Molecular mechanisms of acetylcholine receptor–lipid interactions: from model membranes to human biology

Abstract

Lipids are potent modulators of the Torpedo nicotinic acetylcholine receptor. Lipids influence nicotinic receptor function by allosteric mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations. Recent structures reveal that lipids could alter function by modulating transmembrane α-helix/α-helix packing, which in turn could alter the conformation of the allosteric interface that links the agonist-binding and transmembrane pore domains-this interface is essential in the coupling of agonist binding to channel gating. We discuss potential mechanisms by which lipids stabilize different conformational states in the context of the hypothesis that lipid-nicotinic receptor interactions modulate receptor function at biological synapses.

Specific phospholipid binding to Na,K-ATPase at two distinct sites

“…When a membrane protein is purified in its native membrane or reconstituted into a model bilayer, as is often necessary in order to maintain activity, it is difficult to distinguish whether functional effects of different lipids result from specific protein-lipid interactions or from physical forces associated with nonspecific bilayer interactions. Thus, the different types of protein-lipid interaction have been a matter of extensive debate for channels (20,21), transporters (22), G-protein-coupled receptors (23), and P-type ATPases (SI Appendix, Supplementary Discussion). By contrast, when the membrane protein is purified in soluble mixed protein-lipid-detergent micelles in the absence of a lipid bilayer, the analysis is greatly simplified.…”

A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors

“…Neuronal nAChRs traffic to the cell surface via lipid rafts. Disruption of these rafts leads to both altered cell surface exposure and altered nAChR function 12,48,49 . Integral membrane proteins with shorter transmembrane α-helices tend to remain in intracellular membrane compartments, possibly because they are a better hydrophobic match for the thinner intracellular membranes 33,50 .…”

“…In favorable environments, either direct lipid binding or altered bulk membrane properties could influence transmembrane α-helix packing, thus awakening previously uncoupled receptors 12 .…”

The role of the M4 lipid-sensor in the folding, trafficking, and allosteric modulation of nicotinic acetylcholine receptors

“…Neuronal nAChRs traffic to the cell surface via lipid rafts, and disruption of these rafts leads to both altered cell surface exposure and altered nAChR function (Baenziger and daCosta, 2012;Baier et al, 2010;Borroni and Barrantes, 2011). Integral membrane proteins with shorter transmembrane a-helices tend to remain in intracellular membrane compartments, possibly because they hydrophobically match the thinner intracellular membranes more favorably (Bretscher and Munro, 1993;Lundbaek et al, 2003).…”