A KINETIC MECHANISM FOR NICOTINIC ACETYLCHOLINE-RECEPTORS BASED ON MULTIPLE ALLOSTERIC TRANSITIONS

Nicotinic acetylcholine receptors are transmembrane oligomeric protein s that mediate interconversions between open and closed channel states under the control of neurotransmitters. Fast in vitro chemical kineti cs and in vivo electrophysiological recordings are consistent with the following multi-step scheme. Upon binding of agonists, receptor molec ules in the closed but activatable resting state (the Basal state, B) undergo rapid transitions to states of higher affinities with either o pen channels (the Active state, A) or closed channels (the initial Ina ctivatable and fully Desensitized states, I and D). In order to repres ent the functional properties of such receptors, we have developed a k inetic model that links conformational interconversion rates to agonis t binding and extends the general principles of the Monod-Wyman-Change ux model of allosteric transitions. The crucial assumption is that the linkage is controlled by the position of the interconversion transiti on 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-ch annel events, and several new relationships are predicted. Kinetic sim ulations reveal errors inherent in using the dose-response analysis, b ut justify its application under defined conditions. The model predict s that (in order to overcome the intrinsic stability of the B state an d to produce the appropriate cooperativity) channel activation is driv en by an A state with a K-d in the 50 nM range, hence some 140-fold st ronger than the apparent affinity of the open state deduced previously . According to the model, recovery from the desensitized states may oc cur 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 desensitize d states by low concentration 'pre-pulses' are predicted to occur with out significant channel opening, but equilibrium values of IC50 can be obtained only with long pre-pulse times. Predictions are also made co ncerning allosteric effecters and their possible role in coincidence d etection. In terms of future developments, the analysis presented here provides a physical basis for constructing more biologically realisti c models of synaptic modulation that may be applied to artificial neur al networks.