Two pools of cholesterol in acetylcholine receptor-rich membranes from Torpedo

Leibel, Wayne S.; Firestone, Leonard L.; Legler, Dwight C.; Braswell, Leon M.; Miller, Keith W.

doi:10.1016/0005-2736(87)90421-4

Cited by 45 publications

(25 citation statements)

References 44 publications

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“…Cholesterol and anionic lipids show a strong preference for the annulus of lipids that surrounds the outer surface of the nAChR [68][69][70]147]. At any given moment in time, both cholesterol and anionic lipids in this annulus are "bound" to the nAChR surface, although each bound lipid exchanges rapidly with others in the bulk membrane environment.…”

Section: Sites Of Lipid-nachr Interactionsmentioning

confidence: 99%

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

Baenziger

Hénault

Therien

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Membrane lipids are potent modulators of the nicotinic acetylcholine receptor (nAChR) from Torpedo. Lipids influence nAChR function by both conformational selection and kinetic mechanisms, stabilizing varying proportions of activatable versus non-activatable conformations, as well as influencing the transitions between these conformational states. Of note, some membranes stabilize an electrically silent uncoupled conformation that binds agonist but does not undergo agonist-induced conformational transitions. The uncoupled nAChR, however, does transition to activatable conformations in relatively thick lipid bilayers, such as those found in lipid rafts. In this review, we discuss current understanding of lipid-nAChR interactions in the context of increasingly available high resolution structural and functional data. These data highlight different sites of lipid action, including the lipid-exposed M4 transmembrane α-helix. Current evidence suggests that lipids alter nAChR function by modulating interactions between M4 and the adjacent transmembrane α-helices, M1 and M3. These interactions have also been implicated in both the folding and trafficking of nAChRs to the cell surface. We review current mechanistic understanding of lipid-nAChR interactions, and highlight potential biological roles for lipid-nAChR interactions in modulating the synaptic response. This article is part of a Special Issue entitled: Lipid-protein interactions.

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Section: Sites Of Lipid-nachr Interactionsmentioning

confidence: 99%

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

Baenziger

Hénault

Therien

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…1A). Unfortunately, experiments that do not consider the possibility of deeply buried sites generally preclude their observation; for instance, a recent photolabeling study of cholesterol binding to the nAChR (14) used incubation times that would allow for occupation by labeled cholesterol of external sites but not internal ones, as was already indicated by the cholesterol extraction experiments of Leibel et al (15).…”

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confidence: 99%

Embedded cholesterol in the nicotinic acetylcholine receptor

Brannigan

Hénin

Law

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

150

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The nicotinic acetylcholine receptor (nAChR) is a cation-selective channel central to both neuronal and muscular processes and is considered the prototype for ligand-gated ion channels, motivating a structural determination effort that spanned several decades [Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J Mol Biol 346:967-989]. Purified nAChR must be reconstituted in a mixture containing cholesterol to function. Proposed modes of interaction between cholesterol and the protein range from specific binding to indirect membranemediated mechanisms. However, the underlying cause of nAChR sensitivity to cholesterol remains controversial, in part because the vast majority of functional studies were conducted before a medium resolution structure was reported. We show that the nAChR contains internal sites capable of containing cholesterol, whose occupation stabilizes the protein structure. We detect sites at the protein-lipid interface as conventionally predicted from functional data, as well as deeply buried sites that are not usually considered. Molecular dynamics simulations reveal that occupation of both superficial and deeply buried sites most effectively preserves the experimental structure; the structure collapses in the absence of bound cholesterol. In particular, we find that bound cholesterol directly supports contacts between the agonist-binding domain and the pore that are thought to be essential for activation of the receptor. These results likely apply to those other ion channels within the Cys-loop superfamily that depend on cholesterol, such as the GABA receptor.protein-lipid interaction ͉ ligand-gated ion channel ͉ cys loop receptor C ritical for memory and cognition, the nAChR is implicated in neurological disorders (1), addiction (2, 3), and the mechanism of anesthetics (4). Early efforts to reconstitute the nAChR noted that cholesterol as well as charged lipids (such as phosphatidic acid) are required for proper function (5). Proposed mechanisms for the role of cholesterol in nAChR function fall into two general types: indirect and direct. Indirect mechanisms are those in which a cholesterol-induced change in fluid or elastic properties of the lipid bilayer modulates the protein behavior. Although early studies (6, 7) indicated that current flow through the channel is insensitive to bilayer fluid properties, more recent studies (8, 9) have proposed that this result depends on the choice of order parameters. The direct mechanism requires cholesterol binding to the nAChR and effecting structural and/or dynamic changes. Proponents of this theory have determined that (i) cholesterol molecules in proximity to the protein exchange very slowly with the bulk lipid bilayer (10) (electron spin resonance difference spectroscopy); (ii) cholesterol accesses sites on the protein that cannot be occupied by phospholipids (11) (fluorescence quenching); and (iii) some cholesterol bound to the nAChR interacts with the phospholipids in the surrounding bilayer (12) (substit...

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“…The functional implications of this finding became apparent when it was demonstrated that cholesterol is an essential component for maintaining nAChR agonist-dependent state transitions in the postsynaptic membrane [36]. It has been proposed that there are two cholesterol populations in nAChR-rich membranes from Torpedo: an easily extractable fraction that influences the bulk fluidity of the membrane and a tightly bound receptor-associated fraction [71].…”

Section: Occurrence Of Receptors In Postsynaptic Ordered Lipid Domainsmentioning

confidence: 99%

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

Barrantes

2016

BSI

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Abstract. Once the sterol biosynthetic machinery had progressed over the course of several million years to yield cholesterol, this neutral lipid became an omnipresent and essential component of biomembranes in Eukaryotes. The hopanoids in Prokaryotes and eukaryotic sterols share the ability to provide stability and domain compartmentalization in membranes. Even more important is the intimate association of cholesterol with a wide range of cell-surface membrane proteins, probably responsible for its modulatory effects on neurotransmitter and hormone receptors and ion channels. These effects appear to be exerted via the membrane-embedded segments of essentially all members of the pentameric ligand-gated ion channel and G-protein-coupled receptor superfamilies, which possess consensus linear arrays of amino acid residues recognizing cholesterol with relatively high affinity and specificity, an early evolutionary acquisition already present in ancient bacteria, conserved, and further improved in Eukaryotes. This review focuses on the long-term relationship between cholesterol and these functionally important membrane protein superfamilies, and the ability of cholesterol to induce lateral segregation and ordered domain formation at the nanoscale in cell membranes.

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Two pools of cholesterol in acetylcholine receptor-rich membranes from Torpedo

Cited by 45 publications

References 44 publications

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

Nicotinic acetylcholine receptor–lipid interactions: Mechanistic insight and biological function

Embedded cholesterol in the nicotinic acetylcholine receptor

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

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