ASSIGNING FUNCTIONS TO RESIDUES IN THE ACETYLCHOLINE-RECEPTOR CHANNELREGION (REVIEW)

This review is concerned with the functional domains of the nicotinic acetylcholine receptor (AChR) involved in ion permeation. These compri se the ion pore and its gate. The latter allows the channel to be almo st exclusively closed in the absence of agonist and favours ion flux i n its presence. Early photoaffinity labelling experiments using open-c hannel 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 cha nnel formation with synthetic peptides corroborate these findings. Poi nt mutations combined with electrophysiological techniques have contri buted to dissecting the AChR channel region assigning functions to ind ividual amino acid residues, thus revealing structural and functional stratification of the M2 channel domain. Specific residues have been f ound to be structural determinants of conductance, ion selectivity, ga ting, and desensitization. The three-dimensional structure of the AChR protein at 9 Angstrom resolution suggests a possible arrangement of t he M2 alpha-helices in the open and closed states, respectively. In sp ite of the current wealth of knowledge on the AChR ion channel stemmin g from the combination of experimental approaches discussed in this re view, the mechanistic structure by which the interaction with the agon ist favours the opening of the cationic channel remains unknown.