Abstract
The nicotinic acetylcholine (ACh) receptor is a ligand-gated ion channel involved in rapid signal transmission at the neuromuscular junction. The structure of the receptor in the tubular crystal has been investigated by cryo-electron microscopy. The mechanism of activation by ACh binding to the receptor is not known in detail, but a precise interpretation of the structural change in the activation is given by the comparison of the extracellular domain of the receptor with an ACh-binding protein (AChBP) to which a putative agonist is bound. Substitution in the 3-dimensional maps of the receptor by AChBP mimics the changes seen on activation. When ACh binds, it leads to an extended conformational change, involving 15 degrees rotations of polypeptide chains on the inner pore-facing parts of the extracellular domain of the α subunits. These conformational changes most likely act as the trigger that opens the gate in the membrane-spanning pore of the receptor. The ACh receptor has four predicted membrane-spanning segments, M1-M4, in each subunit. The pore shaped by an inner ring of five α-helices (the second membrane-spanning segment, M2), and an outer ring of fifteen α-helices (M1,M3, and M4), which shield the inner ring from the lipids. The gate is a constricting hydrophobic girdle at the middle of the membrane, formed by weak interactions between neighboring inner helices. When ACh enters the ligand-binding domain, it triggers rotations of the protein chains on the opposite sides of the entrance to the pore. These rotations are communicated through the inner helices and open the pore by breaking the girdle apart. [Jpn J Physiol 55 Suppl:S12 (2005)]
