A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors

The ability of the nicotinic acetylcholine receptor (nAChR) to undergo conformational transitions is exquisitely sensitive to its surrounding lipid environment. Previous work has highlighted a conformational selection mechanism, whereby different lipids stabilize different proportions of activatable resting versus nonactivatable conformations. In the absence of anionic lipids and cholesterol, the nAChR adopts an uncoupled conformation, which binds agonist with resting state-like affinity but does not usually undergo agonist-induced conformational transitions. Very slow (minutes to hours) transitions from uncoupled to coupled (resting, open and/or desensitized) conformations, however, can occur in membranes with relatively thick hydrophobic cores. Increasing membrane hydrophobic thickness 'awakens' uncoupled nAChRs by reducing the large activation energy barrier (or barriers) leading to coupled states, thus allowing conformational transitions to occur on an experimentally tractable timescale. Lipids shape activity by modulating the relative proportions of activatable versus nonactivatable conformations and by controlling the transitions between uncoupled and coupled conformations.