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On the nature of partial agonism in the nicotinic receptor superfamily

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.

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Figure 1: Glycine channels show short interruptions when activated by either full or partial agonists.
Figure 2: Global fit of the taurine data with a flip mechanism provides a good description of the observations.
Figure 3: Activation of the glycine channel by the full agonist glycine and the partial agonist taurine.
Figure 4: Short interruptions in openings of muscle nicotinic channels occur with both partial and full agonists and cannot be attributed entirely to channel block.
Figure 5: The flip mechanism describes well the activation of acetylcholine receptors by TMA.

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Acknowledgements

This work was supported by grants from the MRC (Programme grant G0400869) and the Wellcome Trust (Project grant 074491) to L.G.S. and D.C. We are grateful to F. Abogadie for molecular biology, to I. Vais for programming help, and to D. Jane for purification of taurine.

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Correspondence to David Colquhoun.

Supplementary information

Supplementary Information 1

The file contains the legend to the animated version of Fig 3 (flip-movie.wmv), Supplementary Methods, an extended Supplementary Discussion of results, additional references, Supplementary Tables 1 and 2 and Supplementary Figures 1-5. The value of E1 for ACh at -100 mV in Supplementary Table 2 was corrected from 0.038 to 0.0038 on 06 January 09. (PDF 656 kb)

Supplementary Information 2

The file contains Supplementary Movie 1 which is an animated version of Fig 3 (main text). (WMV 3006 kb)

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Lape, R., Colquhoun, D. & Sivilotti, L. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454, 722–727 (2008). https://doi.org/10.1038/nature07139

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