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On the nature of partial agonism in the nicotinic receptor superfamily

Author

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  • Remigijus Lape

    (University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK)

  • David Colquhoun

    (University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK)

  • Lucia G. Sivilotti

    (University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK)

Abstract

Partial agonists are ligands that bind to receptors but produce only a small maximum response even at concentrations where all receptors are occupied. In the case of ligand-activated ion channels, it has been supposed since 1957 that partial agonists evoke a small response because they are inefficient at eliciting the change of conformation between shut and open states of the channel. We have investigated partial agonists for two members of the nicotinic superfamily—the muscle nicotinic acetylcholine receptor and the glycine receptor—and find that the open–shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change (‘flipping’) that takes place while the channel is still shut. This has implications for the interpretation of structural studies, and in the future, for the design of partial agonists for therapeutic use.

Suggested Citation

  • Remigijus Lape & David Colquhoun & Lucia G. Sivilotti, 2008. "On the nature of partial agonism in the nicotinic receptor superfamily," Nature, Nature, vol. 454(7205), pages 722-727, August.
    • Handle: RePEc:nat:nature:v:454:y:2008:i:7205:d:10.1038_nature07139
    DOI: 10.1038/nature07139
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    Cited by:

    1. Christian J. G. Tessier & Johnathon R. Emlaw & Raymond M. Sturgeon & Corrie J. B. daCosta, 2023. "Derepression may masquerade as activation in ligand-gated ion channels," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Dinesh C Indurthi & Trevor M Lewis & Philip K Ahring & Thomas Balle & Mary Chebib & Nathan L Absalom, 2016. "Ligand Binding at the α4-α4 Agonist-Binding Site of the α4β2 nAChR Triggers Receptor Activation through a Pre-Activated Conformational State," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-20, August.
    3. Klaus Benndorf & Jana Kusch & Eckhard Schulz, 2012. "Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-10, October.
    4. Yuxuan Zhuang & Rebecca J. Howard & Erik Lindahl, 2024. "Symmetry-adapted Markov state models of closing, opening, and desensitizing in α 7 nicotinic acetylcholine receptors," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Jerónimo Auzmendi & Darío Fernández Do Porto & Carla Pallavicini & Luciano Moffatt, 2012. "Achieving Maximal Speed of Solution Exchange for Patch Clamp Experiments," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-12, August.

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