A proteomic study of calpain-3 and its involvement in limb girdle muscular dystrophy type 2a

Bertipaglia, Ilenia; Bourg, N.; Richard, Isabelle; Påhlman, Anna-Karin; Andersson, Lise-Lotte; James, Peter; Carafoli, Ernesto

doi:10.1016/j.ceca.2009.10.003

Cited by 7 publications

(8 citation statements)

References 35 publications

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“…by guest on May 11, 2018 http://circres.ahajournals.org/ Downloaded from adhered to a similar extent when whole blood was perfused over fibrinogen-coated (60 µg/mL) coverslips at an intermediate shear rate of 1000 s −1 (Online Figure IIIB). Activated αIIbβ3 integrin and increased Ca 2+ mobilization have been implicated in the coagulant activity of platelets.…”

Section: Enhanced Aggregate Formation and Procoagulant Activity Of CLmentioning

confidence: 83%

“…The exact mechanism how CLP36 is associated with the negative feedback loop of GPVI could not be completely elucidated here, but our results indicate a complex mechanism that involves weak interactions of CLP36 with components of the GPVI signalosome ( Figure 8A). Studies by Bertipaglia et al 39 revealed calpain-mediated cleavage of CLP36 in muscle cells. Interestingly, we also observed the loss of intact CLP36 on GPVI-induced platelet activation, which was blocked by the calpain inhibitor calpeptin ( Figure 8B).…”

Section: Discussionmentioning

confidence: 99%

“…This might be attributed to the intact N-terminal PDZ domain of the chimeric CLP36 protein, which still could associate with the actin cytoskeleton. The interaction of CLP36 with α-actinin, by guest on May 11, 2018 http://circres.ahajournals.org/ Downloaded from however, was not essential for actin turnover in platelets because Clp36 −/− platelets were able to form filopodia and lamellipodia, and, finally, were able to spread with similar kinetics as Wt platelets (Online Figure IIIC and IIID).…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments in mouse muscle cells with calpain-3 knockout mice revealed that CLP36 was cleaved directly by the protease. 39 To study this process in platelets, we analyzed degradation of CLP36 on stimulation with the GPVI agonist convulxin and the Ca 2+ ionophore ionomycin in the absence or presence of the calpain inhibitor calpeptin. Although ionomycin induced the virtually complete loss of intact CLP36 within 10 minutes, a more delayed effect was seen with convulxin, which could be inhibited in the presence of calpeptin ( Figure 8B).…”

Section: Clp36 Interacts With Components Of the Gpvi Signalosome And mentioning

confidence: 99%

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CLP36 Is a Negative Regulator of Glycoprotein VI Signaling in Platelets

Gupta

Braun

Morowski

et al. 2012

Circulation Research

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Rationale: At sites of vascular injury, exposed subendothelial collagens not only trigger sudden platelet adhesion and aggregation, thereby initiating normal hemostasis, but also can lead to acute ischemic diseases, such as myocardial infarction or stroke. The glycoprotein (GP) VI/Fc receptor γ-chain complex is a central regulator of these processes because it mediates platelet activation on collagens through a series of tyrosine phosphorylation events downstream of the Fc receptor γ-chain-associated immunoreceptor tyrosine-based activation motif. GPVI signaling has to be tightly regulated to prevent uncontrolled intravascular platelet activation, but the underlying mechanisms are not fully understood. Objective:We studied the role of PDZ and LIM domain family member CLP36 in platelet physiology in vitro and in vivo. Methods and Results: Conclusions:These data reveal an inhibitory function of CLP36 in GPVI immunoreceptor tyrosine-based activation motif signaling and establish it as a key regulator of arterial thrombosis.

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Section: Enhanced Aggregate Formation and Procoagulant Activity Of CLmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Clp36 Interacts With Components Of the Gpvi Signalosome And mentioning

confidence: 99%

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CLP36 Is a Negative Regulator of Glycoprotein VI Signaling in Platelets

Gupta

Braun

Morowski

et al. 2012

Circulation Research

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“…1 The clinical diagnosis is suggested by elevation in serum creatinine kinase and myopathic features on electromyography; however, the diagnosis is best confirmed by either muscle biopsy or genetic testing. 5,6 Muscle biopsy can confirm features consistent with muscular dystrophy, and immunohistochemical testing can be used to further specify the diagnosis, using antibodies directed against LGMD-related proteins. 3,6 In this context, it is possible to identify calpain 3 deficiency in muscle via Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

Normal vaginal delivery in a patient with autosomal recessive limb-girdle muscular dystrophy

Black

Said

2010

Obstet Med

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Summary:The limb-girdle muscular dystrophies (LGMDs) are a group of genetically determined disorders of skeletal muscle, predominantly affecting the pelvic and shoulder-girdle musculature. The clinical course is variable but steadily progressive. Type 2ALGMD is the most frequent form, accounting for approximately 30% of identified cases. There are few reports of patients with Type 2A LGMD undergoing pregnancy and delivery. This case outlines a successful vaginal delivery in a woman with this condition.Keywords: high-risk pregnancy, maternal -fetal medicine, neurology, perinatal medicine CASE REPORTThe patient, a 24-year-old primigravida, presented for antenatal care at The Royal Women's Hospital, Melbourne at 26 weeks gestation. Her neurological diagnosis was established at the age of 17 years on the basis of a muscle biopsy, which showed diagnostic features of myopathy. Further immunohistochemical studies using Western immunoblotting were arranged and proved consistent with Type 2A limb-girdle muscular dystrophy (LGMD). Her parents were consanguinous and her sister, aged 15 years, was experiencing similar symptoms at that time but had not undergone formal investigation.At the time of diagnosis the patient underwent calf tendon releases, with no subsequent neurological review. Prior to pregnancy she was unable to walk without assistance and relied on family members to support her while she walked. This included assistance to rise from the seated or lying position. She was unable to run or climb stairs. Her routine booking blood tests were essentially normal except for an elevated glucose tolerance test, consistent with gestational diabetes, which responded to dietary measures. Her body mass index at booking was 26 kg/m 2 . She underwent neurological review at 32 weeks gestation. Examination revealed shoulder-girdle weakness with inability to lift her arms above her head, symmetrical lower limb weakness, calf hypertrophy and wasted quadriceps and hamstring muscles, with power 2/5 in the limb girdles. Echocardiogram, electrocardiograph and pulmonary function tests were performed and were essentially normal. A caesarean section for delivery was initially recommended by the neurology team on the basis of her poor motor function and concerns that this may preclude a vaginal delivery. However, in conjunction with the patient's wishes, a vaginal delivery was proposed, with assistance in the second stage of labour if required.Serial ultrasounds in the third trimester showed appropriate fetal growth. Her antenatal course was complicated by a fall at 34 weeks gestation resulting in a right medial malleolar fracture. This necessitated the use of a wheelchair for mobility, and subcutaneous heparin was commenced for deep venous thrombosis prophylaxis.At 39 weeks gestation, induction of labour was recommended due to unstable blood sugars and numerous social and logistical issues, including difficulty for carers to arrange transport to the hospital for appointments. Artificial rupture of membranes was performed and an oxytocin...

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An eccentric calpain, CAPN3/p94/calpain-3

Ono

Ojima²,

Shinkai-Ouchi

et al. 2016

Biochimie

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Calpains are Ca(2+)-regulated proteolytic enzymes that are involved in a variety of biological phenomena. Calpains process substrates by limited proteolysis to modulate various protein functions in the cell, and are thus called "modulator proteases." CAPN3, previously called p94 or calpain-3, has unique features that are not found in any of the other 14 human calpains, or even in other proteases. For instance, CAPN3 undergoes extremely rapid and exhaustive autodegradation. CAPN3 is also the first (and so far, the only) intracellular enzyme found to depend on Na(+) for its activation. CAPN3 has both proteolytic and non-proteolytic functions. It has the interesting distinction of being the only protease, other than a few virus proteases, with the ability to regain protease function after its autolytic dissociation; this occurs through a process known as intermolecular complementation (iMOC). Gene mutations causing CAPN3 defects are responsible for limb-girdle muscular dystrophy type 2A (LGMD2A). Unusual characteristics of CAPN3 have fascinated researchers, but have also hampered conventional biochemical analysis. In this review, we describe significant findings about CAPN3 from its discovery to the present, and suggest promising avenues for future CAPN3 research.

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A proteomic study of calpain-3 and its involvement in limb girdle muscular dystrophy type 2a

Cited by 7 publications

References 35 publications

CLP36 Is a Negative Regulator of Glycoprotein VI Signaling in Platelets

CLP36 Is a Negative Regulator of Glycoprotein VI Signaling in Platelets

Normal vaginal delivery in a patient with autosomal recessive limb-girdle muscular dystrophy

An eccentric calpain, CAPN3/p94/calpain-3

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