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Lipid Rafts and Caveolae: from Membrane Biophysics to Cell Biology

Cell membranes are not homogeneous structures with components that are uniformly distributed. The existence of microdomains (rafts) within these membranes was used to explain observational data that showed that certain membrane components cluster together. Detergent treatment of cell membranes allows the isolation of detergent-insoluble/-resistant microdomains that are rich in free cholesterol and sphingolipids. It has been hypothesized that these regions, termed lipid rafts and caveolae, are involved in several important biological functions. However, their precise size, structure and role are still a matter of considerable debate.

The editor of this book has assembled a group of internationally renowned contributors who provide a contemporary exposition of this fascinating area of lipid biochemistry. The scene is set in the first chapter, which provides a historical perspective of the subject. This includes a brief review of the caveolins that characterize caveolae; these are small (60-80 nm) plasma membrane invaginations originally described by the Nobel Laureate, George Palade, more than 50 years ago. The second chapter explores the biophysics of caveolae and the forces that shape them, causing them to form invaginations. This chapter is not for the faint hearted. The following chapter contains an excellent critical evaluation of the methods that have been used to characterize lipid rafts, outlining the basis for some of the present controversies.

Caveolae are particularly abundant on adipocytes, endothelial cells and smooth muscle cells. They are probably involved in clathrin-independent endocytosis as discussed in Chapter 4. Caveolae provide a 'multifunctional platform' that appears to be involved in a wide array of roles including cholesterol, glucose and calcium transport, signalling, tumour suppression and endothelial nitric oxide synthase (eNOS) regulation. The latter is discussed in greater detail in Chapter 11. Endothelial dysfunction associated with exposure to high concentrations of LDL, and the benefits of statin therapy on endothelial function, may be mediated in part by their effects on caveolin.

The methods used to investigate the composition of caveolae are described in Chapter 5. Caveolae are enriched in free cholesterol, sphingolipids, glycerolipids and 'signalling lipids', such as phosphatidic acid. Caveolin-1 is a small, highly conserved hydrophobic protein that is the major structural protein of caveolae. It has a hairpin-like structure that inserts into the cytoplasmic leaflet of the cell membrane, and does not span the membrane bilayer. Although other caveolins (-2 and -3) exist, caveolae cannot form in the absence of caveolin-1. Other structural proteins have been found to co-localize with caveolae. These include flotillins, annexins and several growth factor receptors, including those for platelet-derived growth factor (PDGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). ATP-binding cassette (ABC) transporters, A1 and p-glycoprotein, have recently been reported to be found within caveolae, as has the scavenger receptor, SR-B1. These are key proteins in the transportation of free and esterified cholesterol and phospholipids. Chapters 6 and 7 provide an overview of the role of lipid rafts and caveolae in transmembrane signalling. Stress, or treatment with insulin, leads to the phosphorylation of caveolin-1 that is subsequently involved in stabilization of the actin network and inhibits cell migration. The role of caveolin in cell locomotion is discussed further in detail in Chapter 9.

Chapter 8 provides a discussion of the structure and membrane interactions of the caveolins. This is clearly written, and in my view, there would have been merit in putting this chapter much earlier in the book. Inter alia the authors discuss the role of caveolae in sterol uptake. Oestrogen receptors are associated with caveolae in plasma membranes. Oestrogens are tightly bound to HDL particles that may be involved in the delivery of oestrogen to caveolae via SR-Bl. The activation of eNOS by oestrogen appears to rely on its delivery to caveolae by this mechanism. It is also hypothesized that vitamin D uptake in the intestine may be dependent on a pool of nuclear vitamin D receptor that localizes to the caveolae.

The putative role of lipid rafts in Alzheimer's disease is examined in Chapter 10. It appears that prions may use lipid rafts to gain entry to cells, and that the rafts may also be involved in the conversion of prion protein into a protease-resistant readily aggregated isoform. Caveolin-1 has growth inhibitory and pro-survival properties, hence its role in oncogenesis is likely to be complex. This is discussed in the final chapter of this wide ranging book.

The stated aims of the book were to consolidate in one volume the current hypotheses about the structure and function of lipid rafts and caveolae, and to provide a reference work summarizing the field and making it more accessible fora new generation of scientists. I feel that both aims have largely been achieved, although this is not a book for the casual reader hoping to gain an overview of the subject.