Caveolinopathies: From the biology of caveolin-3 to human diseases

European journal of human genetics: EJHG (Impact Factor: 4.35). 12/2009; 17(12):1692. DOI: 10.1038/ejhg.2009.147
Source: PubMed


In muscle tissue the protein caveolin-3 forms caveolae – flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with caveolin-3 mutations.

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Available from: Claudio Bruno, Mar 12, 2014
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    • "In humans, the majority of caveolinopathies often refers to a wide spectrum of skeletal muscle disorders [19,46] and only recently mutations in caveolin-3 were associated to cardiac pathologies including LQTS and SIDS [12,13] and cardiomyopayhies [14,15]. Several mechanisms have been proposed for the skeletal muscle degenerative processes, whereas the molecular bases for the cardiac phenotypes are largely unknown [14,19,46]. "
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    ABSTRACT: Background Sudden cardiac death (SCD) is the clinical outcome of a lethal arrhythmia that can develop on the background of unrecognized channelopathies or cardiomyopathies. Several susceptibility genes have been identified for the congenital forms of these cardiac diseases, including caveolin-3 (Cav-3) gene. In the heart Cav-3 is the main component of caveolae, plasma membrane domains that regulate multiple cellular processes highly relevant for cardiac excitability, such as trafficking, calcium homeostasis, signal transduction and cellular response to injury. Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD. Results In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells. Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress. Conclusion Considering that abnormal loss of myocytes can play a mechanistic role in lethal cardiac diseases, we suggest that the detrimental effect of Cav-3 V82I variant on cell viability may participate in determining the susceptibility to cardiac death.
    Journal of Biomedical Science 06/2014; 21(1):58. DOI:10.1186/1423-0127-21-58 · 2.76 Impact Factor
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    • "Cav3 helps stabilize the curvature of the domain, and acts as scaffolding for association of numerous signaling and cytoskeletal adaptor proteins [22], [23]. Mutations of Cav3 can lead to Limb Girdle muscular dystrophy type 1C and other muscle pathologies [24], [25]. Most caveolinopathies are marked by a reduced Cav3 surface expression due to sequestration of the protein in the Golgi. "
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    ABSTRACT: Mutations that lead to muscular dystrophy often create deficiencies in cytoskeletal support of the muscle sarcolemma causing hyperactive mechanosensitive cation channel (MSC) activity and elevated intracellular Ca(2+). Caveolae are cholesterol-rich microdomains that form mechanically deformable invaginations of the sarcolemma. Mutations to caveolin-3, the main scaffolding protein of caveolae in muscle, cause Limbe-Girdle muscular dystrophy. Using genetic and acute chemical perturbations of developing myotubes we investigated whether caveolae are functionally linked to MSCs. MSC sensitivity was assayed using suction application to patches and probe-induced indentation during whole-cell recordings. Membrane mechanical stress in patches was monitored using patch capacitance/impedance. Cholesterol depletion disrupted caveolae and caused a large increase in MSC current. It also decreased the membrane mechanical relaxation time, likely reflecting cytoskeleton dissociation from the bilayer. Reduction of Cav3 expression with miRNA also increased MSC current and decreased patch relaxation time. In contrast Cav3 overexpression produced a small decrease in MSC currents. To acutely and specifically inhibit Cav3 interactions, we made a chimeric peptide containing the antennapedia membrane translocation domain and the Cav3 scaffolding domain (A-CSD3). A-CSD3 action was time dependent initially producing a mild Ca(2+) leak and increased MSC current, while longer exposures decreased MSC currents coinciding with increased patch stiffening. Images of GFP labeled Cav3 in patches showed that Cav3 doesn't enter the pipette, showing patch composition differed from the cell surface. However, disruption via cholesterol depletion caused Cav3 to become uniformly distributed over the sarcolemma and Cav3 appearance in the patch dome. The whole-cell indentation currents elicited under the different caveolae modifying conditions mirror the patch response supporting the role of caveolae in MSC function. These studies show that normal expression levels of Cav3 are mechanoprotective to the sarcolemma through multiple mechanisms, and Cav3 upregulation observed in some dystrophies may compensate for other mechanical deficiencies.
    PLoS ONE 08/2013; 8(8):e72894. DOI:10.1371/journal.pone.0072894 · 3.23 Impact Factor
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    • "All caveolins form an hairpin structure that crosses the plasma membrane with the N-and C-terminus domain of the protein facing the cytoplasm. Caveolins are usually found in the majority of mammalian adherent cells, where CAV1 and -2 are mainly expressed in endothelial cells (EC) and adipocytes [Hansen and Nichols, 2010]while CAV3 is referred to as muscle specific, being restricted to skeletal, smooth and cardiac muscle [Gazzerro et al., 2010]. The ability of CAV1 to form homooligomers and heterooligomers with CAV2, typically in the endoplasmic reticulum (ER), and their high affinity for cholesterol and glycosphingolipids are crucial for the insertion of the protein into the plasma membrane and for the formation of flask-like invaginations called caveolae [Sengupta, 2012; Thiele et al., 2000], small non-clathrin coated invaginations found in many cell types [Parton and Simons, 2007]. "
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    ABSTRACT: Caveolin-1 (CAV1) is the principal structural component of caveolae which functions as scaffolding protein for the integration of a variety of signaling pathways. In this study, we investigated the involvement of CAV1 in endothelial cell functions and show that siRNA-induced CAV1 silencing in the human EC line EA.hy926 induces distinctive morphological changes, such as a marked increase in cell size and formation of stress fibers. Design-based stereology was employed in this work to make unbiased quantification of morphometric properties such as volume, length and surface of CAV1 silenced vs. control cells. In addition, we showed that down regulation CAV1 affects cell cycle progression at G1/S phase transition most likely by perturbation of AKT signaling. With the aim to assess the contribution of CAV1 to typical biological processes of EC, we report here that CAV1 targeting affected cell migration and matrix metalloproteinases (MMPs) activity, and reduced angiogenesis in response to VEGF, in vitro. Taken together our data suggest that the proper expression of CAV1 is important not only for maintaining the appropriate morphology and size of endothelial cells but it might represent a prospective molecular target for studying key biological mechanisms such as senescence and tumorigenesis. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24526 · 3.26 Impact Factor
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