Dialogue between membrane lipids and acetylcholine receptor

The nicotinic acetylcholine receptor (AChR) is the archetype molecule in the superfamily of Cys-looped ligandgated ion channels. Members of this superfamily mediate fast intercellular communication in response to endogenous neurotransmitters. This review focuses on structural and functional crosstalk between the AChR and the lipids in its membrane microenvironment. Influence on receptor properties is mainly exerted by the AChR-vicinal ('shell', 'boundary' or 'annular') lipids, which occur in the liquid-ordered phase as opposed to the more disordered and 'fluid' bulk membrane lipids. Changes in Förster's energy transfer (FRET) efficiency induced by fatty acids, phospholipids and cholesterol have led to the identification of discrete sites for these lipids on the AChR protein. Electron-spin resonance spectroscopy has established the stoichiometry and selectivity of the shell lipid for the AChR and disclosed lipid sites in the AChR transmembrane region. Combined single-channel and site-directed mutagenesis data fostered the recognition of lipidsensitive residues in the transmembrane region, dissecting their contribution to ligand binding and channel gating, opening and closing. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids.