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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References
Hatton, C. J., Shelley, C., Brydson, M., Beeson, D. & Colquhoun, D. Properties of the human muscle nicotinic receptor, and of the slow-channel myasthenic syndrome mutant εL221F, inferred from maximum likelihood fits. J. Physiol. 547, 729–760 (2003)
Burzomato, V., Beato, M., Groot-Kormelink, P. J., Colquhoun, D. & Sivilotti, L. G. Single-channel behavior of heteromeric α1β glycine receptors: An attempt to detect a conformational change before the channel opens. J. Neurosci. 24, 10924–10940 (2004)
del Castillo, J. & Katz, B. Interaction at end-plate receptors between different choline derivatives. Proc. R. Soc. Lond. B 146, 369–381 (1957)
Wyman, J. & Allen, D. W. The problem of the heme interactions in hemoglobin and the basis of the Bohr effect. J. Polym. Sci. C 7, 499–518 (1951)
Grosman, C., Zhou, M. & Auerbach, A. Mapping the conformational wave of acetylcholine receptor channel gating. Nature 403, 773–776 (2000)
Chakrapani, S., Bailey, T. D. & Auerbach, A. Gating dynamics of the acetylcholine receptor extracellular domain. J. Gen. Physiol. 123, 341–356 (2004)
Zhou, Y., Pearson, J. E. & Auerbach, A. φ-value analysis of a linear, sequential reaction mechanism: theory and application to ion channel gating. Biophys. J. 89, 3680–3685 (2005)
Auerbach, A. Gating of acetylcholine receptor channels: brownian motion across a broad transition state. Proc. Natl Acad. Sci. USA 102, 1408–1412 (2005)
Purohit, P., Mitra, A. & Auerbach, A. A stepwise mechanism for acetylcholine receptor channel gating. Nature 446, 930–933 (2007)
Armstrong, N., Sun, Y., Chen, G. Q. & Gouaux, E. Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395, 913–917 (1998)
Jin, R., Banke, T. G., Mayer, M. L., Traynelis, S. F. & Gouaux, E. Structural basis for partial agonist action at ionotropic glutamate receptors. Nature Neurosci. 6, 803–810 (2003)
Celie, P. H. et al. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41, 907–914 (2004)
Hansen, S. B. et al. Structures of aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J. 24, 3635–3646 (2005)
Colquhoun, D., Hatton, C. J. & Hawkes, A. G. The quality of maximum likelihood estimates of ion channel rate constants. J. Physiol. 547, 699–728 (2003)
Adams, P. R. Voltage jump analysis of procaine action at frog end-plate. J. Physiol. 268, 291–318 (1977)
Neher, E. & Steinbach, J. H. Local anaesthetics transiently block currents through single acetylcholine-receptor channels. J. Physiol. 277, 153–176 (1978)
Colquhoun, D. & Ogden, D. C. Activation of ion channels in the frog end-plate by high concentrations of acetylcholine. J. Physiol. 395, 131–159 (1988)
Salamone, F. N., Zhou, M. & Auerbach, A. A re-examination of adult mouse nicotinic acetylcholine receptor channel activation kinetics. J. Physiol. 516, 315–330 (1999)
Colquhoun, D. & Sakmann, B. Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels. Nature 294, 464–466 (1981)
Colquhoun, D. & Sakmann, B. Fast events in single-channel currents activated by acetylcholine and its analogues at the frog muscle end-plate. J. Physiol. (Lond.) 369, 501–557 (1985)
Gardner, P., Ogden, D. C. & Colquhoun, D. Conductances of single ion channels opened by nicotinic agonists are indistinguishable. Nature 309, 160–162 (1984)
Colquhoun, D. Binding, gating, affinity and efficacy. The interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125, 923–948 (1998)
Han, N. L., Clements, J. D. & Lynch, J. W. Comparison of taurine- and glycine-induced conformational changes in the M2–M3 domain of the glycine receptor. J. Biol. Chem. 279, 19559–19565 (2004)
Colquhoun, D., Unwin, N., Shelley, C., Hatton, C. & Sivilotti, L. G. Drug Discovery and Drug Development (ed. Abrahams, D.) 357–405 (John Wiley, New York, 2003)
Groot-Kormelink, P. J., Beato, M., Finotti, C., Harvey, R. J. & Sivilotti, L. G. Achieving optimal expression for single channel recording: a plasmid ratio approach to the expression of α1 glycine receptors in HEK293 cells. J. Neurosci. Methods 113, 207–214 (2002)
Andersen, O. S. Editorial: Graphic representation of the results of kinetic analyses. J. Gen. Physiol. 114, 589–590 (1999)
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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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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DOI: https://doi.org/10.1038/nature07139
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