Degradation of skeletal muscle plasma membrane proteins by calpain

Zaidi, S. Iqbal Mehdi; Narahara, H. T.

doi:10.1007/bf01869151

Cited by 15 publications

(6 citation statements)

References 48 publications

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“…Both the proteasome and the lysosome are involved in the degradation of the epithelial Na ϩ channel (Staub et al, 1997). In addition, degradation of membrane proteins by calpain has also been reported (Zaidi and Narahara, 1989;Salamino et al, 1994;Ohkawa et al, 1999).…”

Section: Ubiquitination and P-glycoprotein Stability 399mentioning

confidence: 98%

Regulation of the Stability of P-Glycoprotein by Ubiquitination

Zhang¹,

Jin²,

Hait³

et al. 2004

Mol Pharmacol

108

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Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquitinated in drug-resistant cancer cells. Transfection of multidrug-resistant cells with wild-type ubiquitin or treatment with an N-glycosylation inhibitor increased the ubiquitination of P-glycoprotein and increased P-glycoprotein degradation. Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), a proteasome inhibitor, induced accumulation of ubiquitinated P-glycoprotein, suggesting the involvement of the proteasome in the turnover of the transporter. Treatment of multidrug-resistant cells with 12-O-tetradecanoylphorbol-13-acetate, a phorbol ester that increases the phosphorylation of P-glycoprotein through activation of protein kinase C, or substituting phosphorylation sites of P-glycoprotein by nonphosphorylatable residues did not affect the ubiquitination of the transporter. Enhanced ubiquitination of P-glycoprotein resulted in a decrease of the function of the transporter, as demonstrated by increased intracellular drug accumulation and increased cellular sensitivity to drugs transported by P-glycoprotein. Our results indicate that the stability and function of P-glycoprotein can be regulated by the ubiquitin-proteasome pathway and suggest that modulating the ubiquitination of P-glycoprotein might be a novel approach to the reversal of drug resistance.Drug resistance is a major impediment to successful cancer chemotherapy. Multidrug resistance (MDR) mediated by Pglycoprotein (P-gp), the product of the MDR1 (ABCB1) gene, is believed to be one of the major causes of failure of cancer therapy. P-gp is a 150-to 180-kDa heavily glycosylated and phosphorylated plasma membrane protein that functions as a drug transporter. Overexpression of P-gp confers resistance to a variety of structurally and functionally diverse anticancer drugs such as paclitaxel, doxorubicin, and vinblastine. Despite promising early studies showing that blocking of P-gp by pharmacological means could sensitize drug-resistant cells, the ultimate goal of restoring drug sensitivity has met with limited success in clinical trials. Therefore, we and others began to elucidate the factors that control P-gp synthesis. For example, we have demonstrated that several substances control the expression of MDR1 through activation of phospholipase C and that the transcriptional modulation of MDR1 expression by phospholipase C is mediated by the Raf-mitogen-activated protein kinase pathway (Yang et al., 2001). We recently have become interested in the factors that regulate P-gp stability.P-gp, at steady state, is located in the plasma membrane and undergoes endocytosis and recycling (Kim et al., 1997). Experimentally induced alterations in trafficking of P-gp can change the steady-state distribution of the transporter, thereby affecting the...

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Section: Ubiquitination and P-glycoprotein Stability 399mentioning

confidence: 98%

Regulation of the Stability of P-Glycoprotein by Ubiquitination

Zhang¹,

Jin²,

Hait³

et al. 2004

Mol Pharmacol

108

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“…40 Particular attention has been giventothe calciumactivated cysteine protease, calpain, which is known to degrade a wide range of skeletal muscle proteins, including some cytoskeletal and membrane proteins. 41,42 Calpain activity has been shown to be greater in muscles from mdx mice than wild-type mice 43 and it has been reported that the increased calpain activity in mdx mice occurs during periods of both muscle degeneration and regeneration. 44 When the calpain inhibitor,l eupeptin, wasi njected intramuscularly for 30 days, muscle degeneration and necrosis was reduced in mdx muscles by up to 50%.…”

Section: Proteasesmentioning

confidence: 99%

MUSCLE DAMAGE IN MDX (DYSTROPHIC) MICE: ROLE OF CALCIUM AND REACTIVE OXYGEN SPECIES

Whitehead

Yeung

Allen

2006

Clin Exp Pharma Physio

271

234

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SUMMARY Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease caused by a genetic mutation that leads to the complete absence of the cytoskeletal protein dystrophin in muscle fibres. The present review provides an overview of some of the physiological pathways that may contribute to muscle damage and degeneration in DMD, based primarily on experimental findings in the mdx mouse, an animal model of this disease. A rise in intracellular calcium is widely thought to be an important initiating event in the dystrophic pathogenesis. The pathway(s) leading to increased intracellular calcium in dystrophin deficient muscle is uncertain, but recent work from our laboratory provides evidence that stretch‐activated channels are an important source of the calcium influx. Other possible routes of calcium entry are also discussed. The consequences of elevated cytosolic calcium may include activation of proteases, such as calpain, and increased production of reactive oxygen species (ROS), which can cause protein and membrane damage. Another possible cause of damage in dystrophic muscle involves inflammatory pathways, such as those mediated by neutrophils, macrophages and associated cytokines. There is recent evidence that increased ROS may be important in both the activation of and the damage caused by this inflammatory pathway in mdx muscle.

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“…It has been shown in vitro that incubating skeletal muscle with calpain produces changes identical to those reported in vivo following exercise (for references, see Belcastro 1993). Other studies have shown that calpain is capable of degrading proteins in skeletal muscle plasma membranes ( Zaidi & Narahara 1989), and that tetanic contractions in isolated frog sartorius muscle lead to a loss of a plasma membrane protein ( Narahara & Green 1983). It is important that calpain I has been found to be activated at Ca 2+ concentrations as low as 1 μ M ( Belcastro 1993) or 5 μ M ( Dayton et al .…”

Section: Ca2+‐induced Cell Damage As a Vicious Cyclementioning

confidence: 99%

Excitation‐induced Ca²⁺ influx and skeletal muscle cell damage

Gissel

Clausen

2001

Acta Physiologica Scandinavica

102

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Excessive exercise may lead to skeletal muscle cell damage with degradation of cellular components and leakage of intracellular enzymes. Calcium has repeatedly been proposed to be involved in these processes. Studies have shown that the resting level of cytoplasmic Ca2+ increases up to threefold during long-term low-frequency stimulation. We have shown that electrical stimulation produces a marked increase in Ca2+ uptake and Ca2+ content in rat skeletal muscle, both in vivo and in vitro. Continuous stimulation for 240 min at 1 Hz results in an increased release (18-fold) of lactate dehydrogenase (LDH) from extensor digitorum longus (EDL) muscle. This was associated with an increased total Ca2+ content (185%), was augmented at high [Ca2+]o and suppressed at low [Ca2+]o. The release of LDH may reflect partial loss of sarcolemmal integrity as a result of degradation of membrane components by Ca2+-activated enzymes (e.g. calpain or phospholipase A2). After cessation of stimulation the increased release of LDH continues for at least 120 min. This is associated with an up to sevenfold increase in 45Ca uptake. The increased permeability to Ca2+ may further activate calpain and phospholipase A2 and accelerate the loss of membrane integrity. Stimulation-induced uptake of Ca2+ and release of LDH is most pronounced in EDL (mainly composed of fast-twitch fibres at variance with soleus which is mainly composed of slow-twitch fibres). This may account for the observation that prolonged exercise leads to preferential damage to fast-twitch fibres. We hypothesize that excessive exercise may lead to an intracellular accumulation of Ca2+ and increased cytoplasmic Ca2+ causing activation of self-accelerating degradative pathways leading to muscle damage.

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Degradation of skeletal muscle plasma membrane proteins by calpain

Cited by 15 publications

References 48 publications

Regulation of the Stability of P-Glycoprotein by Ubiquitination

Regulation of the Stability of P-Glycoprotein by Ubiquitination

MUSCLE DAMAGE IN MDX (DYSTROPHIC) MICE: ROLE OF CALCIUM AND REACTIVE OXYGEN SPECIES

Excitation‐induced Ca²⁺ influx and skeletal muscle cell damage

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Degradation of skeletal muscle plasma membrane proteins by calpain

Cited by 15 publications

References 48 publications

Regulation of the Stability of P-Glycoprotein by Ubiquitination

Regulation of the Stability of P-Glycoprotein by Ubiquitination

MUSCLE DAMAGE IN MDX (DYSTROPHIC) MICE: ROLE OF CALCIUM AND REACTIVE OXYGEN SPECIES

Excitation‐induced Ca2+ influx and skeletal muscle cell damage

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Excitation‐induced Ca²⁺ influx and skeletal muscle cell damage