Structure and dynamics of acetylcholine receptor and its lipid microenvironment: from molecule to cell.

ANTOLLINI, S.S.; BAIER, C.J.; BLANTON, M.; BONINI, I.; DE LOS SANTOS, B.; GALLEGOS, M.C.; GARBUS, I.; PEDICONI, M.F.; PRIETO, M.; ROCCAMO, A.M.; WENZ, J.J.; BARRANTES, F.J.

Cholinergic Mechanisms: Function and Dysfunction.

Taylor & Francis

Lugar: Londres; Año: 2004; p. 33 - 38

The nicotinic acetylcholine receptor (AChR) is one of the best-characterized members of the ligandgated ion channel superfamily.1 It is a pentameric integral membrane protein of homologous 2 subunits. Each subunit contains four hydrophobic segments (M1–M4) and experimental evidence supports the view that they all constitute membrane- spanning domains.2–5 The M2 segment from each subunit is thought to contribute structurally to form the ion channel proper. The M4 segment was proposed to be exposed to the bilayer lipid,2 and the M1 and M3 segments must have some contact with lipid, since they effectively incorporate membrane-partitioning photoactivable probes.3–5 Although it has not yet been determined unambiguously, it is usually accepted that the four hydrophobic segments M1–M4 form the TM region of the AChR.6 Experimental evidence from various groups, including ours, has reinforced the view that the function of the AChR is influenced by its lipid microenvironment.6–8 The exact nature of the interactions between the AChR TM region and the adjacent lipids has not been clearly established. Since the discovery of an immobilized layer of lipids surrounding the AChR ‘annular lipids’,9 this distinct lipid region has been postulated as the likely candidate where the modulation of the AChR function by lipids occurs. Several hypotheses have been put forward with regard to the biophysical state of these lipids10 and/or the existence of distinct sites for specific lipids at the AChR–lipid interface.11,12 All hypotheses have in common the occurrence of lipid modulatory effects on AChR function, and both endogenous and exogenous lipids (acting as hydrophobic noncompetitive inhibitors) are postulated to influence the ability of AChR to undergo conformational transitions from the resting to the open and finally to the desensitized AChR states upon binding of the natural neurotransmitter acetylcholine. 13–14 Fluorescence and electrophysiological studies from our group providing evidence on the subtle modulation of AChR gating function by surrounding lipids will be reviewed briefly here.