Although originally defined by their distinct morphology (invaginated cave-like structures 50–100 nm in diameter, found on cell surfaces), caveolae are now defined as pleomorphic lateral assemblies (rafts) of glycolipids, cholesterol, various glycosylphosphatidylinositol (GPI)-anchored molecules and a 22 000-MW protein, caveolin-1.10 Caveolae assume a variety of shapes, including flat, vesicular, and tubular forms. They can be either open at the cell surface or closed off, forming a vesicular compartment. Although the main forces driving the formation of these microdomains are lipid–lipid interactions that are dependent on the biophysical characteristics of the lipid components, caveolin protein appears to contribute to the aggregate structure possibly by serving as a scaffolding protein. Although some have believed caveolae to be present in virtually all cell types, their presence in haematopoietic cells has been unclear. Earlier studies employing cell lines of lymphocytes7 and mast cells11 have shown that while microdomains comprising glycolipids, cholesterol and various GPI-anchored molecules were clearly detectable in these cells, the presence of caveolin was not. Hence these structures were referred to as lipid rafts rather than caveolae. Transfection of lymphocyte cell lines with cDNA for caveolin-1 resulted in the migration of caveolin to the lipid rafts, triggering the formation of distinct cave-like caveolae in the plasmalemmal surface of the transfectants.12 Thus, the caveolin protein can also contribute to the morphological appearance of caveolae. Caveolin has the intrinsic ability to form stable homo-oligomers,13,14 and rapid-freeze, deep-etch ultra-electron microscopy of fibroblasts have revealed that these homo-oligomerized caveolin give rise to distinct filamentous striated strands at the base (cytoplasmic face) of each invaginated caveolae.15
Ever since their discovery, the cellular function(s) of caveolae has been the focus of much study. In recent years, caveolae have been implicated as a conduits for transmembrane signal transduction because of the high concentration of receptors and signalling molecules found concentrated within their structure.16,17 Receptors for various growth factors and hormones have been localized to caveolae including epidermal growth factor,18 platelet-derived growth factor19 and insulin.20 Signalling molecules are also specifically localized to these sites including Src family protein tyrosine kinases, protein kinase C isoforms, Ha-Ras and heterotrimeric G protein α subunits.21 Caveolin can directly interact with some of these signalling molecules via a conserved 20 amino acid domain termed the caveolin-scaffolding domain (residues 82–101 of caveolin-1). In addition to serving as a conduit for signalling, caveolae have been implicated in several different endocytic events, including the transcytosis of macromolecules across cells. Caveolae appear to contain all the molecular machinery for docking and fusion that is necessary for a vesicular trafficking system.22 However, the caveolae-mediated endocytic pathway is distinct from the classical endosome–lysosome pathway in a number of ways. For example, in contrast to the classical pathway, the nascent endocytic compartment formed during the uptake of a ligand comprised of lipid-rich elements, often containing caveolin, but is distinctly devoid of clathrin. In the classical pathway, following scission from the plasma membrane, intracellular ligand-containing endosomes typically fuse with lysosomes where the ligand is degraded, whereas there is apparently no fusion of caveolar vesicles with endosomes.10,23 Based mainly on literature obtained from the study of endothelial and epithelial cells, there appears to be several modes of caveolae-mediated entry and intracellular trafficking, depending on the ligand. In certain cases, the entry of the ligand involves a phenomenon called potocytosis, a potential method for ‘pumping’ small molecules and ions from the extracellular medium into the cytoplasm as exemplified by the uptake of folate via its GPI-anchored receptors concentrated within plasmalemmal caveolae.8 In other cases, the ligand is encapsulated and translocated directly to the endoplasmic reticulum as in the case of cholesterol10 or to the nucleus as in the case of some hormones,24 yet in others, the caveolae-bound ligand is translocated across the cell and discharged outside at the basolateral plasma membrane as in the case of albumin,9 immunoglobulin A (IgA) antibodies,25 and certain chemokines.26 Because some caveolae can assume a tubular form (formed by the fusion of multiple swollen caveolae27), there is no scission of the caveolar compartment following binding of the ligand, instead the ligand is funnelled from cell surface to cell surface through the length of the tubular caveolae.28 Regardless of the heterogeneity in intracellular trafficking, ligands endocytozed by caveolae, appear to share at least two common features. The first is that they are not readily degraded following entry into the host cell because the caveolar compartments bearing the ligand fail to fuse with lysosomes, and second, the cognate plasmalemmal receptor for the ligand is an integral component of caveolae. Taken together, caveolae appear to serve a critical physiological function for the cell by internalizing macromolecules (nutrients, growth factors, hormones, antibodies, chemokines, etc.) and trafficking them without degradation and in a functionally active state to various intracellular sites and sometimes, back to the extracellular sites. Obviously, there is selectivity in which macromolecules can utilize caveolae for their entry, because only ligands whose cognate receptors are associated with caveolae are endocytozed in this manner.