Cyclic activation of endplate acetylcholine receptors

Significance The binding of agonists to receptors is an essential event in cell signaling. We propose a general mechanism for agonist binding based on a model allosteric protein, the neuromuscular acetylcholine receptor. Binding constants were measured for different agonists, to both resting and active individual target sites. The results confirm a cyclic activation mechanism. Agonist binding requires diffusion and a local conformational change, with receptor activation accelerating the latter so that association becomes nearly diffusion-limited. At each site, receptor activation approximately doubles the agonist-binding energy. These results indicate that binding (“affinity”) and activation (“efficacy”), long considered to be independent processes, are linked obligatorily. We speculate that cyclic activation and coupling between activation and binding are fundamental aspects of receptor operation.