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PubMed1995

Reduction of caveolin and caveolae in oncogenically transformed cells.

Caveolae are flask-shaped non-clathrin-coated invaginations of the plasma membrane. In addition to the demonstrated roles for caveolae in potocytosis and transcytosis, caveolae may regulate the transduction of signals from the plasma membrane. Transformation of NIH 3T3 cells by various oncogenes leads to reductions in cellular levels of caveolin, a principal component of the protein coat of caveolae. The reduction in caveolin correlates very well with the size of colonies formed by these transformed cells when grown in soft agar. Electron microscopy reveals that caveolae are morphologically absent from these transformed cell lines. These observations suggest that functional alterations in caveolae may play a critical role in oncogenic transformation, perhaps by disrupting contact inhibition in transformed cells.

3T3 Cells↗
PubMed1996

Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae.

Endothelial nitric-oxide synthase (eNOS) generates the key signaling molecule nitric oxide in response to intralumenal hormonal and mechanical stimuli. We designed studies to determine whether eNOS is localized to plasmalemmal microdomains implicated in signal transduction called caveolae. Using immunoblot analysis, eNOS protein was detected in caveolar membrane fractions isolated from endothelial cell plasma membranes by a newly developed detergent-free method; eNOS protein was not found in noneaveolar plasma membrane. Similarly, NOS enzymatic activity was 9.4-fold enriched in caveolar membrane versus whole plasma membrane, whereas it was undetectable in non-caveolar plasma membrane. 51-86% of total NOS activity in postnuclear supernatant was recovered in plasma membrane, and 57-100% of activity in plasma membrane was recovered in caveolae. Immunoelectron microscopy showed that eNOS heavily decorated endothelial caveolae, whereas coated pits and smooth plasma membrane were devoid of gold particles. Furthermore, eNOS was targeted to caveolae in COS-7 cells transfected with wild-type eNOS cDNA. Studies with eNOS mutants revealed that both myristoylation and palmitoylation are required to target the enzyme to caveolae and that each acylation process enhances targeting by 10-fold. Thus, acylation targets eNOS to plasmalemmal caveolae. Localization to this microdomain is likely to optimize eNOS activation and the extracellular release of nitric oxide.

Acylation↗
PubMed1996

Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells.

The endothelial isoform of nitric oxide synthase (eNOS) modulates cardiac myocyte function and is expressed in the particulate subcellular fraction. We have previously shown that eNOS is targeted to plasmalemmal caveolae in endothelial cells. Caveolae, specialized domains of the plasma membrane, may serve to sequester signaling proteins; a family of transmembrane proteins, the caveolins, form a key structural component of these microdomains. Caveolae in cardiac tissues contain the muscle-specific isoform caveolin-3, and caveolae in endothelial cells contain the widely expressed isoform caveolin-1, which shares limited sequence identity with caveolin-3. Our immunohistochemical analyses of rat cardiac muscle used isoform-specific caveolin antibodies to reveal prominent caveolin-3 staining in myocyte sarcolemmal membranes and at intercalated discs, whereas caveolin-1 staining was prominent in the vascular endothelium. Caveolin or eNOS antibodies were utilized to immunoprecipitate cardiac myocyte or cultured aortic endothelial cell lysates, which then were analyzed in immunoblots. In endothelial cells, we found that eNOS is quantitatively immunoprecipitated by antibodies to caveolin-1. In cardiac myocyte lysates, nearly all the eNOS is immunoprecipitated instead by antibodies to caveolin-3 and, conversely, eNOS antiserum immunoprecipitated primarily caveolin-3. These studies establish expression of eNOS in cardiac myocyte caveolae and document tissue-specific and quantitative associations of eNOS with caveolin. These findings may have important implications for the regulation of eNOS by caveolin isoforms and by other signaling proteins targeted to caveolae.

Animals↗
PubMed1997

Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains.

Regulated signal transduction in discrete microdomains of the cell surface is an attractive hypothesis for achieving spatial and temporal specificity in signaling. A procedure for purifying caveolae separately from other similarly buoyant microdomains including those rich in glycosylphosphatidylinositol-anchored proteins has been developed (Schnitzer, J. E., McIntosh, D. P., Dvorak, A. M., Liu, J., and Oh, P. (1995) Science 269, 1435-1439) and used here to show that caveolae contain many signaling molecules including select kinases (platelet-derived growth factor (PDGF) receptors, protein kinase C, phosphatidylinositol 3-kinase, and Src-like kinases), phospholipase C, sphingomyelin, and even phosphoinositides. More importantly, two different techniques reveal that caveolae function as signal transducing subcompartments of the plasma membrane. PDGF rapidly induces phosphorylation of endothelial cell plasmalemmal proteins residing in caveolae as detected by membrane subfractionation and confocal immunofluorescence microscopy. This PDGF signaling cascade is halted when the caveolar compartment is disassembled by filipin. Finally, in vitro kinase assays show that caveolae contain most of the intrinsic tyrosine kinase activity of the plasma membrane. As signal transducing organelles, caveolae organize a distinct set of signaling molecules to permit direct regionalized signal transduction within their boundaries.

Animals↗
PubMed1998

Up-regulation of caveolae and caveolar constituents in multidrug-resistant cancer cells.

Cancer chemotherapy often results in the development of multidrug resistance (MDR), which is commonly associated with overexpression of P-glycoprotein (P-gp), a plasma membrane drug efflux ATPase. It was shown recently that glycosphingolipids are elevated in MDR cells. Sphingolipids are major constituents of caveolae and of detergent-insoluble, glycosphingolipid-rich membrane domains. Here we report that multidrug-resistant HT-29 human colon adenocarcinoma cells exhibit a 12-fold overexpression of caveolin-1, a 21-kDa coat/adaptor protein of caveolae. Similar observations were made in adriamycin-resistant MCF-7 human breast adenocarcinoma cells. Caveolin-2 expression is also up-regulated in MCF-7-AdrR cells, but neither caveolin-1 nor caveolin-2 were detected in MCF-7 cells stably transfected with P-gp. The up-regulation of caveolins is associated with a 5-fold increase in the number of caveolae-like structures observed in plasma membrane profiles of HT-29-MDR cells and with the appearance of a comparable number of caveolae in MCF-7-AdrR cells. A significant fraction (approximately 40%) of cellular P-gp is localized in low density detergent-insoluble membrane fractions derived from either HT-29-MDR or MCF-7-AdrR cells. The distribution of recombinant P-gp in stably transfected MCF-7 cells was similar, even though these cells do not express caveolins and are devoid of caveolae. The possibility that caveolae contribute to the multidrug resistance and thus are co-selected with P-gp during the acquisition of this phenotype is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

In situ flow activates endothelial nitric oxide synthase in luminal caveolae of endothelium with rapid caveolin dissociation and calmodulin association.

Acute changes in pressure or shear stress induce the rapid release of nitric oxide (NO) from the vascular endothelium resulting in vasodilation. Endothelial nitric oxide synthase (eNOS) regulates this flow-induced NO secretion. The subcellular location of flow-induced eNOS activity in the endothelium in vivo as well as the mechanisms by which hemodynamic forces regulate eNOS activity are unknown. The luminal cell surface of the endothelium, which is directly exposed to circulating blood stressors, has been examined for eNOS expression and functional activity. Immunoelectron microscopy of rat lung tissue shows eNOS labeling on the endothelial cell surface primarily within caveolae. Subcellular fractionation to purify luminal endothelial cell plasma membranes and their caveolae directly from rat lungs reveals that eNOS is not only concentrated but also enzymatically active in caveolae. Increasing vascular flow and pressure in situ rapidly activates caveolar eNOS with apparent eNOS dissociation from caveolin and association with calmodulin. Hemodynamic forces resulting from increased flow appear to transmit through caveolae to release eNOS from its inhibitory association with caveolin, apparently to allow more complete activation by calmodulin and other possible effectors. These data demonstrate a physiological relevant mechanotransduction event directly in caveolae at the luminal endothelial cell surface. Caveolae may serve as flow-sensing organelles with the necessary molecular machinery to transduce rapidly, mechanical stimuli and thereby regulate eNOS activity.

Animals↗
PubMed2000

A chimeric transmembrane domain directs endothelial nitric-oxide synthase palmitoylation and targeting to plasmalemmal caveolae.

The endothelial nitric-oxide synthase (eNOS), a key signaling protein, undergoes a series of covalent modifications, including co-translational N-myristoylation at Gly(2), as well as post-translational thiopalmitoylation at Cys(15) and Cys(26). Myristoylation of eNOS is required for the subsequent palmitoylation of the enzyme, and both acylations are required for the efficient subcellular targeting of eNOS to plasmalemmal caveolae. We constructed chimeric cDNAs encoding proteins comprised of various acylation-deficient eNOS mutants fused at their N termini to the hydrophobic transmembrane domain of the glycoprotein CD8 and characterized these constructs in transient transfection experiments in COS-7 cells. One construct (termed CD8-myr(-)eNOS) encodes a fusion protein comprised of the eNOS myristoylation-deficient mutant coupled to the CD8 transmembrane domain. In biosynthetic labeling experiments using [(3)H]palmitic acid, we found that the CD8-myr(-)eNOS chimera undergoes palmitoylation. Subcellular fractionation showed that the CD8-myr(-)eNOS chimera is targeted to caveolae. We also constructed and characterized a cDNA encoding the CD8 transmembrane domain fused to the palmitoylation-deficient mutant eNOS (in which Cys(15) and Cys(26) are changed to serine). This chimera (termed CD8-myr(-).palm(-)eNOS) did not undergo palmitoylation, indicating that the palmitoylation seen with the CD8. myr(-)eNOS fusion protein occurs on the same residues as in the wild-type enzyme. Importantly, the CD8-myr(-).palm(-)eNOS fusion protein remained efficiently targeted to caveolae, in contrast to the palm(-)eNOS mutant lacking the CD8 transmembrane domain, which has nominal caveolar localization. A construct encoding the CD8 transmembrane domain alone was insufficient for selective targeting to caveolae. These results indicate that membrane targeting per se, but not necessarily myristoylation, is sufficient for eNOS palmitoylation and localization to plasmalemmal caveolae, and suggest further that sequences within eNOS itself, in addition to its palmitoylation sites, facilitate the selective localization of the enzyme within caveolae.

Base Sequence↗
PubMed2000

Palmitoylation of caveolin-1 is required for cholesterol binding, chaperone complex formation, and rapid transport of cholesterol to caveolae.

We previously demonstrated that a caveolin-chaperone complex transports newly synthesized cholesterol from the endoplasmic reticulum through the cytoplasm to caveolae. Caveolin-1 has a 33-amino acid hydrophobic domain and three sites of palmitoylation in proximity to the hydrophobic domain. In the present study, we hypothesized that palmitoylation of caveolin-1 is necessary for binding of cholesterol, formation of a caveolin-chaperone transport complex, and rapid, direct transport of cholesterol to caveolae. To test this hypothesis, four caveolin-1 constructs were generated that substituted an alanine for a cysteine at position 133, 143, or 156 or all three sites (triple mutant). These mutated caveolins and wild type caveolin-1 were stably expressed in the lymphoid cell line, L1210-JF, which does not express caveolin-1, does not form a caveolin-chaperone complex, and does not transport newly synthesized cholesterol to caveolae. All of the caveolins were expressed and the proteins localized to plasma membrane caveolae. Wild type caveolin-1 and mutant 133 assembled into complete transport complexes and rapidly (10-20 min) transported cholesterol to caveolae. Caveolin mutants 143 and 156 did not assemble into complete transport complexes, weakly associated with cholesterol, and transported small amounts of cholesterol to caveolae. The triple mutant did not assemble into complete transport complexes and did not associate with cholesterol. We conclude that palmitoylation of caveolin-1 at positions 143 and 156 is required for cholesterol binding and transport complex formation.

Animals↗
PubMed2004

Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells.

Albumin transcytosis, a determinant of transendothelial permeability, is mediated by the release of caveolae from the plasma membrane. We addressed the role of Src phosphorylation of the GTPase dynamin-2 in the mechanism of caveolae release and albumin transport. Studies were made in microvascular endothelial cells in which the uptake of cholera toxin subunit B, a marker of caveolae, and (125)I-albumin was used to assess caveolae-mediated endocytosis. Albumin binding to the 60-kDa cell surface albumin-binding protein, gp60, induced Src activation (phosphorylation on Tyr(416)) within 1 min and resulted in Src-dependent tyrosine phosphorylation of dynamin-2, which increased its association with caveolin-1, the caveolae scaffold protein. Expression of kinase-defective Src mutant interfered with the association between dynamin-2, which caveolin-1 and prevented the uptake of albumin. Expression of non-Src-phosphorylatable dynamin (Y231F/Y597F) resulted in reduced association with caveolin-1, and in contrast to WT-dynamin-2, the mutant failed to translocate to the caveolin-rich membrane fraction. The Y231F/Y597F dynamin-2 mutant expression also resulted in impaired albumin and cholera toxin subunit B uptake and reduced transendothelial albumin transport. Thus, Src-mediated phosphorylation of dynamin-2 is an essential requirement for scission of caveolae and the resultant transendothelial transport of albumin.

Albumins↗
PubMed1993

Calcium pump of the plasma membrane is localized in caveolae.

The Ca2+ pump in the plasma membrane plays a key role in the fine control of the cytoplasmic free Ca2+ concentration. In the present study, its subcellular localization was examined with immunocytochemical techniques using a specific antibody generated against the erythrocyte membrane Ca2+ pump ATPase. By immunofluorescence microscopy of cultured cells, the labeling with the antibody was seen as numerous small dots, often distributed in linear arrays or along cell edges. Immunogold EM of cryosections revealed that the dots correspond to caveolae, or smooth invaginations of the plasma membrane. The same technique applied to mouse tissues in vivo showed that the Ca2+ pump is similarly localized in caveolae of endothelial cells, smooth muscle cells, cardiac muscle cells, epidermal keratinocytes and mesothelial cells. By quantitative analysis of the immunogold labeling, the Ca2+ pump in capillary endothelial cells and visceral smooth muscle cells was found to be concentrated 18-25-fold in the caveolar membrane compared with the noncaveolar portion of the plasma membrane. In renal tubular and small intestinal epithelial cells, which have been known to contain the Ca2+ pump but do not have many caveolae, most of the labeling was randomly distributed in the basolateral plasma membrane, although caveolae were also positively labeled. The results demonstrate that the caveolae in various cells has the plasmalemmal Ca2+ pump as a common constituent. In conjunction with our recent finding that an inositol 1,4,5-trisphosphate receptor-like protein exists in the caveolae (Fujimoto, T., S. Nakade, A. Miyawaki, K. Mikoshiba, and K. Ogawa. 1992. J. Cell Biol. 119:1507-1513), it is inferred that the smooth plasmalemmal invagination is an apparatus specialized for Ca2+ intake and extrusion from the cytoplasm.

3T3 Cells↗
PubMed1994

Regulated internalization of caveolae.

Caveolae are specialized invaginations of the plasma membrane which have been proposed to play a role in diverse cellular processes such as endocytosis and signal transduction. We have developed an assay to determine the fraction of internal versus plasma membrane caveolae. The GPI-anchored protein, alkaline phosphatase, was clustered in caveolae after antibody-induced crosslinking at low temperature and then, after various treatments, the relative amount of alkaline phosphatase on the cell surface was determined. Using this assay we were able to show a time- and temperature-dependent decrease in cell-surface alkaline phosphatase activity which was dependent on antibody-induced clustering. The decrease in cell surface alkaline phosphatase activity was greatly accelerated by the phosphatase inhibitor, okadaic acid, but not by a protein kinase C activator. Internalization of clustered alkaline phosphatase in the presence or absence of okadaic acid was blocked by cytochalasin D and by the kinase inhibitor staurosporine. Electron microscopy confirmed that okadaic acid induced removal of caveolae from the cell surface. In the presence of hypertonic medium this was followed by the redistribution of groups of caveolae to the center of the cell close to the microtubule-organizing center. This process was reversible, blocked by cytochalasin D, and the centralization of the caveolar clusters was shown to be dependent on an intact microtubule network. Although the exact mechanism of internalization remains unknown, the results show that caveolae are dynamic structures which can be internalized into the cell. This process may be regulated by kinase activity and require an intact actin network.

Alkaline Phosphatase↗
PubMed1994

Filipin-sensitive caveolae-mediated transport in endothelium: reduced transcytosis, scavenger endocytosis, and capillary permeability of select macromolecules.

Caveolae or noncoated plasmalemmal vesicles found in a variety of cells have been implicated in a number of important cellular functions including endocytosis, transcytosis, and potocytosis. Their function in transport across endothelium has been especially controversial, at least in part because there has not been any way to selectively inhibit this putative pathway. We now show that the ability of sterol binding agents such as filipin to disassemble endothelial noncoated but not coated plasmalemmal vesicles selectively inhibits caveolae-mediated intracellular and transcellular transport of select macromolecules in endothelium. Filipin significantly reduces the transcellular transport of insulin and albumin across cultured endothelial cell monolayers. Rat lung microvascular permeability to albumin in situ is significantly decreased after filipin perfusion. Conversely, paracellular transport of the small solute inulin is not inhibited in vitro or in situ. In addition, we show that caveolae mediate the scavenger endocytosis of conformationally modified albumins for delivery to endosomes and lysosomes for degradation. This intracellular transport is inhibited by filipin both in vitro and in situ. Other sterol binding agents including nystatin and digitonin also inhibit this degradative process. Conversely, the endocytosis and degradation of activated alpha 2-macroglobulin, a known ligand of the clathrin-dependent pathway, is not affected. Interestingly, filipin appears to inhibit insulin uptake by endothelium for transcytosis, a caveolae-mediated process, but not endocytosis for degradation, apparently mediated by the clathrin-coated pathway. Such selective inhibition of caveolae not only provides critical evidence for the role of caveolae in the intracellular and transcellular transport of select macromolecules in endothelium but also may be useful for distinguishing transport mediated by coated versus noncoated vesicles.

Animals↗
PubMed1995

Hormonal regulation of caveolae internalization.

Caveolae undergo a cyclic transition from a flat segment of membrane to a vesicle that then returns to the cell surface. Here we present evidence that this cycle depends on a population of protein kinase C-alpha (PKC-alpha) molecules that reside in the caveolae membrane where they phosphorylate a 90-kD protein. This cycle can be interrupted by treatment of the cells with phorbol-12,13-dibutyrate or agents that raise the concentration of diacylglycerol in the cell. Each of these conditions displaces PKC-alpha from caveolae, inhibits the phosphorylation of the 90-kD protein, and prevents internalization. Caveolae also contain a protein phosphatase that dephosphorylates the 90-kD once PKC-alpha is gone. A similar dissociation of PKC-alpha from caveolae and inhibition of invagination was observed when cells were treated with histamine. This effect was blocked by pyrilamine but not cimetidine, indicating the involvement of histamine H1 receptors. These findings suggest that the caveolae internalization cycle is hormonally regulated.

Aluminum Compounds↗
PubMed1998

Targeting of protein kinase Calpha to caveolae.

Previously, we showed caveolae contain a population of protein kinase Calpha (PKCalpha) that appears to regulate membrane invagination. We now report that multiple PKC isoenzymes are enriched in caveolae of unstimulated fibroblasts. To understand the mechanism of PKC targeting, we prepared caveolae lacking PKCalpha and measured the interaction of recombinant PKCalpha with these membranes. PKCalpha bound with high affinity and specificity to caveolae membranes. Binding was calcium dependent, did not require the addition of factors that activate the enzyme, and involved the regulatory domain of the molecule. A 68-kD PKCalpha-binding protein identified as sdr (serum deprivation response) was isolated by interaction cloning and localized to caveolae. Antibodies against sdr inhibited PKCalpha binding. A 100-amino acid sequence from the middle of sdr competitively blocked PKCalpha binding while flanking sequences were inactive. Caveolae appear to be a membrane site where PKC enzymes are organized to carry out essential regulatory functions as well as to modulate signal transduction at the cell surface.

Amino Acid Sequence↗
PubMed2004

Caveolin-1 and caveolae in atherosclerosis: differential roles in fatty streak formation and neointimal hyperplasia.

PURPOSE OF REVIEW: Caveolae are 50-100 nm cell surface plasma membrane invaginations observed in terminally differentiated cells. They are characterized by the presence of the protein marker caveolin-1. Caveolae and caveolin-1 are present in almost every cell type that has been implicated in the development of an atheroma. These include endothelial cells, macrophages, and smooth muscle cells. Caveolae and caveolin-1 are involved in regulating several signal transduction pathways and processes that play an important role in atherosclerosis. RECENT FINDINGS: Several recent studies using genetically engineered mice (Cav-1 (-/-) null animals) have now clearly demonstrated a role for caveolin-1 and caveolae in the development of atherosclerosis. In fact, they suggest a rather complex one, either proatherogenic or antiatherogenic, depending on the cell type examined. For example, in endothelial cells, caveolin-1 and caveolae may play a proatherogenic role by promoting the transcytosis of LDL-cholesterol particles from the blood to the sub-endothelial space. In contrast, in smooth muscle cells, the ability of caveolin-1 to negatively regulate cell proliferation (neointimal hyperplasia) may have an antiatherogenic effect. SUMMARY: Caveolin-1 and caveolae play an important role in several steps involved in the initiation of an atheroma. Development of new drugs that regulate caveolin-1 expression may be important in the prevention or treatment of atherosclerotic vascular disease.

Animals↗
PubMed1999

Caveolae require intact VAMP for targeted transport in vascular endothelium.

Caveolae appear to function in vesicular trafficking of specific molecular cargo into and across vascular endothelial and other cells. They contain the molecular machinery for docking and fusion, similar to other vesicular trafficking systems, yet the mechanisms mediating ligand internalization and targeted intracellular transport by caveolae remain unclear. Using immunoelectron microscopy, we show that caveolae in the microvascular endothelium of rat lung express vesicle-associated membrane protein (VAMP)-2 (also called synaptobrevin) on their cytoplasmic surface. Immunofluorescence studies of cholera toxin B (CTB)-FITC internalization in toxin-treated cells demonstrate that intact VAMP-2 is necessary for the efficient trafficking of caveolar ligands. The CTB subunit binds preferentially to GM1 in caveolae, and N-ethylmaleimide treatment drastically inhibits the intracellular accumulation of CTB. The cleavage of caveolar VAMP-2 with VAMP-specific neurotoxins (botulinum D and F but not A) significantly inhibits CTB endocytosis and targeted intracellular accumulation in cultured endothelial cells. This impairment of caveolae-mediated trafficking provides evidence that caveolae require intact VAMP-2 for efficient targeted delivery via vesicle docking with target organelles.

Animals↗
PubMed1993

Rat atrial myocyte plasmalemmal caveolae in situ. Reversible experimental increases in caveolar size and in surface density of caveolar necks.

The structure, size, and surface density of the conspicuous flask-shaped structures called caveolae that are located under the plasma membrane of cardiac myocytes in intact rat atria were studied by electron microscopy after physiological perturbations designed to examine whether caveolae and/or their necks are fixed or mobile and whether the caveolar lumen is always open or can close off from the interstitial space. We showed that, in stretched and unstretched atria, horseradish peroxidase could enter or be washed out of caveolae at 37 degrees, 18 degrees, and 4 degrees C, but this finding does not rule out that caveolae and/or their necks can cycle rapidly between states closed and open to the interstitial space. Electron microscopy of thin sections revealed that exposure of atria at 37 degrees or 18 degrees C to physiological salt solutions made hypertonic by adding 150 mM sucrose or mannitol resulted in a striking enlargement of caveolar profiles within 1 to 5 minutes. Caveolar enlargement was rapidly reversible on return to control saline. After freeze fracture of atria exposed to these hypertonic solutions, quantitative analysis of electron micrographs of the fracture faces revealed statistically significant increases in cross-sectional diameter of cross-fractured caveolar necks and in mean number of caveolar necks penetrating per unit area of plasmalemmal fracture face. These results suggest that atrial myocyte caveolae are dynamic structures whose necks may be reversibly inserted into and withdrawn from the plasmalemma, possibly (but not necessarily) corresponding to states in which caveolae are, respectively, open and closed to the interstitial spaces.

Animals↗
PubMedDate not supplied

[Caveolae membrane domains, specialized transmembrane exchange zones implicated in cell signalling].

Caveolae are small pockets or invaginations localized at the plasma membrane. They are enriched in glycosphingolipids, cholesterol, sphingomyelin and lipid-enchored membrane proteins, and they are characterized by a light buoyant density and resistance to solubilization by Triton X-100 at 4 C. Caveolins are the principal protein components of caveolae and play an important structural role in the formation of caveolae membranes. Numerous molecules involved in cell signalling have been identified in caveolae, suggesting that these structures may serve to compartimentalize, modulate and integrate signalling events at the cell surface. Depletion of membrane cholesterol disrupts the formation and function of caveolae, suggesting that these membrane microdomains are involved in a range of biological processes. Moreover, exposure of endothelial cells to high levels of cholesterol upregulates the caveolin abundance in caveolae, and decreases nitric oxide synthesis, suggesting that this may be an early event in atherogenesis. Alteration in the expression of caveolin genes has also been implicated in human diseases such as cancers, diabetes, Alzheimer's disease and muscular distrophy.

Caveolin 1↗