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Caveolin-3 and Limb-Girdle Muscular Dystrophy

and .

Caveolin-3 is the principal structural protein component of caveolae membrane domains in skeletal muscle cells. Caveolae are plasma membrane invaginations implicated in the regulation of signal transduction events. The roles that caveolin-3 plays in skeletal muscle cell physiology are becoming more apparent. Several mutations within the human caveolin-3 gene have been identified over the last few years. These mutations are responsible for different forms of muscle diseases, including limb-girdle muscular dystrophy type 1C (LGMD-1C), hyperCKemia (HCK), distal myopathy (DM), and rippling muscle disease (RMD). In this chapter, we will discuss the functional significance of these caveolin-3 mutations in humans.

Caveolae and Caveolins

Caveolae are 50-100 nm flask-shaped invaginations of the plasma membrane (fig. 1). Caveolin is the principal protein component of caveolae membranes in vivo.1-3 The caveolin gene family consists of three members, namely caveolin-1, -2, and -3. Caveolin-1 and caveolin-2 contribute to the formation of caveolae in many cell types. Caveolin-3 is the only caveolin family member that is expressed in striated muscle cell types (i.e., skeletal muscle and heart). Several independent investigations have demonstrated that caveolins play a crucial role in cell signaling—by acting as scaffolding proteins to concentrate, organize, and functionally modulate signaling molecules.4-7 These molecules include H-Ras, Src-like tyrosine kinases, nitric oxide synthase (NOS) isoforms, hetero-trimeric G-proteins, protein kinase A (PKA), protein kinase C (PKC), and components of the p42-44 mitogen activated protein (MAP) kinase pathway.8-24

Figure 1. Caveolae in skeletal muscle fibers.

Figure 1

Caveolae in skeletal muscle fibers. Transmission electron micrographs of skeletal muscle tissue from normal (Cav-3 +/+) and caveolin-3 null (Cav-3 -/-) mice. Note the presence of flask-shaped invaginations at the plasma membrane of normal skeletal muscle (more...)

Functional Roles of Caveolin-3 in Skeletal Muscle Fibers

Caveolin-3 is not expressed in undifferentiated myoblasts, but only in differentiated multinucleated myotubes in vitro.25 In myotubes, caveolin-3 is localized at the plasma membrane25 (fig. 2). Consistent with this data, caveolin-3 was found at the sarcolemma (skeletal muscle cell plasma membrane) in mature skeletal muscle tissue in vivo26,27 (fig. 2). Interestingly, caveolin-3 was observed in T-tubules during the differentiation of myoblasts in culture and during skeletal muscle development in mice.28 These results suggest that caveolin-3 may have a role in the formation of the T-tubule system during muscle development. In support of this hypothesis, Lisanti, Galbiati and colleagues have demonstrated that caveolin-3 (-/-) null mice, which do not express caveolin-3, show T-tubule abnormalities.27 Thus, it appears that caveolin-3 localization changes during muscle formation: caveolin-3 is localized mainly within T-tubules in developing muscle, while it is found primarily at the sarcolemma in adult mature skeletal muscle.

Figure 2. Caveolin-3 is expressed at the sarcolemma of skeletal muscle cells, both in vivo and in vitro.

Figure 2

Caveolin-3 is expressed at the sarcolemma of skeletal muscle cells, both in vivo and in vitro. Caveolin-3 localization was assessed in skeletal muscle tissue from normal mice by immunolfuorescence analysis using an antibody probe specific for caveolin-3 (more...)

Caveolin-3 interacts with a number of signaling molecules at the plasma membrane of skeletal muscle cells. For example, c-Src, Src-like kinases (Lyn), and hetero-trimeric G-proteins were found to be associated with caveolae membranes in C2C12 cells, a myoblast cell line,29 suggesting that caveolin-3 may functionally modulate Src- and G-protein-mediated signaling pathways.

There are a number of lines of evidence suggesting that caveolin-3 may also play a role in the regulation of energy metabolism in skeletal muscle fibers. In fact, caveolin-3 was shown to interact with phosphofructokinase-M (PFK-M; M, muscle-specific isoform) in C2C12 cells.30 PFK-M is a key regulatory enzyme in the glycolytic pathway within skeletal muscle. In addition, the interaction between caveolin-3 and PFK-M was positively modulated by extracellular glucose and stabilized by activators of PFK-M.30

Glucose uptake is essential for normal muscle functioning. Interestingly, caveolin-3 was able to stimulate the phosphorylation of IRS-1, a downstream regulator of the insulin receptor, if coexpressed with the insulin receptor itself.31 In support of a possible role for caveolae in mediating insulin signaling, the ligand-bound insulin receptor was localized to plasma membrane caveolae by electron microscopy in adipocytes32.

Neuronal nitric oxide synthase (nNOS) mediates nitric oxide production in skeletal muscle cells. Caveolin-3 has been demonstrated to directly interact with nNOS in vitro.33,34 Interaction with caveolin-3 resulted in the inhibition of nNOS enzymatic activity.33,34 Thus, it appears that caveolin-3 may functionally regulate nitric oxide-dependent functions in muscle tissue. Consistent with these data, Galbiati and colleagues have shown that the transgenic overexpression of caveolin-3 in the heart results in the inhibition of NOS activity in vivo.35 These authors demonstrated that the increased interaction between caveolin-3 and both endothelial NOS (eNOS), and nNOS, in the hearts of caveolin-3 transgenic mice, represents a valid molecular explanation for the described NOS inhibition.35

Dystrophin and its associated glycoproteins, such as dystroglycans and sarcoglycans, form the “dystrophin complex” in skeletal muscle cells (fig. 3). The major role of this complex is to act as a link between the extracellular matrix and intracellular cytoskeletal elements. Several independent investigations have shown that caveolin-3 participates in the organization of the dystrophin complex in muscle. For example, dystrophin, α-sarcoglycan, and β-dystroglycan were found within caveolae membranes in differentiated C2C12 cells.29 Consistent with this data, dystrophin coimmunoprecipitated and coimmunolocalized with caveolin-3 in differentiated C2C12 cells.29 In addition, dystrophin was localized to caveolae membranes in smooth muscle cells by immunoelectron microscopy.36 These data indicate that caveolin-3 is dystrophin-associated, although the biogenesis of the dystrophin complex does not absolutely require caveolin-3. In fact, caveolin-3 can be physically separated from the dystrophin complex under certain conditions.37

Figure 3. The dystrophin glycoprotein complex (DGC) and associated proteins at the muscle cell plasma membrane.

Figure 3

The dystrophin glycoprotein complex (DGC) and associated proteins at the muscle cell plasma membrane. The dystrophin glycoprotein complex links the extracellular matrix to cytoskeletal elements. β-dystroglycan is the only component of the DGC (more...)

Interestingly, dystrophin and its associated glycoproteins are dramatically reduced in transgenic mice over-expressing caveolin-3, which show a Duchenne-like muscular dystrophy phenotype.26 The virtual absence of the dystrophin complex from skeletal muscle tissue of caveolin-3 transgenic mice may be explained by considering that the WW-like domain of caveolin-3 binds the PPXY sequence at the C-terminus of β-dystroglycan, which is the same binding site recognized by the WW domain of dystrophin.38(fig. 3). As dystrophin is anchored to the plasma membrane through direct binding to β-dystroglycan, over-expression of caveolin-3 may competitively displace dystrophin from the plasma membrane and promote, as a consequence, its degradation.


Caveolinopathies are a class of muscle diseases associated with mutations in the human caveolin-3 gene. They include hyperCKemia (HCK), distal myopathy (DM), rippling muscle disease (RMD), and limb-girdle muscular dystrophy type 1C (LGMD-1C) (Table 1).

Table 1. Caveolin-3 Mutations in Caveolinopathies.

Table 1

Caveolin-3 Mutations in Caveolinopathies.



Creatine kinase (CK) is a cytosolic enzyme. Upon muscle injury (either lysis or necrosis), the enzyme is released into the blood. As a consequence, elevated CK levels in the blood are an indication of myopathy. Minetti, Lisanti and colleagues have reported a mutation in the caveolin-3 gene in two unrelated children with persistent elevated blood levels of creatine kinase.39 These patients did not show muscle weakness or other symptoms of myopathy. Sequence analysis of the caveolin-3 gene indicated a substitution of a glutamine for an arginine at amino acid position 26 (R26Q). The expression of caveolin-3 was only partially reduced in the two children. Heterologous expression of the R26Q caveolin-3 mutant (Cav-3 R26Q) in culture indicated that Cav-3 R26Q is expressed at significantly lower levels as compared with wild-type caveolin-3, and is retained at the level of the Golgi complex.40 However, Cav-3 R26Q did not behave in a dominant negative fashion when coexpressed with wild-type caveolin-3. These results may explain the partial reduction of caveolin-3 expression in the muscle biopsies of these two patients.


More recently, a novel mutation in the caveolin-3 gene was described in two patients (mother and son) with isolated elevated CK levels, but without muscle symptoms.41 Genetic analysis revealed a proline to leucine substitution at amino acid position 28 (P28L), the first caveolin-3 mutation associated with isolated familial hyperCKemia. Muscle biopsies from these two patients indicated a reduced caveolin-3 membrane association. This phenotype appears similar to that observed in patients with the caveolin-3 R26Q mutation.

Thus, these results suggest that caveolin-3 expression should be evaluated in the differential diagnosis of isolated hyperCKemia.

Distal Myopathy

The same substitution of a glutamine for an arginine at amino acid position 26 (R26Q) in the caveolin-3 gene was described in one patient with sporadic distal myopathy. In this patient, muscle atrophy was restricted to the small muscles of the hands and feet.42 Caveolin-3 expression was reduced in these muscle fibers, as demonstrated by immunohistochemistry and Western blotting analysis. These data are indicative of the clinical heterogeneity of myopathies with mutations in the caveolin-3 gene.

Rippling Muscle Disease

Rippling muscle disease is a muscle disorder characterized by involuntary, mechanically induced contractions of skeletal muscle. Interestingly, three different groups reported the caveolin-3 R26Q mutation in patients with rippling muscle disease.43-45 These patients are representative of both autosomal dominant and sporadic cases. Caveolin-3 expression is reduced in the skeletal muscle of these patients. Interestingly, Schroder and colleagues have shown that the Cav-3 R26Q mutation gives rise to 3 different disease phenotypes—rippling muscle disease, distal myopathy, and limb girdle muscular dystrophy—all within the same family 44

The caveolin-3 R26Q mutation is not the only one associated with rippling muscle disease. Additional mutations within the human caveolin-3 gene have been shown to cause RMD by Kubisch and colleagues. More precisely, the caveolin-3 A45T and P104L mutations were found in three families with rippling muscle disease.43 Moreover, the same authors described the caveolin-3 A45V and A45T mutations in two additional families with RMD. All these mutants were expressed at lower levels at the plasma membrane, compared to wild type caveolin-3, if transfected into C2C12 cells.

Vorgered and colleagues have reported two novel homozygous mutations in the caveolin-3 gene (L86P and A92T) in two unrelated patients with an unusually severe form of RMD.46 Immunohistochemical and immunoblot analysis of muscle biopsies from these patients revealed a severe reduction of caveolin-3 expression. Caveolae were almost completely absent from the sarcolemma, as demonstrated by electron microscopy.

Caveolin-3 Mutations in LGMD-1C

Limb-girdle muscular dystrophies are a genetically heterogeneous group of disorders. They are characterized by weakness affecting the pelvic and shoulder girdle musculature. The diagnostic criteria include elevated CK, proximal muscular dystrophy, and, in many cases, cardiomyopathy. LGMDs range from severe forms with early onset and rapid progression, to milder forms with later onset and slower progression (see Chapter 8).

The inheritance of LGMDs may be autosomal dominant (LGMD-1) or recessive (LGMD-2). To date, at least sixteen LGMD genes have been mapped. Six of them are autosomal dominant (LGMD-1A→F), and ten autosomal recessive (LGMD-2A→J). Many of the LGMD genes have been identified and cloned (See chapter 8). Among them, LGMD-1C is caused by a number of mutations in the human caveolin-3 gene. These mutations include the following amino acid substitutions: P104L, ΔTFT/63-65 (deletion of amino acids 63 to 65), A45T, T63P, and R26Q (fig. 4 and Table 1).

Figure 4. Schematic diagram summarizing Cav-3 gene mutations associated with Limb-girdle Muscular Dystrophy in humans.

Figure 4

Schematic diagram summarizing Cav-3 gene mutations associated with Limb-girdle Muscular Dystrophy in humans. Four point mutations (R26Q, A45T, T63P, and P104L) and one deletion (ΔTFT, deletion of amino acids 63-65) have been described in LGMD-1C (more...)

P104L and ΔTFT/63-65

The first mutations in the caveolin-3 gene were reported by Minetti, Sotgia, Lisanti, and colleagues in 1998.47 They demonstrated that autosomal dominant limb-girdle muscular dystrophy (termed LGMD-1C) was due to i) a missense mutation within the membrane spanning domain (P104L), and ii) a 9-base pair microdeletion that removes three amino acids within the caveolin scaffolding domain (ΔTFT/63-65). Patients with LGMD-1C displayed ~95% reduction of caveolin-3 protein expression. In contrast, the expression of dystrophin and dystrophin-associated glycoproteins was not affected by the loss of caveolin-3 expression. Calf hypertrophy and mild-to-moderate proximal muscle weakness were the clinical features of these patients.

A molecular characterization was then performed in vitro by Lisanti, Galbiati and colleagues. They over-expressed caveolin-3 P104L (Cav-3 P/L) and ΔTFT/63-65 (Cav-3 ΔTFT) in NIH 3T3 cells and demonstrated that these mutants are expressed at lower levels, as compared with wild- type caveolin-3, and undergo degradation through a proteasome-dependent pathway.48,49 In addition, they showed that Cav-3 P/L and Cav-3 ΔTFT are retained at the level of the Golgi complex (fig. 5) and behave in a dominant negative fashion, causing the degradation, and retention at the Golgi complex, of wild-type caveolin-3 as well.48,49 Interestingly, treatment with proteosomal inhibitors prevented the degradation of LGMD-1C mutants, although they did not reach the plasma membrane. Importantly, proteasomal inhibitor treatment rescued wild-type caveolin-3 when coexpressed with LGMD-1C mutants of caveolin-3. In fact, wild-type caveolin-3 was not degraded and reached the plasma membrane.48,49 Thus, these results have direct clinical implications for treatment of patients with LGMD-1C.

Figure 5. Caveolin-3 mutants are retained intracellularly in L6 skeletal muscle myoblasts.

Figure 5

Caveolin-3 mutants are retained intracellularly in L6 skeletal muscle myoblasts. L6 cells were transiently transfected with Cav-3 (WT), Cav-3 (R26Q), Cav-3 (P104L), or Cav-3 (ΔTFT [63-65]). Thirty-six hours after transfection, cells were immunostained (more...)


Voit and colleagues have shown a heterozygous 136G→A substitution in the caveolin-3 gene in a 4-year-old girl with limb girdle muscular dystrophy type 1C.50 The patient presented with myalgia and muscle cramps in her dystrophic skeletal muscle. The sporadic missense mutation resulted in an alanine to threonine substitution at amino acid position 45 (A45T). Caveolin-3 expression at the sarcolemma was dramatically reduced in this LGMD-1C patient, suggesting a dominant-negative effect of the mutant on wild-type caveolin-3.50

As caveolin-3 participates in the organization of the dystrophin complex, the authors examined the expression of dystrophin and its associated glycoproteins. They demonstrated that the expression of α-dystroglycan was almost completely lost in the skeletal muscle of the LGMD-1C patient.50 In contrast, the expression of β-dystroglycan, α-, β-, γ-, δ-sarcoglycan, dystrophin, and α2-laminin was normal.50

nNOS has been shown to directly interact with caveolin-3 in vitro.33,34 Thus, these authors asked whether the expression of nNOS was affected by the near complete loss of caveolin-3 in the LGMD-1C patient. They demonstrated that nNOS expression is dramatically reduced in the Cav-3 A45T-expressing muscle, suggesting that alterations of nitric oxide production may represent a possible molecular explanation for the muscle disease observed in this patient.50


The novel missense mutation T63P has been described by Brown and colleagues in an eleven-year-old Japanese girl.51 The patient had proximal muscle weakness, exercise-induced myalgia, and mildly elevated CK levels. In addition, muscle biopsy revealed a marked variation in the diameter of muscle fibers, necrotic and degenerating fibers.51 In addition, they observed an increased number of fibers with central nuclei, which is indicative of muscle regeneration.51 Caveolin-3 expression was significantly reduced, but not absent, in this patient. Interestingly, the authors reported that dysferlin, a surface membrane protein whose deficiency results in LGMD-2B, is mislocalized in the skeletal muscle tissue of the Cav-3 T63P patient. More precisely, although the total protein expression is unaffected, dysferlin displayed a patchy staining with some cytoplasmic localization.51 In contrast, dystrophin and α-sarcoglycan immunostaining was normal. Interestingly, they also demonstrated that caveolin-3 coimmunoprecipitated with dysferlin in normal skeletal muscle tissue.51 Thus, these data suggest that caveolin-3 may play a role in the anchoring of dysferlin to the plasma membrane, and that reduced caveolin-3 expression may result in a weaker association of dysferlin to the sarcolemma (see chapter 8).


As discussed above, the R26Q substitution was reported in patients with hyperCKemia, distal myopathy, and rippling muscle disease. However, the Cav-3 R26Q mutation was also described in patients with limb-girdle muscular dystrophy. Pellissier and colleagues reported a 71-year-old woman with LGMD associated with a R26Q mutation in the caveolin-3 gene.52 Caveolin-3 expression was reduced at the plasma membrane of skeletal muscle tissue from this patient. A similar reduction of caveolin-3 expression was reported by Brown and colleagues in skeletal muscle tissue from a LGMD patient with an R26Q substitution.51 Thus, it appears that the arginine to glutamine substitution at amino acid position 26 within the human caveolin-3 gene can lead to various clinical phenotypes, including HCK, DM, RMD, and LGMD-1C. As described earlier in this chapter, the R26Q mutation was also found in HCK, DM, RMD, and LGMD-1C patients-all within the same family.44

Mouse Models of LGMD-1C

Caveolin-3 P104L Transgenic Mice

The first mouse model of LGMD-1C was generated by Shimizu and colleagues (Table 2). These authors expressed the Cav-3 P104L mutant in mouse skeletal muscle tissue as a transgene.53 As previously discussed, the P104L mutation is one of the first two mutations described within the caveolin-3 gene in LGMD patients. Caveolin-3 is virtually absent from the sarcolemma of Cav-3 P104L transgenic mice.53 This is consistent with the autosominal dominant form of genetic transmission of the Cav-3 P104L mutation in humans,47 and the dominant-negative effect that this mutant form exercises on wild-type caveolin-3.48 Transgenic mice expressing mutant caveolin-3 showed a myopathic phenotype resembling LGMD-1C in humans.53 However, the muscle damage was much more severe in caveolin-3 P104L transgenic mice, as compared with LGMD-1C patients. Given the fact that the Cav-3 P104L mutant promotes the degradation of wild-type caveolin-3, this discrepancy may be explained considering that additional signaling molecules that directly interact with caveolin-3 may undergo degradation in the skeletal muscle of Cav-3 P104L transgenic mice.

Table 2. Mouse models of LGMD-1C.

Table 2

Mouse models of LGMD-1C.

The authors also evaluated the effect of the Cav-3 P104L mutant on the dystrophin complex. They showed that both dystrophin and β-dystroglycan protein expression in skeletal muscle is unchanged in these transgenic mice, as assessed by Western blotting analysis.53 This result is consistent with the observations of Minetti, Lisanti and colleagues in LGMD patients with the P104L mutation.47 Interestingly, nNOS activity was significantly increased in skeletal muscle tissue expressing the caveolin-3 mutant.53 This data is supported by the previously reported ability of caveolin-3 to inhibit nNOS activity in vitro.33,34 Thus, it is possible to speculate that elevated nNOS activity may explain, at least in part, the myopathic phenotype observed in the muscle of Cav-3 P104L transgenic mice.

Caveolin-3 (-/-) Null Mice

LGMD-1C mutations within the caveolin-3 gene, with the exception of the R26Q substitution, induce a dramatic reduction of total caveolin-3 protein expression in the skeletal muscles of LGMD-1C patients. For this reason, caveolin-3 (-/-) null mice, which do not express caveolin-3 in skeletal muscle tissue, represent a valid mouse model for studying this form of muscular dystrophy. Lisanti, Galbiati and colleagues have generated caveolin-3 null mice and demonstrated that a lack of caveolin-3 induces a mild muscle myopathy27(Table 2). Interestingly, this data is consistent with the relative weak dystrophic phenotype observed in patients with LGMD-1C.47 In addition, as observed in LGMD-1C patients,47 the expression of dystrophin, α-sarcoglycan, and β-dystroglycan is not affected by the loss of caveolin-3,27 However, these proteins are excluded from cholesterol-enriched plasma membrane microdomains, termed lipid rafts.27 It is possible to speculate that such mislocalization may contribute to the dystrophic phenotype observed in caveolin-3 null mice.

As discussed earlier, caveolin-3 has been proposed to mediate the development of the T-tubule system. A number of experimental observations indicate that the T-tubule system is altered in caveolin-3 null mice. Dihydropyridine receptor-1α and ryanodine receptor, two markers of the T-tubules system, were mislocalized in caveolin-3 null mice, as demonstrated by immunofluorescence analysis.27 In addition, T-tubules were specifically stained with potassium ferrocyanate and visualized by electron microscopy. T-tubules appeared dilated, swollen, and ran in irregular directions in skeletal muscle tissue of caveolin-3 null mice, in contrast to an orderly transverse orientation in normal control wild-type muscle.27

Consistent with this data, disorganization of the T-tubule system was reported in skeletal muscle biopsies from LGMD-1C patients.54 T-tubules play a key role in skeletal muscle functioning, as they participate in the signaling events that lead to muscle contraction. Thus, the alteration of the T-tubule system may partially explain the muscle weakness reported in LGMD-1C patients.47

The dystrophic phenotype of caveolin-3 null mice observed by Lisanti, Galbiati and colleagues is consistent with data published by Kikuchi et al which have also developed caveolin-3-deficient mice.55 Lack of caveolin-3 resulted in the loss of caveolae at the sarcolemma, without affecting the level of expression of dystrophin and its associated glycoproteins.55 The authors also demonstrated muscle degeneration in the soleus and diaphragm of caveolin-3 null mice.55


As discussed throughout this chapter, nine different mutations within the human caveolin-3 gene have been associated with a variety of disease phenotypes, including hyperCKemia, distal myopathy, rippling muscle disease, and limb-girdle muscular dystrophy type 1C. The existence of distinct phenotypes in patients with the same mutation, even within the same family, would suggest that specific polymorphisms within modified genes may influence the individual phenotype. One of the many challenges ahead of us will be the identification of possible modifying factors and/or genes in the individual genetic background of affected patients that may contribute to the four different clinical phenotypes observed in caveolinopathies.


We thank Dr. R. Campos-Gonzalez (BD-Pharmingen/Transduction Laboratories) for donating mAbs directed against caveolin-3. M.P.L. was supported by grants from the National Institutes of Health (NIH), and the Susan G. Komen Breast Cancer Foundation, as well as a Hirschl/Weil-Caulier Career Scientist Award. F.G. was supported by a grant from the American Heart Association (AHA) and start-up funds from the Department of Pharmacology at the University of Pittsburgh.


Glenney JR. Tyrosine phosphorylation of a 22 kD protein is correlated with transformation with Rous sarcoma virus. J Biol Chem. 1989;264:20163–20166. [PubMed: 2479645]
Glenney JR, Soppet D. Sequence and expression of caveolin, a protein component of caveolae plasma membrane domains phosphorylated on tyrosine in RSV-transformed fibroblasts. Proc Natl Acad Sci USA. 1992;89:10517–10521. [PMC free article: PMC50370] [PubMed: 1279683]
Rothberg KG, Heuser JE, Donzell WC. et al. Caveolin, a protein component of caveolae membrane coats. Cell. 1992;68:673–682. [PubMed: 1739974]
Lisanti MP, Scherer P, Tang Z-L. et al. Caveolae, caveolin and caveolin-rich membrane domains: A signalling hypothesis. Trends Cell Biol. 1994;4:231–235. [PubMed: 14731661]
Couet J, Li S, Okamoto T. et al. Molecular and cellular biology of caveolae: Paradoxes and Plasticities. Trends Cardiovasc Med. 1997;7:103–110. [PubMed: 21235872]
Okamoto T, Schlegel A, Scherer PE. et al. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem. 1998;273:5419–5422. [PubMed: 9488658]
Sargiacomo M, Scherer PE, Tang Z-L. et al. Oligomeric structure of caveolin: Implications for caveolae membrane organization. Proc Natl Acad Sci USA. 1995;92:9407–9411. [PMC free article: PMC40994] [PubMed: 7568142]
Song KS, Li S, Okamoto T. et al. Copurification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent free purification of caveolae membranes. J Biol Chem. 1996;271:9690–9697. [PubMed: 8621645]
Li S, Couet J, Lisanti MP. Src tyrosine kinases, G alpha subunits and H-Ras share a common membrane-anchored scaffolding protein, Caveolin. Caveolin binding negatively regulates the auto-activation of Src tyrosine kinases. J Biol Chem. 1996;271:29182–29190. [PMC free article: PMC6687395] [PubMed: 8910575]
Garcia-Cardena G, Oh P, Liu J. et al. Targeting of nitric oxide synthase to endothelilal cell caveolae via palmitoylation: Implications for caveolae localization. Proc Natl Acad Sci USA. 1996;93:6448–6453. [PMC free article: PMC39043] [PubMed: 8692835]
Smart E, Ying Y-S, Conrad P. et al. Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation. J Cell Biol. 1994;127:1185–1197. [PMC free article: PMC2120264] [PubMed: 7962084]
Moldovan N, Heltianu C, Simionescu N. et al. Ultrastructural evidence of differential solubility in Triton X-100 of endothelial vesicles and plasma membrane. Exp Cell Res. 1995;219:309–313. [PubMed: 7628548]
Mineo C, James GL, Smart EJ. et al. Localization of EGF-stimulated Ras/Raf-1 interaction to caveolae membrane. J Biol Chem. 1996;271:11930–11935. [PubMed: 8662667]
Liu P, Ying YS, Anderson RGW. PDGF activates MAP kinase in isolated caveolae. Proc Natl Acad Sci USA. 1997;94:13666–13670. [PMC free article: PMC28363] [PubMed: 9391083]
Shenoy-Scaria AM, Dietzen DJ, Kwong J. et al. Cysteine-3 of Src family tyrosine kinases determines palmitoylation and localization in caveolae. J Cell Biol. 1994;126:353–363. [PMC free article: PMC2200018] [PubMed: 7518463]
Smart EJ, Foster D, Ying Y-S. et al. Protein kinase C activators inhibit receptor-mediated potocytosis by preventing internalization of caveolae. J Cell Biol. 1993;124:307–313. [PMC free article: PMC2119940] [PubMed: 8294514]
Schnitzer JE, Oh P, Jacobson BS. et al. Caveolae from luminal plasmalemma of rat lung endothelium: Microdomains enriched in caveolin, Ca2+-ATPase, and inositol triphosphate receptor. Proc Natl Acad Sci USA. 1995;92:1759–1763. [PMC free article: PMC42599] [PubMed: 7878055]
Robbins S, Quintrell N, Bishop JM. Differential palmitoylation of the two isoforms of the Src family kinase, HCK, affects their localization to caveolae J Cell Biochem 1995Supplement 19A27(abstr.).
Chang W-J, Ying Y, Rothberg KG. et al. Purification and characterization of smooth muscle cell caveolae. J Cell Biol. 1994;126:127–138. [PMC free article: PMC2120085] [PubMed: 8027172]
Couet J, Sargiacomo M, Lisanti MP. Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem. 1997;272:30429–30438. [PubMed: 9374534]
Ju H, Zou R, Venema VJ. et al. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J Biol Chem. 1997;272(30):18522–18525. [PubMed: 9228013]
Feron O, Belhassen L, Kobzik L. et al. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem. 1996;271(37):22810–22814. [PubMed: 8798458]
Segal SS, Brett SE, Sessa WC. Codistribution of NOS and caveolin throughout peripheral vasculature and skeletal muscle of hamsters. Am J Physiol. 1999;277:H1167–1177. [PubMed: 10484439]
Garcia-Cardena G, Fan R, Stern D. et al. Endothelial nitric oxide synthase is regulated by tyrsosine phosphorylation and interacts with caveolin-1. J Biol Chem. 1996;271:27237–27240. [PubMed: 8910295]
Volonte D, Peoples AJ, Galbiati F. Modulation of myoblast fusion by caveolin-3 in dystrophic skeletal muscle cells: Implications for Duchenne muscular dystrophy and limb-girdle muscular dystrophy-1C. Mol Biol Cell. 2003;14:4075–4088. [PMC free article: PMC207001] [PubMed: 14517320]
Galbiati F, Volonte D, Chu JB. et al. Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. Proc Natl Acad Sci USA. 2000;97:9689–9694. [PMC free article: PMC16926] [PubMed: 10931944]
Galbiati F, Engelman JA, Volonte D. et al. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and T-tubule abnormalities. J Biol Chem. 2001;276:21425–21433. [PubMed: 11259414]
Patron RG, Way M, Zorzi N. et al. Caveolin-3 associates with developing T-tubules during muscle differentiation. J Cell Biol. 1997;136:137–154. [PMC free article: PMC2132459] [PubMed: 9008709]
Song KS, Scherer PE, Tang Z-L. et al. Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and cofractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem. 1996;271:15160–15165. [PubMed: 8663016]
Scherer PE, Lisanti MP. et al. Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes: Dynamic regulation by extracellular glucose and intracellular metabolites. J Biol Chem. 1997;272:20698–20705. [PubMed: 9252390]
Yamamoto M, Toya Y, Schwencke C. et al. Caveolin is an activator of insulin receptor signaling. J Biol Chem. 1998;273:26962–26968. [PubMed: 9756945]
Gustavsson J, Parpal S, Karlsson M. et al. Localization of the insulin receptor in caveolae of adipocyte plasma membrane. FASEB J. 1999;13:1961–1971. [PubMed: 10544179]
Garcia-Cardena G, Martasek P, Masters BS. et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem. 1997;272(41):25437–25440. [PubMed: 9325253]
Venema VJ, Ju H, Zou R. et al. Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain. J Biol Chem. 1997;272:28187–28190. [PubMed: 9353265]
Aravamudan B, Volonte D, Ramani R. et al. Transgenic overexpression of caveolin-3 in the heartinduces a cardiomyopathic phenotype. Hum Mol Genet. 2003;12:2777–2788. [PubMed: 12966035]
North A, Galazkiewicz B, Byers T. et al. Complementary distribution of vinculin and dystrophin define two distinct sarcolemma domains in smooth muscle. J Cell Biol. 1993;120:1159–1167. [PMC free article: PMC2119721] [PubMed: 8436588]
Crosbie RH, Yarnada H, Venzke DP. et al. Caveolin-3 is not an essential component of the dystrophin glycoprotein complex. FEBS Lett. 1998;427:279–282. [PubMed: 9607328]
Sotgia F, Lee JK, Das K. et al. Caveolin-3 Directly Interacts with the C-terminal Tail of beta - Dystroglycan. Identification of a central ww-like domain within caveolin family members. Biol Chem. 2000;275:38048–38058. [PubMed: 10988290]
Carbone I, Bruno C, Sotgia F. et al. Mutation in the CAV3 gene cause partial caveolin-3 deficiency and hyperCKemia. Neurology. 2000;54:1373–1376. [PubMed: 10746614]
Sotgia F, Woodman SE, Bonuccelli G. et al. Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease. Am J Physiol Cell Physiol. 2003;285:C1150–1160. [PubMed: 12839838]
Merlini L, Carbone I, Capanni C. et al. Familial isolated hyperCKemia associated with a new mutation in the caveolin-3 (CAV-3) gene. J Neurol Neurosurg Psychiatry. 2002;73:65–67. [PMC free article: PMC1757305] [PubMed: 12082049]
Tateyama M, Aoki M, Nishino I. et al. Mutation in the caveolin-3 gene causes a peculiar form of distal myopathy. Neurology. 2002;58:323–325. [PubMed: 11805270]
Betz RC, Schoser BG, Kasper D. et al. Mutation in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease. Nat Genet. 2001;28:218–219. [PubMed: 11431690]
Fischer D, Schroers A, Blumcke I. et al. Consequences of a novel caveolin-3 mutation in a large German family. Ann Neurol. 2003;53:233–241. [PubMed: 12557291]
Vorgerd M, Ricker K, Ziemssen F. et al. A sporadic case of rippling muscle disease caused by a de novo caveolin-3 mutation. Neurology. 2001;57:2273–2277. [PubMed: 11756609]
Kubisch C, Schoser BG, von During M. et al. Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease. Ann Neurol. 2003;53:512–520. [PubMed: 12666119]
Minetti C, Sotogia F, Bruno C. et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet. 1998;18:365–368. [PubMed: 9537420]
Galbiati F, Volonte D, Minneti C. et al. Phenotypic behavior of caveolin-3 mutations that cause autosomal dominant limb girdle muscular dystrophy (LGMD-1C). Retention of LGMD-1C caveolin-3 mutants within the Golgi complex. J Biol Chem. 1999;274:25632–25641. [PubMed: 10464299]
Galbiati F, Volonte D, Minneti C. et al. Limb-girdle muscular dystrophy (LGMD-1C) mutants of caveolin-3 Undergo Ubiquitination and Proteasomal Degradation. Treatment with proteasomal in-hibitors blocks the dominant negative effect of LGMD-1C mutants and rescues wild-type caveolin-3. J Biol Chem. 2000;275:37702–37711. [PubMed: 10973975]
Herrmann R, Straub V, Blank M. et al. Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. Hum Mol Gene. 2000;9:2335–2340. [PubMed: 11001938]
Matsuda C, Hayashi YK, Ogawa M. et al. The sarcolemmal proteins dysferlin and caveolin-3 inter-act in skeletal muscle. Hum Mol Genet. 2001;10:1761–1766. [PubMed: 11532985]
Figarella-Branger D, Pouget J, Bernard R. et al. Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene. Neurology. 2003;61:562–564. [PubMed: 12939441]
Sunada Y, Ohi H, Hase A. et al. Transgenic mice expressing mutant caveolin-3 show severe my-opathy associated with increased nNOS activity. Hum Bol Genet. 2001;10:173–178. [PubMed: 11159934]
Minetti C, Bado M, Broda P. et al. Impairment of caveolae formation and T-system disorganiza-tion in human muscular dystrophy with caveolin-3 deficiency. Am J Pathol. 2002;160:265–270. [PMC free article: PMC1867137] [PubMed: 11786420]
Hagiwara Y, Sasaoka T, Araishi K. et al. Caveolin-3 deficiency causes muscle degeneration in mice. Hum Mol Genet. 2000;9:3047–3054. [PubMed: 11115849]
Galbiati F, Razani B, LisantiAraishi MP. et al. Caveolae and caveolin-3 in muscular dystrophy. Trends Mol Med. 2001;7:435–441. [PubMed: 11597517]
Tang Z, Okamoto T, Boontrakulpoontawee P. et al. Identification, sequence, and expression of an invertebrate caveolin gene family from the nematode Caenorhabditis elegans: Implications for the molecular evolution of mammalian caveolin genes. J Biol Chem. 1997;272:2437–2445. [PubMed: 8999956]
Mathews KD, Morris SA. Limb-Girdle Muscular Dystrophy, Current Neurology and Neuroscience Reports. 2003. pp. 78–85. [PubMed: 12507416]
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