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Edelstein (1996), Nicotinic receptor

March 2007, model of the month by Nicolas Le Novère
Original model: BIOMD0000000001

An allosteric effector is a compound that affects the function of a protein by binding to a site distant from the "active" site responsible of the function (e.g. a catalytic site, or the pore of a channel). The model of concerted allosteric transitions is arguably one of the great successes of mechanistic modelling in biology. This model designed by Jean-Pierre Changeux [1], also called MWC from the initials of the authors of the paper that popularised it [2], describes an elegant ultrasensitivity (cooperative) device based only on an equilibrium between two conformational states of unequal affinity for the effector. Over the last four decades, the model has been successfully applied to a wide-range of proteins, the most famous being haemoglobin [3].

nAChR DeltaG
Figure 1: Free energy scheme of a nicotinic receptor with four-states

As soon as the mid-sixties, Jean-Pierre Changeux hypothesised that such a mechanism could explain the response of a cell to hormones and neurotransmitters. The concerted model was first applied to the nicotinic acetylcholine receptors by Arthur Karlin [4] and later refined by Stuart Edelstein [5]. Those models used two states for the receptor, closed and open. Fluorescence analysis later revealed that nicotinic receptors existed under more states, including one or more desensitized states [6]. Allosteric models with more than two states were soon designed. However, such models describe the behaviour of the different species at equilibrium, and are not immediately usable in kinetic simulations.

Figure 2: Linkage between ligand binding, rates of interconversion and transition state properties.

Edelstein and collaborators [7] developed a kinetic model that links conformational interconversion rates to the agonist binding constants. To do that, they assumed that this link is controlled by the position of the interconversion transition state on a putative linear reaction path. They then run stochastc kinetic simulations and show that the recovery of the receptor from desensitised states may pass through quick open conformations. Direct transitions from closed to desenzitised states without opening of the receptors are predicted to occur. This mechanism has since been hypothesised to intervene in the dependence to nicotine. Low concentrations of nicotine, such as the one obtained in the brain of smokers, would desensitise the nicotinic receptors and block the effect of endogenous acetylcholine rather than mimicking it.

Figure 3: Kinetic simulation representing the population of the different states before, during and after application of the agonist.

Bibliographic References

  1. Changeux J.-P. (1964). Allosteric interactions interpreted in terms of quaternary structure. Brookhaven Symposia in Biology, 17: 232-249. [SRS@EBI]
  2. Monod J., Wyman J., and Changeux J.-P. (1965). On the nature of allosteric transitions: a plausible model. Journal of Molecular Biology, 12: 88-118. [SRS@EBI]
  3. Edelstein S.J. (1971). Extensions of the allosteric model for haemoglobin. Nature 230: 224-227. [SRS@EBI]
  4. Karlin A (1967). On the application of "a plausible model" of allosteric proteins to the receptor for acetylcholine. Journal of Theoretical Biology, 16: 306-320. [SRS@EBI]
  5. Edelstein S.J. (1972). An allosteric mechanism for the acetylcholine receptor. Biochem Biophys Res Commun 48: 1160-1165. [SRS@EBI]
  6. Sugiyama H., Changeux J.-P. (1975). Interconversion between different states of affinity for acetylcholine of the cholinergic receptor protein from Torpedo marmorata. Eur. J. Biochem., 55: 505-515. [SRS@EBI]
  7. Sugiyama H., Changeux J.-P. (1975). Interconversion between different states of affinity for acetylcholine of the cholinergic receptor protein from Torpedo marmorata. Eur. J. Biochem., 55: 505-515. [SRS@EBI]
  8. Edelstein SJ, Schaad O, Henry E, Bertrand D, Changeux JP. A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions. Biol Cybern, 75: 361-379. [SRS@EBI]