In addition to the actin cytoskeleton, which seems to be involved in the immobility of caveolae (see Section 4.2), caveolin-1 itself apparently immobilizes caveolae. Thus, Le et al.  and Nabi and Le  suggested that lipid rafts can invaginate in a cholesterol-dependent but caveolin-independent way to give rise to caveolae-like invaginations of the plasma membrane, which become rapidly internalized in a dynamin-dependent way. Such endocytic raft structures may then be immobilized by caveolin-1 and only become internalized after specific stimulation (e.g., virus binding). Pang et al.  recently showed that the content of GM1 varies among cells, and that cells with a low GM1 content also had a relatively low CT uptake which was independent of caveolin-1 expression.
It remains an open question as to whether there exist subpopulations of cav-eolae, or a subpopulation of caveolae-like invaginations with so little caveolin that it cannot be immobilized, but rather is endocytic . Such a subpopulation could account for the small fraction of caveolae that appears to become constitutively internalized (see Section 4.6).
As mentioned above (see Section 4.5), CT-B can be internalized by mechanisms that are caveolin-, clathrin- and dynamin-independent . Although such an endocytic mechanism (or several mechanisms) is far from well characterized, it is clear that for instance other protein toxins may enter cells in such a manner . It should be noted that caveolin-, clathrin- and dynamin-independent endocytosis is not necessarily dependent on lipid rafts , but one such internalization pathway could be via a noncaveolar, raft-based and cholesterol-dependent mechanism [101,102]. For example, in a study on lymphocytes it was found that after ligand stimulation the interleukin-2 receptor became internalized in a clathrin-and caveolin-independent, but dynamin-dependent way via detergent-resistant membrane domains . It should be stressed, however, that noncaveolar rafts, which do not form characteristic, regular, 50- to 70-nm invaginations during their pinching-off [14,100] (in contrast to caveolae or caveolae-like invaginated rafts) are poorly defined morphologically. This indeed makes the study of a possible role of noncaveolar rafts in endocytosis difficult. Several years ago we identified small, uncoated endocytic vesicles which differed from coated pits/vesicles and caveolae ultrastructurally . In a recent study, Kirkham et al.  found that CT was mainly internalized in a clathrin-, caveolin-, and dynamin-independent way by means of uncoated tubular or ring-shaped structures, as identified ultrastructu-rally. These structures also contained GPI-anchored proteins. That uptake of this type of protein can occur independently of clathrin, caveolin and dynamin is in agreement with our study of a GPI-anchored diphtheria toxin receptor . The mechanism reported by Kirkham et al.  was operating both in primary fibro-blasts from wild-type and cav-1-/-(cav-1-null) mice. Moreover, it was recently reported also that SV40 virus can be rapidly internalized in both cav-1-null and wildtype fibroblasts in a caveolin-, clathrin- and dynamin-independent manner .
The special caveolar lipid-environment appears to be of functional importance for caveolae-mediated endocytosis. Thus, increasing the cellular cholesterol level increases caveolae-mediated uptake of albumin and lactosylceramide. A similar effect is seen after the addition of exogenous lactosylceramide or GM1. In fact, the balance between the cellular amount of caveolin and glycosphingolipids may be of vital importance for the ability of caveolae to pinch off. In control cells, increasing the amount of caveolin-1 leads to a decrease in the caveolar-mediated endocytosis of albumin. In contrast, increasing both the amount of caveolin-1 and glycos-phingolipid leads to an increased endocytosis of albumin, presumably because in the latter case the correct balance between caveolin-1 and glycosphingolipids is maintained .
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