Ecto-ATPase Activity of α-Sarcoglycan (Adhalin)

Betto, Romeo; Senter, L.; Ceoldo, Stefania; Tarricone, Elena; Biral, Donatella; Salviati, G.

doi:10.1074/jbc.274.12.7907

Cited by 80 publications

(78 citation statements)

References 58 publications

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“…In addition, ␤-dystroglycan and the ␣-and ␥-sarcoglycans have been shown to be tyrosine-phosphorylated upon stimulation with different ligands, implicating them as signaltransducing molecules (35,53). Specifically, ␣-sarcoglycan may function in bi-directional signaling in concert with the integrinadhesion system as well as possess ecto-ATPase activity (35,36).…”

Section: Discussionmentioning

confidence: 99%

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Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Woodman

Park

Cohen

et al. 2002

Journal of Biological Chemistry

269

241

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A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane microdomains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (؊/؊) knockout mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, ␣-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

“…In this regard, ␣-sarcoglycan is the best-studied member of the DG complex that has been implicated in signaling (35)(36)(37)(38). Thus, we further examined the expression and membrane localization of ␣-sarcoglycan, as a biochemical marker for the DG complex.…”

Section: Cav-3 Ko Mice Do Not Express Caveolin-3 In the Heart Andmentioning

confidence: 99%

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Woodman

Park

Cohen

et al. 2002

Journal of Biological Chemistry

269

241

View full text Add to dashboard Cite

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“…Sarcolemma purified from rabbit skeletal muscles was used to determine the stoichiometry of the recombinant sarcoglycans. 22 …”

Section: Sds-page and Western Blottingmentioning

confidence: 99%

“…20 Recently, it has been shown that the cytoplasmic tail of ␥-sarcoglycan is phosphorylated after mechanical stimulation. 21 Lastly, ␣-sarcoglycan possesses an ectoATPase activity, 22,23 which could play a role in the extracellular ATP-dependent modulation of skeletal muscle contractility. 24 Studies on the assembly of the sarcoglycan complex, during the early stage of myotube differentiation, have provided evidence that sarcoglycans are co-translationally translocated in the endoplasmic reticulum (ER), where they associate during the transport through the Golgi to the plasma membrane.…”

mentioning

confidence: 99%

Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing α-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing β-, γ-, and δ-Sarcoglycan

Gastaldello

D'Angelo

Franzoso

et al. 2008

The American Journal of Pathology

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Sarcoglycanopathies are progressive muscle-wasting disorders caused by genetic defects of four proteins, ␣-, ␤-, ␥-, and ␦-sarcoglycan, which are elements of a key transmembrane complex of striated muscle. The proper assembly of the sarcoglycan complex represents a critical issue of sarcoglycanopathies, as several mutations severely perturb tetramer formation. Misfolded proteins are generally degraded through the cell's quality-control system; however, this can also lead to the removal of some functional polypeptides. To explore whether it is possible to rescue sarcoglycan mutants by preventing their degradation, we generated a heterologous cell system, based on human embryonic kidney (HEK) 293 cells, constitutively expressing three (␤, ␥, and ␦) of the four sarcoglycans. In these ␤␥␦-HEK cells, the lack of ␣-sarcoglycan prevented complex formation and cell surface localization, wheras the presence of ␣-sarcoglycan allowed maturation and targeting of the tetramer. As in muscles of sarcoglycanopathy patients, transfection of ␤␥␦-HEK cells with disease-causing ␣-sarcoglycan mutants led to dramatic reduction of the mutated proteins and the absence of the complex from the cell surface. Proteasomal inhibition reduced the degradation of mutants and facilitated the assembly and targeting of the sarcoglycan complex to the plasma membrane. These data provide important insights for the potential development of pharmacological therapies for sarcoglycanopathies.

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“…α-Sarcoglycan has been reported to have ectoATPase activity and it was suggested that the activity of P2X receptors may be modulated by α-sarcoglycan which buffers the extracellular ATP concentration [353]. Elevated concentrations of extracellular ATP and its activation of P2X receptors lead to Ca 2+ overload and muscle fibre death in the absence of α-sarcoglycan in sarcoglycanopathies.…”

Section: Muscular Dystrophymentioning

confidence: 99%

Purinergic signalling in the musculoskeletal system

Burnstock

Arnett

Orriss

2013

Purinergic Signalling

111

114

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It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y 1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.

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Ecto-ATPase Activity of α-Sarcoglycan (Adhalin)

Cited by 80 publications

References 58 publications

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Inhibition of Proteasome Activity Promotes the Correct Localization of Disease-Causing α-Sarcoglycan Mutants in HEK-293 Cells Constitutively Expressing β-, γ-, and δ-Sarcoglycan

Purinergic signalling in the musculoskeletal system

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