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The role of kinetic context in apparent biased agonism at GPCRs

Author

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  • Carmen Klein Herenbrink

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • David A. Sykes

    (Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre)

  • Prashant Donthamsetti

    (College of Physicians and Surgeons, Columbia University
    College of Physicians and Surgeons, Columbia University)

  • Meritxell Canals

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Thomas Coudrat

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Jeremy Shonberg

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Peter J. Scammells

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Ben Capuano

    (Monash Institute of Pharmaceutical Sciences, Monash University)

  • Patrick M. Sexton

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • Steven J. Charlton

    (Cell Signalling Research Group, School of Life Sciences, University of Nottingham, Queen's Medical Centre)

  • Jonathan A. Javitch

    (College of Physicians and Surgeons, Columbia University
    College of Physicians and Surgeons, Columbia University
    New York State Psychiatric Institute)

  • Arthur Christopoulos

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

  • J. Robert Lane

    (Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University)

Abstract

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usually inferred from pharmacological data with the assumption that the confounding influences of observational (that is, assay dependent) and system (that is, cell background dependent) bias are excluded by experimental design and analysis. Here we reveal that ‘kinetic context’, as determined by ligand-binding kinetics and the temporal pattern of receptor-signalling processes, can have a profound influence on the apparent bias of a series of agonists for the dopamine D2 receptor and can even lead to reversals in the direction of bias. We propose that kinetic context must be acknowledged in the design and interpretation of studies of biased agonism.

Suggested Citation

  • Carmen Klein Herenbrink & David A. Sykes & Prashant Donthamsetti & Meritxell Canals & Thomas Coudrat & Jeremy Shonberg & Peter J. Scammells & Ben Capuano & Patrick M. Sexton & Steven J. Charlton & Jon, 2016. "The role of kinetic context in apparent biased agonism at GPCRs," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10842
    DOI: 10.1038/ncomms10842
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    Cited by:

    1. Jason Wallach & Andrew B. Cao & Maggie M. Calkins & Andrew J. Heim & Janelle K. Lanham & Emma M. Bonniwell & Joseph J. Hennessey & Hailey A. Bock & Emilie I. Anderson & Alexander M. Sherwood & Hamilto, 2023. "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    3. Shane C. Wright & Aikaterini Motso & Stefania Koutsilieri & Christian M. Beusch & Pierre Sabatier & Alessandro Berghella & Élodie Blondel-Tepaz & Kimberley Mangenot & Ioannis Pittarokoilis & Despoina-, 2023. "GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Kazem Asadollahi & Sunnia Rajput & Lazarus Andrew Zhang & Ching-Seng Ang & Shuai Nie & Nicholas A. Williamson & Michael D. W. Griffin & Ross A. D. Bathgate & Daniel J. Scott & Thomas R. Weikl & Guy N., 2023. "Unravelling the mechanism of neurotensin recognition by neurotensin receptor 1," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Chanjuan Xu & Yiwei Zhou & Yuxuan Liu & Li Lin & Peng Liu & Xiaomei Wang & Zhengyuan Xu & Jean-Philippe Pin & Philippe Rondard & Jianfeng Liu, 2024. "Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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