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Pharmacology

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Nature Reviews Drug Discovery volume 7, page 732 (2008)Cite this article

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The authors investigated two related channels: the muscle nicotinic acetylcholine receptor and the glycine receptor. Single-channel electrophysiological recordings with the heteromeric a1b glycine receptor showed that the probability of being open was greater for the full agonist glycine compared with the partial agonist taurine. However, when the distributions of apparent shut times were analysed, the mean lifetime of brief shuttings was very similar for taurine and glycine, irrespective of ligand concentration.

To investigate what mechanism could underlie these observations, the authors fitted a 'flipping' mechanism — an intermediate conformational state that occurs while the channel is shut — to the data using a maximum-likelihood mechanism-fitting program. This analysis showed that the open–shut equilibrium constants for taurine and glycine were similar, but there was a 180-fold difference in flipping equilibrium constants. This demonstrated that the major difference between taurine and glycine does not lie in the open–shut reaction but at an earlier stage — in the flipping reaction.

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References

ORIGINAL RESEARCH PAPER

  1. Lape, R. et al. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454, 722–727 (2008)

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FURTHER READING

  1. Colquhoun, D. et al. The quality of maximum likelihood estimation of ion channel rate constants. J. Physiol. 547, 699–728 (2003)

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Authors
  1. Charlotte Harrison
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Harrison, C. Flip to open. Nat Rev Drug Discov 7, 732 (2008). https://doi.org/10.1038/nrd2672

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