Preface

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This volume is the first book-length survey of caveolae and lipid rafts. Interest has developed rapidly in the role of these surface microdomains in such diverse fields as transmembrane signaling, cell locomotion, vascular relaxation, senescence, and the uptake and exit from cells of viruses and bacteria. Individual chapters in this volume cover areas as diverse as the forces that induce and maintain membrane invaginations, and the clinical relevance of multiprotein complexes at the cell surface, defects in which are associated with cancer, and Alzheimer's and prion-de-pendent diseases.

The book includes contributors from twelve countries. This reflects the growth and spread of these studies over the last twenty-five years, since the recognition of free cholesterol/sphingolipid (FC/SPH) rich cell microdomains as a distinct class of cell-surface structures. The historical origin of this concept is presented in the Overview by Drs Meder and Simons. Their chapter places caveolar and lipid rafts in context as biological membranes with special roles in information transfer across the plasma membrane, and between cell compartments. Other contributions described research, in a number of cases for the first time, in key areas of the molecular physiology of lipid-protein complexes in rafts and caveolae.

One area addressed in several chapters is the physical nature of FC/SPH-rich microdomains, their origin, and their lifetimes as independent structures within the cell membrane. Are planar lipid rafts, and invaginated caveolae, variations of a common theme? Can they be interconverted? Contributions by Dr Mayor and colleagues and by Drs Sens and Turner on the biophysics of lipid rafts and caveolae respectively, break new ground in describing the techniques now available to analyze these structures. They also summarize the physical forces sustaining them in the cell membrane.

A second group of chapters describes how these physical forces at the surface regulate cell behaviour. The chapter by Dr van Deurs and colleagues addresses one of the most important of these, the significance of caveolae in endocytosis, a pathway alternate to that mediated by clathrin-coated pits. The balance of evidence indicates that though caveolae are usually relatively stable, they can be induced to bud off by a variety of physiological and pathological stimuli. The chapter by Drs Park and Cho reviews the role of caveolae in maintaining cell shape, and promoting locomotion, though their interaction with the actin skeleton.

A third group of contributions deals with recent research on the factors controlling the level of lipid (especially FC) and protein (especially the structural protein caveolin) in cell surface caveolae. Drs Everson and Smart summarizes research indicating that caveolins play key roles in FC homeostasis and intracellular transport, in addition to promoting caveola formation at the cell surface. The chapter by Drs C. and P. Fielding describes mechanisms by which the level of FC at the cell surface affects the structure and function of caveolae, and re-examines the concept of caveolin as scaffold. Data from these and other laboratories have shown that the composition of caveolae is dynamically regulated, and can respond to the extracellular environment as well as the current internal needs of the cell.

One of the best characterized functions of FC/SPH-rich domains is to serve as an assembly point for the multiprotein complexes that promote signal transduc-tion. Recent research has identified structural features that contribute to the assembly of these complexes. These include reversible covalent modifications, such as changes in protein phosphorylation and acylation, that promote assembly and disassembly, leading to signal propagation to the nucleus. The chapter by Dr Dam-janovitch and colleagues gives a detailed review of the most recent data on these events in lipid rafts. Dr Mastick and colleagues dissect the regulatory role of cav-eolin within caveolae during signaling via transmembrane growth factor receptors.

Perhaps the most detailed of all investigation in the field of caveolae has concerned the mechanism by which the activity of endothelial nitric oxide synthase (eNOS) a major determinant of vascular relaxation, is regulated by its association with caveolae. The chapter by Dr Feron, based on the work of his own and other laboratories, describes in detail the complex relationship between e-nos, caveolin and FC.

A final group of chapters discusses the roles of FC/SPH rich domains in human disease. Drs David and Liscovitch discuss the roles of caveolin and caveolin in cancer cells, and show that under different conditions both positive and negative pathways can be identified. The chapter by Dr Zurzolo and colleagues describes the recently identified roles of FC/SPH domains in the pathophysiology of prion-based and Alzheimer's diseases.

The present volume has two main purposes. It brings together current hypotheses about the structure and functions of lipid rafts and caveolae by leading experts. These ideas will be of interest to biophysicists, biochemists, cell biologists and clinicians who study biological membranes. The book also provides a convenient reference work summarizing published work in this rapidly growing area. We hope that this will assist the research of a new generation of investigators drawn to this subtle but fascinating field, with its ramifications in many areas of current biology.

San Francisco, December 2005

Christopher J. Fielding

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