Abstract
Anionic lipids influence the ability of the nicotinic acetylcholine receptor to gate open in response to neurotransmitter binding, but the underlying mechanisms are poorly understood. We show here that anionic lipids with relatively small headgroups, and thus the greatest ability to influence lipid packing/bilayer physical properties, are the most effective at stabilizing an agonist-activatable receptor. The differing abilities of anionic lipids to stabilize an activatable receptor stem from differing abilities to preferentially favor resting over both uncoupled and desensitized conformations. Anionic lipids thus modulate multiple acetylcholine receptor conformational equilibria. Our data suggest that both lipids and membrane physical properties act as classic allosteric modulators influencing function by interacting with and thus preferentially stabilizing different native acetylcholine receptor conformational states.
Highlights
Lipids are potent modulators of Cys loop receptor function [4]
Reconstitution of nicotinic acetylcholine receptor (nAChR) into PC/Anionic Lipid Membranes— To test if phosphatidic acid (PA) is unique among anionic lipids in its ability to stabilize an agonist-activatable nAChR, the structural and functional properties of the nAChR were examined in a broader range of PC/anionic lipid mixtures
We initially focused on PC membranes containing the anionic lipid, phosphatidylglycerol (PG), because the cross-sectional area of the PG headgroup and its effects on bilayer physical properties are more similar to that of PA than to that of PC or other anionic lipids (Fig. 1) [24, 25]
Summary
Lipids are potent modulators of Cys loop receptor function [4]. The lipid sensitivity of one Cys loop receptor, the nicotinic acetylcholine receptor (nAChR) from Torpedo, has been well studied. The nAChR reconstituted into phosphatidylcholine membranes (PC-nAChR) does not undergo agonist-induced allosteric transitions unless neutral and/or anionic lipids are present [5,6,7,8,9,10,11,12,13]. PC-nAChR is unresponsive to agonist because it adopts an uncoupled conformation where allosteric communication between the agonist-binding and transmembrane pore domains is lost, even though both domains adopt structures suggestive of the activatable resting state [14]. Most studies suggest that the nAChR requires both anionic and neutral lipids in a PC membrane to adopt an agonist-activatable conformation [6, 11, 12]. The strikingly different efficacies of PA and PS suggest that PA imparts a unique chemical and/or physical property onto the reconstituted membranes that is required to stabilize the resting conformation. We examined a variety of reconstituted PC/anionic lipid membranes and found that anionic lipids with relatively
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