Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the alpha subunits

J Mol Biol. 2002 Jun 21;319(5):1165-76. doi: 10.1016/S0022-2836(02)00381-9.


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 alpha 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 alpha subunit before activation, and the other characteristic of all three non-alpha subunits and the protomer of AChBP. Substitution in the three-dimensional maps of alpha by non-alpha subunits mimics the changes seen on activation, suggesting that the structures of the alpha subunits are modified initially by their interactions with neighbouring subunits and switch to the non-alpha form when ACh binds. This structural change, which entails 15-16 degrees rotations of the inner pore-facing parts of the alpha subunits, most likely acts as the trigger that opens the gate in the membrane-spanning pore.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Binding Sites
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Microscopy, Electron
  • Models, Molecular
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Protein Subunits
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism*
  • Receptors, Nicotinic / ultrastructure
  • Torpedo


  • AChBP protein, Lymnaea
  • Carrier Proteins
  • Protein Subunits
  • Receptors, Nicotinic
  • Acetylcholine