Detergent-insoluble glycosphingolipid/cholesterol-rich membrane domains, lipid rafts and caveolae (review)

Within the cell membrane glycosphingolipids and cholesterol cluster togethe r in distinct domains or lipid rafts, along with glycosyl-phosphatidylinosi tol (GPI)-anchored proteins in the outer leaflet and acylated proteins in t he inner leaflet of the bilayer. These lipid rafts are characterized by ins olubility in detergents such as Triton X-100 at 4 degrees C. Studies an mod el membrane systems have shown that the clustering of glycosphingolipids an d GPI-anchored proteins in lipid rafts is an intrinsic property of the acyl chains of these membrane components, and that detergent extraction does no t artefactually induce clustering. Cholesterol is not required for clusteri ng in model membranes but does enhance this process. Single particle tracki ng, chemical cross-linking, fluorescence resonance energy transfer and immu nofluorescence microscopy have been used to directly visualize lipid rafts in membranes. The sizes of the rafts observed in these studies range from 7 0-370 nm, and depletion of cellular cholesterol levels disrupts the rafts. Caveolae, flask-shaped invaginations of the plasma membrane, that contain t he coat protein caveolin, are also enriched in cholesterol and glycosphingo lipids. Although caveolae are also insoluble in Triton X-100, more selectiv e isolation procedures indicate that caveolae do not equate with detergent insoluble lipid rafts. Numerous proteins involved in cell signalling have b een identified in caveolae, suggesting that these structures may function a s signal transduction centres. Depletion of membrane cholesterol with chole sterol binding drugs or by blocking cellular cholesterol biosynthesis disru pts the formation and function of both lipid rafts and caveolae, indicating that these membrane domains are involved in a range of biological processe s.