Modulation of nicotinic acetylcholine receptor function through the outer and middle rings of transmembrane domains

The photoaffinity labeling of amino acid residues embedded in the lipid bilayer, in combination with site-directed mutagenesis and patch-clamp electrophysiology, are beginning to delineate a topographic map of lipid-sensitive residues in the transmembrane (TM) region of the nicotinic acetylcholine receptor (nAChR), and to dissect their contribution to channel gating, opening and closing mechanisms. Recent structural data reveal that the TM segments form three concentric layers around the ion channel. An inner ring, shaped by five M2 segments (one from each subunit) excluded from contact with the lipid, forms the walls of the channel. The middle ring is formed by M1 and M3 segments, which exhibit contact with lipids, and the M4 membrane-embedded domains constitute an outer ring, distant from the channel and loosely separated from the middle ring. Although they are not part of the ion conduction pathway, the lipid-exposed middle and outer rings significantly modulate nAChR function. Sterols and steroids, in particular, are among the ligands that act on this functionally relevant moiety of the nAChR. A major challenge for the future is to elucidate the mechanism of propagation of information from the lipid-exposed TM rings to the rest of the receptor molecule.