Activation of the Nicotinic Acetylcholine Receptor Involves a Switch in Conformation of the α Subunits

Abstract

The nicotinic acetylcholine (ACh) receptor belongs to a superfamily of synaptic ion channels that open in response to the binding of chemical transmitters. Their mechanism of activation is not known in detail, but a time-resolved electron microscopic study of the muscle-type ACh receptor had suggested that a local disturbance in the ligand-binding region and consequent rotations in the ligand-binding α subunits, connecting to the transmembrane portion, are involved. A more precise interpretation of this structural change is given here, based on comparison of the extracellular domain of the ACh receptor with an ACh-binding protein (AChBP) to which a putative agonist is bound. We find that, to a good approximation, there are two alternative extended conformations of the ACh receptor subunits, one characteristic of either α subunit before activation, and the other characteristic of all three non-α subunits and the protomer of AChBP. Substitution in the three-dimensional maps of α by non-α subunits mimics the changes seen on activation, suggesting that the structures of the α subunits are modified initially by their interactions with neighbouring subunits and switch to the non-α form when ACh binds. This structural change, which entails 15–16° rotations of the inner pore-facing parts of the α subunits, most likely acts as the trigger that opens the gate in the membrane-spanning pore.