Lipid matters: nicotinic acetylcholine receptor-lipid interactions (Review)

Abstract

Ligand-gated ion channels mediate fast intercellular communication in response to endogenous neurotransmitters. The nicotinic acetylcholine receptor (AChR) is the archetype molecule in the superfamily of these membrane proteins. Early electron spin resonance studies led to the discovery of a lipid fraction in direct contact with the AChR, with rotational dynamics 50-fold slower than those of the bulk lipids. This AChR-vicinal lipid region has since been postulated to be a possible site of lipid modulation of receptor function. The polarity and molecular dynamics of solvent dipoles-mainly water-of AChR-vicinal lipids in the membrane have been studied with Laurdan extrinsic fluorescence, and Forster-type resonance energy transfer (FRET) was introduced to characterize the receptor-associated lipid microenvironment. FRET enabled one to discriminate between the bulk lipid and the AChR-vicinal lipid. The latter is in a liquid-ordered phase and exhibits a higher degree of order than the bulk bilayer lipid. Changes in FRET efficiency induced by fatty acids, phospholipids and cholesterol also led to the identification of discrete sites for these lipids on the AChR protein. After delineating the topography of the AChR membrane-embedded domains with fluorescence methods, sites for steroids are being explored with site-directed mutagenesis and patch-clamp recording. Pyrene-labelled Cys residues in alphaM1, alphaM4, gammaM1 and gammaM4 transmembrane regions were found to lie in a shallow position. For M4 segments, this is in agreement with a canonical linear alpha-helix; for M1, it is necessary to postulate a substantial amount of non-helical structure, and/or of kinks, to rationalize the shallow location of Cys residues. Mutations of Thr422, a residue close to the extracellular-facing membrane hemilayer in alphaM4, affect the steroid modulation of AChR function, suggesting its involvement in steroid-AChR interactions.

Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol

“…In general, as cholesterol resides in the plasma membrane, it is logical to expect that it is the TM domains that are critical for the sensitivity of the channels to cholesterol. Indeed, 2 current models of cholesterol-ion channel interactions, a lipid belt model (10,11) and a hydrophobic mismatch model (12,13), both focus on the interactions of cholesterol, directly or indirectly, with the TM domains of the channels. In the lipid belt model, it is proposed that channels interact directly with the boundary lipids surrounding the TM domains (10,11), and in the hydrophobic mismatch model, it is proposed that the hydrophobic mismatch between the TM domains and the lipid core of the membrane determines the energy required to change the conformation state of the channels from closed to open (12,13).…”

“…In contrast, epithelial Na ϩ channels and TrpC channels were shown to be inhibited by cholesterol depletion (8,9). In general, 3 basic mechanisms have been proposed: (i) specific interaction of a channel protein with cholesterol as a boundary lipid (10,11), (ii) hydrophobic mismatch between the channel and the lipid core of the membrane (12,13), and (iii) indirect effects through the interactions of ion channels with regulatory lipids or proteins within the environment of cholesterol-rich membrane domains (1,14,15). The structural basis of the sensitivity of ion channels to cholesterol, however, is unknown.…”

Structure and Function of the Glycine Receptor and Related Nicotinicoid Receptors

“…62). Delipidation studies of nAChR indicated that a lipid/protein mole ratio below ϳ45 causes irreversible inactivation of the receptor, consistent with the requirement of an annular shell of lipids around the periphery of the hydrophobic region (63).…”

Structural Basis for Allosteric Coupling at the Membrane-Protein Interface in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC)

“…However, it is to be noted that these interactions are not conserved across the family (21). The strategic location of the ECD-TMD interface also makes this region a likely target for lipid-mediated effects on channel function (22)(23)(24). Interestingly, sequence analysis predicts the presence of a potential cholesterol-binding motif in GLIC at the pre-M1 region of the interface (25).…”