Caveolae: Stable Membrane Domains with a Potential for Internalization

Abstract

The role of caveolae in endocytosis is hotly debated. Here, we argue that most caveolae are stable microdomains at the cell surface. Only a small fraction of caveolae is constitutively internalized, leading to a quantitatively minor uptake of ligands and receptors. In addition, we suggest that a more pronounced downregulation of caveolae from the plasma membrane can occur, presumably stimulated by receptor cross-linking and clustering in caveolae. Finally, we propose that future studies dealing with internalization of caveolae should actually document such internalization and include kinetic data. In recent years, increasing attention has been paid to the role of caveolae in various cellular processes, and a plethora of functions have been ascribed to these small, characteristically shaped invaginations of the plasma membrane that are associated with caveolin. However, currently there is still much confusion about the role of caveolae in endocytosis. Supporting a role in endocytosis are several reports on the uptake of cholera toxin (CT) and also studies on SV40 virus internalization (1,2). Against a role in endocytosis are findings from fluorescence recovery after photobleaching (FRAP) studies showing that caveolae are highly immobile structures that do not have a high turnover at the plasma membrane (3). Indeed, caveolin apparently prevents caveolae from pinching off (4,5) and very recent data also show that caveolae are not obligatory for SV40 entry (6). In addition, other recent studies, for instance, on the uptake of prion proteins (7) and CT (8-13) have brought new life to the discussion. A summary of the evidence against caveolae as a major endocytic carrier is shown in Table 1. In this review, we present a unifying working model for caveolar internalization on the basis of available information.

A New N-Terminal Recognition Domain in Caveolin-1 Interacts with Sterol Carrier Protein-2 (SCP-2)

“…Third, the C-terminal deletion mutants of α-caveolin-1 1-156 and β-caveolin-1 1-156 interacted with SCP-2 1-32 and Pro-SCP-2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] by the in vitro peptide binding technique, but only weakly bound full-length β-caveolin-1. These data indicate: (i) deletion of the β-caveolin-1 C-terminus facilitates exposure of the β-caveolin-1 N-terminus to interact with SCP-2; (ii) the α-caveolin-1 C-terminus is not essential to SCP-2 binding; and (iii) the caveolin-1 C-terminus influences the exposure of the caveolin-1 N-terminus.…”

“…To begin to resolve this issue, the N-terminal SCP-2 1-32 was synthesized, coupled to sepharose 4B beads, and used in an in vitro binding assay wherein caveolin-1 binding was detected by Western blot analyses. Synthetic peptides corresponding to caveolin-1 residues 2-31, 19-40, 34-55, 76-101, and 161-178 (Table 1), a peptide corresponding to mature 13 kDa SCP-2 aa 1-32 (SCP-2 1-32 ), a peptide wherein residue aa20L was mutated to E (SCP-2 1-32E20 ), and a peptide corresponding to the 20 aa presequence of pro-SCP-2 (pro-SCP-2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] ) present in 15 kDa pro-SCP-2 (61,62) were synthesized as described earlier (Table 1) (63)(64)(65)To confirm the in vivo yeast two-hybrid assay that identified the caveolin-1 N-domain as the interaction site with SCP-2, the in vitro peptide binding assay was repeated using yeast lysates expressing full length caveolin-1 (pY52DCaveolin-1), a caveolin-1 mutant with the putative binding site present (e.g. pY52DCaveolin-1 1-156), and an N-terminal deletion mutant of caveolin-1 with the putative binding site deleted (e.g.…”

“…To determine if the 20 aa amino acid pre-sequence present in pro-SCP-2 also interacted with caveolin-1, pro-SCP-2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] was linked to beads and tested for binding to full-length and mutant caveolin-1, pro-SCP-2 1-20 -linked beads predominantly bound to full length α-caveolin-1 (Fig. 3D, lane 4), whereas pro-SCP-2 1-20 bound to both α-and β-caveolin-1 when the caveolin-1 C-terminus was deleted (Fig.…”

“…structural and functional entity (9,10). Diverse processes such as transmembrane signal transduction (e.g.…”

Caveolin proteins and estrogen signaling in the brain

“…Surface receptors in which trafficking to the membrane has been reported to be dependent on caveolin function include, but are not limited to, the D1 dopamine receptor [46], M1 muscarinic receptor [47], angiotensin II type 1 receptor [48], and glucagon-like peptide 1 receptor [49]. Notably, caveolins also play a role in receptor endocytosis [47,[50][51][52][53][54] providing an additional regulatory mechanism to modulate cell signaling. Caveolin-dependent endocytosis is a mechanism involving internalization of membrane components within caveolae resulting in the diminution of function.…”