Role of Caveolae and Caveolins in Health and Disease

Abstract

Although they were discovered more than 50 years ago, caveolae have remained enigmatic plasmalemmal organelles. With their characteristic “flasklike” shape and virtually ubiquitous tissue distribution, these interesting structures have been implicated in a wide range of cellular functions. Similar to clathrin-coated pits, caveolae function as macromolecular vesicular transporters, while their unique lipid composition classifies them as plasma membrane lipid rafts, structures enriched in a variety of signaling molecules. The caveolin proteins (caveolin-1, -2, and -3) serve as the structural components of caveolae, while also functioning as scaffolding proteins, capable of recruiting numerous signaling molecules to caveolae, as well as regulating their activity. That so many signaling molecules and signaling cascades are regulated by an interaction with the caveolins provides a paradigm by which numerous disease processes may be affected by ablation or mutation of these proteins. Indeed, studies in caveolin-deficient mice have implicated these structures in a host of human diseases, including diabetes, cancer, cardiovascular disease, atherosclerosis, pulmonary fibrosis, and a variety of degenerative muscular dystrophies. In this review, we provide an in depth summary regarding the mechanisms by which caveolae and caveolins participate in human disease processes.

Ancient origin of reggie (flotillin), reggie-like, and other lipid-raft proteins: convergent evolution of the SPFH domain

“…For example, the three proteins neph, nephrin and podocin form microdomains in the slit diaphragm of the kidney [62]; prion proteins and other GPI-anchored proteins assemble in reggie/flotillin microdomains [6], and mechanosensory ion channels function within stomatin microdomains [63]. Even unrelated proteins such as caveolins perform comparable scaffolding functions in analogous caveolae DRM structures [64]. Interestingly, caveolins present certain structural similarities to reggies/flotillins, such as palmitoylation sites [65] and oligomers in DRM fractions [66].…”

Mechanisms of action of glucagon-like peptide 1 in the pancreas

“…A recent paper has shown evidence that GLP-1R may also undergo a caveolin-1-dependent trafficking to and from the cell membrane (Syme et al, 2006). The caveolins are a family of scaffolding proteins encoded by three genes (caveolin-1, 2, and 3) that coat caveolae (Cohen et al, 2004). Caveolae are plasmalemmal organelles, with a high lipid content, that, similar to clathrin-coated pits, function as macromolecular vesicular transporters.…”

Intracellular trafficking of nonviral vectors

“…76 This pathway is of considerable interest in particular for molecular conjugates containing pathogen-derived trafficking peptides, since many pathogens (SV40 and cholera toxin included) are thought to use the caveolar pathway to evade degradation in the lysosomes. 77 Using different sized microspheres, Rejman et al 78 showed that molecular size can dictate whether cell entry occurs by clathrin or caveolae-mediated endocytosis. Microspheres of 200 nm in diameter or less entered cells through clathrin-coated pits by a microtubule dependent pathway.…”

“…Another inhibitor of caveolae-mediated uptake, genistein, blocked internalization of 450% of 500 nm microspheres whereas 200 nm microspheres were unaffected. As caveolae are typically sized from 55 to 65 nm, 77 this inhibitory effect of anticaveolar agents on large particle uptake was somewhat surprising.…”