REGULATION OF THE NICOTINIC ACETYLCHOLINE RECEPTOR BY CHOLESTEROL AS A BOUNDARY LIPID

BARRANTES FJ

CHOLESTEROL REGULATION OF ION CHANNELS AND RECEPTORS

John Willey & Sons

Lugar: Hoboken; Año: 2012; p. 183 - 204

The nicotinic acetylcholine receptor (AChR) protein is the archetype molecule in the Cys-loop superfamily of rapid ligand-gated ion channels, characterized by mediating fast intercellular communication in response to endogenous neurotransmitters. Cholesterol, an abundant lipid in the postsynaptic membrane, influences structural and functional properties of the receptor protein. A wealth of evidence stemming from biochemical and biophysical experimental data has disclosed lipid sites in the AChR transmembrane region, and in particular in the boundary area surrounding the protein. Cholesterol sites have been more difficult to characterize. A cholesterol recognition motif, coined ?CARC?, has been recently identified in the transmembrane regions of AChR subunits that bear extensive contact with the surrounding lipid, and are thus optimally suited to convey cholesterol-mediated signaling from the latter. The motif is also found in other members of the Cys-loop receptors and bacterial homologs, and significantly in the important superfamily of G protein coupled receptors. The motif is matched by corresponding functional sites defined by the successful combination of site-directed mutagenesis and single-channel electrophysiological data, which have led to the recognition of lipid-sensitive residues in the transmembrane region and the dissection of their contribution to ligand binding and channel gating, opening and closing. This cumulative experimental evidence supports the notion that the interface region between the protein moiety and the adjacent AChR-vicinal (?shell?, ?boundary? or ?annular?) lipids is the locus of a variety of pharmacologically relevant processes, including the action of cholesterol, general and local anesthetics, and other biologically and pharmacologically relevant molecules.