Sphingolipid/cholesterol regulation of neurotransmitter receptor conformation and function

Abstract

Like all other monomeric or multimeric transmembrane proteins, receptors for neurotransmitters are surrounded by a shell of lipids which form an interfacial boundary between the protein and the bulk membrane. Among these lipids, cholesterol and sphingolipids have attracted much attention because of their well-known propensity to segregate into ordered platform domains commonly referred to as lipid rafts. In this review we present a critical analysis of the molecular mechanisms involved in the interaction of cholesterol/sphingolipids with neurotransmitter receptors, in particular acetylcholine and serotonin receptors, chosen as representative members of ligand-gated ion channels and G protein-coupled receptors. Cholesterol and sphingolipids interact with these receptors through typical binding sites located in both the transmembrane helices and the extracellular loops. By altering the conformation of the receptors ("chaperone-like" effect), these lipids can regulate neurotransmitter binding, signal transducing functions, and, in the case of multimeric receptors, subunit assembly and subsequent receptor trafficking to the cell surface. Several sphingolipids (especially gangliosides) also exhibit low/moderate affinity for neurotransmitters. We suggest that such lipids could facilitate (i) the attachment of neurotransmitters to the post-synaptic membrane and in some cases (ii) their subsequent delivery to specific protein receptors. Overall, various experimental approaches provide converging evidence that the biological functions of neurotransmitters and their receptors are highly dependent upon sphingolipids and cholesterol, which are active partners of synaptic transmission. Several decades of research have been necessary to untangle the skein of a complex network of molecular interactions between neurotransmitters, their receptors, cholesterol and sphingolipids. This sophisticated crosstalk between all four distinctive partners may allow a fine biochemical tuning of synaptic transmission.

Cellular prion protein: A co-receptor mediating neuronal cofilin-actin rod formation induced by β-amyloid and proinflammatory cytokines

“…Several ligand-gated ion channels and G-protein coupled receptors contain specific binding sites, either in their transmembrane helices or extracellular loop structures, for cholesterol and sphingolipids, the binding of which allows conformational changes necessary for function. 10 Subtle changes in lipid species alter membrane architecture and impose constraints on lipid-protein and/or protein-protein interactions influencing the function of membrane proteins. Levels of raft-associated lipids such as sphingomyelin, ceramides, and cholesterol significantly increase with age, 11 suggesting that lipid raft densities and associated signaling process are likely subjected to age-dependent alterations that could contribute to the initiation and/or progression of AD, 9 as could dietary factors that affect lipid accumulation and metabolism and alterations in membrane lipids resulting from oxidative stress (e.g.…”

Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice

“…They are major components of membrane microdomains known as "lipid rafts" (22) and are important players in cell signaling (23) and cell-cell interaction (24). By influencing membrane properties and/or by direct interaction with membrane proteins, gangliosides modulate the activity of many tyrosine kinase (25)(26)(27)(28) and neurotransmitter receptors (29), ion channels (30,31), and downstream cell signaling pathways. In addition, gangliosides regulate axon-myelin communication and the maintenance of myelinated axons in the adult central and peripheral nervous systems (32)(33)(34).…”

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

“…The bifacial geometry of cholesterol appears to be the outcome of this struggle [48]. The dissymmetrical nature of the molecule is manifested in the contrast between the rough β face, with methyl substituents in C10 and C13 and an iso-octyl chain in C17, with the featureless, smooth α face.…”

“…Comparative analyses of the energy of interaction of cholesterol with pLGIC, GPCRs and various other membrane proteins revealed that the CARC motif generally exhibits higher affinity for cholesterol than the CRAC motif [49]. Essentially two explanations lie at the root of the difference in the predictive value of the CRAC and CARC linear algorithms: the snorkeling effect of Lys/Arg residues, which places the polar residues exposed to the aqueous milieu and the hydrophobic residues buried in the bilayer hydrophobic core [128] on the one hand and the structure of cholesterol itself [48], as reviewed in [46,49] on the other.…”

“…The molecular dynamics studies further indicated that the cholesterol contacts with the CARC motif within γ TM4 involved the β-face, leaving the α-face exposed. This suggested that the cholesterol-mediated oligomerization of the peptide is dictated by cholesterol-cholesterol interactions rather than by protein-protein interactions [48]. We next compared the interaction between cholesterol and either wild-type or mutant TM4 peptides.…”