Assigning functions to residues in the acetylcholine receptor channel region (Review)

Abstract

This review is concerned with the functional domains of the nicotinic acetylcholine receptor (AChR) involved in ion permeation. These comprise the ion pore and its gate. The latter allows the channel to be almost exclusively closed in the absence of agonist and favours ion flux in its presence. Early photoaffinity labelling experiments using open-channel blockers and site-directed mutagenesis studies identified M2 of each AChR subunit as the transmembrane domain lining the walls of the ion pore. Several biochemical, electrophysiological, and mutagenesis studies as well as molecular modelling and in vitro studies of ion channel formation with synthetic peptides corroborate these findings. Point mutations combined with electrophysiological techniques have contributed to dissecting the AChR channel region assigning functions to individual amino acid residues, thus revealing structural and functional stratification of the M2 channel domain. Specific residues have been found to be structural determinants of conductance, ion selectivity, gating, and desensitization. The three-dimensional structure of the AChR protein at 9 Å resolution suggests a possible arrangement of the M2 α-helices in the open and closed states, respectively. In spite of the current wealth of knowledge on the AChR ion channel stemming from the combination of experimental approaches discussed in this review, the mechanistic structure by which the interaction with the agonist favours the opening of the cationic channel remains unknown.

Key Words:

• ligand-gated ion channel
• acetylcholine receptor
• cholinergic receptor
• ion channel
• M2 segment