Abstract
Lipids influence the ability of Cys-loop receptors to gate open in response to neurotransmitter binding, but the underlying mechanisms are poorly understood. With the nicotinic acetylcholine receptor (nAChR) from Torpedo, current models suggest that lipids modulate the natural equilibrium between resting and desensitized conformations. We show that the lipid-inactivated nAChR is not desensitized, instead it adopts a novel conformation where the allosteric coupling between its neurotransmitter-binding sites and transmembrane pore is lost. The uncoupling is accompanied by an unmasking of previously buried residues, suggesting weakened association between structurally intact agonist-binding and transmembrane domains. These data combined with the extensive literature on Cys-loop receptor-lipid interactions suggest that the M4 transmembrane helix plays a key role as a lipid-sensor, translating bilayer properties into altered nAChR function.
Highlights
One factor that is known to affect the activity of several Cysloop receptors is the lipid composition of the membrane in which they are embedded [2]
PC-nicotinic acetylcholine receptor (nAChR) adopts a novel conformation in which allosteric coupling between the agonist-binding sites and transmembrane pore is lost (Fig. 1D)
Agonist-induced Conformational Change—Affinity purified nAChR, reconstituted into proteoliposomes with different lipid compositions, exhibits varying abilities to respond to agonist
Summary
One factor that is known to affect the activity of several Cysloop receptors is the lipid composition of the membrane in which they are embedded [2]. The agonist-binding sites, which are located on the extra-membranous surface of the receptor, are allosterically coupled to the distant transmembrane ion pore (Fig. 1).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
