at least engages G proteins from all G protein subfamilies, including Gi2, Gz, Gq, G12, and G13. Their relative activation may explain its Gs-independent signalling.

  • arrestin
  • Biased agonism
  • G protein coupled signaling
  • g protein-coupled receptors (GPCRS)
  • G proteins (GTP-binding proteins)
  • modeling and simulation
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics

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Molecular Pharmacology: 102 (2)
Molecular Pharmacology
Vol. 102, Issue 2
1 Aug 2022
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OtherArticle

Michaelis Menten quantification of GPCR-G protein signalling

Franziska Marie Heydenreich, Bianca Plouffe, Aurelien Rizk, Dalibor Milic, Joris Zhou, Billy Breton, Christian Le Gouill, Asuka Inoue, Michel Bouvier and Dmitry Veprintsev
Molecular Pharmacology July 2, 2022, MOLPHARM-AR-2022-000497; DOI: https://doi.org/10.1124/molpharm.122.000497

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OtherArticle

Michaelis Menten quantification of GPCR-G protein signalling

Franziska Marie Heydenreich, Bianca Plouffe, Aurelien Rizk, Dalibor Milic, Joris Zhou, Billy Breton, Christian Le Gouill, Asuka Inoue, Michel Bouvier and Dmitry Veprintsev
Molecular Pharmacology July 2, 2022, MOLPHARM-AR-2022-000497; DOI: https://doi.org/10.1124/molpharm.122.000497
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