A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions |
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Authors: | Stuart J Edelstein Olivier Schaad Eric Henry Daniel Bertrand Jean-Pierre Changeux |
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Institution: | (1) Département de Biochimie, Université de Genève, CH-1211 Geneva 4, Switzerland, CH;(2) Neurobiologie Moléculaire, Institut Pasteur, F-75734 Paris Cedex 15, France , FR;(3) Laboratory of Chemical Physics, NIDDK, NIH, Bethesda, MD 20892, USA, US;(4) Départment de Physiologie, Université de Genève, CH-1211 Geneva 4, Switzerland, CH |
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Abstract: | Nicotinic acetylcholine receptors are transmembrane oligomeric proteins that mediate interconversions between open and closed
channel states under the control of neurotransmitters. Fast in vitro chemical kinetics and in vivo electrophysiological recordings
are consistent with the following multi-step scheme. Upon binding of agonists, receptor molecules in the closed but activatable
resting state (the Basal state, B) undergo rapid transitions to states of higher affinities with either open channels (the
Active state, A) or closed channels (the initial Inactivatable and fully Desensitized states, I and D). In order to represent
the functional properties of such receptors, we have developed a kinetic model that links conformational interconversion rates
to agonist binding and extends the general principles of the Monod-Wyman-Changeux model of allosteric transitions. The crucial
assumption is that the linkage is controlled by the position of the interconversion transition states on a hypothetical linear
reaction coordinate. Application of the model to the peripheral nicotinic acetylcholine receptor (nAChR) accounts for the
main properties of ligand-gating, including single-channel events, and several new relationships are predicted. Kinetic simulations
reveal errors inherent in using the dose-response analysis, but justify its application under defined conditions. The model
predicts that (in order to overcome the intrinsic stability of the B state and to produce the appropriate cooperativity) channel
activation is driven by an A state with a Kd in the 50 nM range, hence some 140-fold stronger than the apparent affinity of the open state deduced previously. According
to the model, recovery from the desensitized states may occur via rapid transit through the A state with minimal channel opening,
thus without necessarily undergoing a distinct recovery pathway, as assumed in the standard ‘cyclic’ model. Transitions to
the desensitized states by low concentration ‘pre-pulses’ are predicted to occur without significant channel opening, but
equilibrium values of IC50 can be obtained only with long pre-pulse times. Predictions are also made concerning allosteric effectors and their possible
role in coincidence detection. In terms of future developments, the analysis presented here provides a physical basis for
constructing more biologically realistic models of synaptic modulation that may be applied to artificial neural networks.
Received: 22 November 1995/Accepted in revised form: 24 July 1996 |
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