Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium-ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis.
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PMID:Pathogenesis of Duchenne muscular dystrophy: the calcium hypothesis revisited. 149 54

We measured free intracellular calcium ([Ca2+]i) in cultured cerebellar granule cells from normal and mdx mice. Resting levels of ([Ca2+]i) were 24% higher in the dystrophic neurons (normal: 61.2 +/- 1.5 nM calcium, n = 104; dystrophic: 76.1 +/- 2.4 nM calcium, n = 136, P less than 0.01). Dystrophic neurons showed a significantly greater increase in ([Ca2+]i) in the presence of elevated (18 mM) extracellular calcium levels. Resting sodium levels ([Na+]i), however, were found to be similar in normal and dystrophic granule neurons. In addition, sodium influx rates after ouabain inhibition of the Na+/K+ ATPase were also identical. Therefore, the increased permeability of granule neurons was specific to calcium, and did not result from a non-selective cation-permeable conductance. Unlike granule cells, astrocytes do not express dystrophin. Glial cells from normal and dystrophic mice showed no difference in their resting free calcium levels or their response to a high calcium load. Thus, cerebellar granule neurons from mdx mice show a calcium-specific regulatory defect similar to that found in dystrophic muscle fibers, while cerebellar glial cells, which do not normally express dystrophin, have no such defect.
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PMID:Regulation of intracellular free calcium in normal and dystrophic mouse cerebellar neurons. 151 Dec 88

The chronic stimulation of predominantly fast-twitch mammalian skeletal muscle causes a transformation to physiological characteristics of slow-twitch skeletal muscle. Here, we report the effects of chronic stimulation on the protein components of the sarcoplasmic reticulum and transverse tubular membranes which are directly involved in excitation-contraction coupling. Comparison of protein composition of microsomal fractions from control and chronically stimulated muscle was performed by immunoblot analysis and also by staining with Coomassie blue or the cationic carbocyanine dye Stains-all. Consistent with previous experiments, a greatly reduced density was observed for the fast-twitch isozyme of Ca(2+)-ATPase, while the expression of the slow-twitch Ca(2+)-ATPase was found to be greatly enhanced. Components of the sarcolemma (Na+/K(+)-ATPase, dystrophin-glycoprotein complex) and the free sarcoplasmic reticulum (Ca(2+)-binding protein sarcalumenin and a 53-kDa glycoprotein) were not affected by chronic stimulation. The relative abundance of calsequestrin was slightly reduced in transformed skeletal muscle. However, the expression of the ryanodine receptor/Ca(Ca2+)-release channel from junctional sarcoplasmic reticulum and the transverse tubular dihydropyridine-sensitive Ca2+ channel, as well as two junctional sarcoplasmic reticulum proteins of 90 kDa and 94 kDa, was greatly suppressed in transformed muscle. Thus, the expression of the major protein components of the triad junction involved in excitation-contraction coupling is suppressed, while the expression of other muscle membrane proteins is not affected in chronically stimulated muscle.
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PMID:Analysis of excitation-contraction-coupling components in chronically stimulated canine skeletal muscle. 166 14

Phospholipid incorporation of 32P by primary myotube cultures and the tissue activity of sarcolemmal Na+/K(+)-transporting ATPase were studied to determine whether the absence of dystrophin from dystrophic (mdx) muscle would affect membrane lipid synthesis and membrane function. The incorporation of 32P by phospholipid as a ratio with total protein was greater in cultured dystrophic cells compared with control cells. The mdx cells also incorporated more 32P than control cells into phosphatidylethanolamine, which is thought to increase prior to myoblast fusion, and less into phosphatidylserine, phosphatidylinositol, and lysophosphatidylcholine. There was no difference in total protein content or [3H]leucine or 32P incorporation into the aqueous fraction of dystrophic and control cells, although dystrophic cells incorporated less [35S]methionine into protein than controls. Isolated sarcolemma from mdx skeletal muscle tissue demonstrated a consistently greater specific activity of ouabain-sensitive Na+/K(+)-transporting ATPase than sarcolemmal preparations from control skeletal muscle. These observations suggest that cytoskeletal changes such as dystrophin deficiency may alter the differentiation of membrane composition and function.
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PMID:Myotube phospholipid synthesis and sarcolemmal ATPase activity in dystrophic (mdx) mouse muscle. 166 76

mAbs specific for protein components of the surface membrane of rabbit skeletal muscle have been used as markers in the isolation and characterization of skeletal muscle sarcolemma membranes. Highly purified sarcolemma membranes from rabbit skeletal muscle were isolated from a crude surface membrane preparation by wheat germ agglutination. Immunoblot analysis of subcellular fractions from skeletal muscle revealed that dystrophin and its associated glycoproteins of 156 and 50 kD are greatly enriched in purified sarcolemma vesicles. The purified sarcolemma was also enriched in novel sarcolemma markers (SL45, SL/TS230) and Na+/K(+)-ATPase, whereas t-tubule markers (alpha 1 and alpha 2 subunits of dihydropyridine receptor, TS28) and sarcoplasmic reticulum markers (Ca2(+)-ATPase, ryanodine receptor) were greatly diminished in this preparation. Analysis of isolated sarcolemma by SDS-PAGE and densitometric scanning demonstrated that dystrophin made up 2% of the total protein in the rabbit sarcolemma preparation. Therefore, our results demonstrate that although dystrophin is a minor muscle protein it is a major constituent of the sarcolemma membrane in skeletal muscle. Thus the absence of dystrophin in Duchenne muscular dystrophy may result in a major disruption of the cytoskeletal network underlying the sarcolemma in dystrophic muscle.
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PMID:Dystrophin-glycoprotein complex is highly enriched in isolated skeletal muscle sarcolemma. 198 2

In 5 children with a progressive congenital myopathy representing 3 different families, unusual histological, immunohistochemical and ultrastructural changes in skeletal muscle have been found. Histologically, this myopathy was characterized by the presence of fine hyaline plaques devoid of oxidative as well as ATPase enzyme activities. At the ultrastructural level plaques were composed of helical filaments and amorphous dense material. Helical filament storage corresponded to strong desmin as well as ubiquitin immunoreactivity. In addition they were also dystrophin positive. The exclusive appearance of desmin, ubiquitin and dystrophin positive plaques in muscle specimens from 5 children emphasize the uniqueness of these plaques as well as this special form of a congenital myopathy.
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PMID:A new familial congenital myopathy in children with desmin and dystrophin reacting plaques. 756 54

We studied muscle biopsies from 36 Becker muscular dystrophy patients, and correlated dystrophin negative fibers with regenerating and degenerating myofibers. Dystrophin immunohistochemistry was used to identify dystrophin-negative and dystrophin-positive fibers. Immunohistochemical staining for fetal myosin and acid ATPase identified regenerating fibers, and calcium glioxalate and beta-spectrin staining identified necrotic fibers. All Becker biopsies contained detectable dystrophin in the majority of muscle fibers. 13 cases (36%) showed no dystrophin negative fibers, 9 cases (25%) showed a generalized, markedly decreased immunostaining pattern, and 14 cases (39%) showed a subset of dystrophin negative fibers (0.3-8% of total). Most dystrophin-negative fibers in Becker muscle were judged to be in the process of regeneration, and not in degeneration. No correlation was observed between the age of the patients and number of dystrophin negative fibers. We conclude that the absence of dystrophin and spectrin labeling in some BMD myofibers is associated with regeneration, probably due to incomplete expression of dystrophin secondary to myofibers immaturity. Our results might be explained by a developmental delayed expression of these two proteins, or by abnormal assembling in membrane's components during regeneration in dystrophy. Furthermore, our results rationalize the recently reported finding of some dystrophin-negative fibers in polymyositis.
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PMID:Absence of dystrophin and spectrin in regenerating muscle fibers from Becker dystrophy patients. 806 27

Recent evidence indicates that in dystrophin-deficient muscle, intracellular sodium content (Na(i)) may be elevated and sodium regulation may be altered or impaired. If there is an elevation in Na(i), this could be due to decreased active pumping of sodium from the cell or increased passive influx of sodium. The present study has therefore determined the content of plasma membrane-bound Na+/K(+)-ATPase in the skeletal muscle of mdx mice; a genetically homologous model of Duchenne muscular dystrophy. Measurements were made on muscles from 5-6-month-old mdx mice and age-matched controls of the C57B1/10ScSn strain (n = 9 pairs), using the vanadate-facilitated ouabain-binding technique. The Na+/K(+)-ATPase concentration per unit weight increased by 2.3-fold in the longissimus dorsi and 1.4-fold in the gastrocnemius of mdx mice compared with controls. The increase in Na+/K(+)-ATPase content is of similar magnitude to the previously reported increase in ouabain-sensitive Na+/K(+)-ATPase activity in mdx muscle, suggesting that this elevated enzyme activity occurs largely through an increase in its concentration. This compensatory increase in the main regulator of internal sodium is likely to occur in an attempt to maintain homeostasis. Nevertheless, the elevated pump concentration is unable to compensate entirely for the increased Na(i). These results are consistent with a previously proposed hypothesis that sodium regulation is abnormal in dystrophin deficient muscles, and also that cell death in these muscles may be due to abnormal regulation of cell volume.
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PMID:Ouabain sensitive Na+/K(+)-ATPase content is elevated in mdx mice: implications for the regulation of ions in dystrophic muscle. 858 12

In Duchenne muscular dystrophy, muscle cells, which lack the protein dystrophin, have been reported to have elevated resting intracellular calcium levels. It has also been noted that, compared to normal muscle, intracellular [Ca2+] in dystrophic muscle returns more slowly to its resting level following contractile stimulation. Consistent with this, it has been suggested that dystrophin is directly involved in the regulation of Ca2+ influx. A secondary alteration in the sarcoplasmic reticulum Ca2+ pump, however, could also contribute to, or be responsible for, the abnormal Ca2+ handling seen. To determine whether the Ca2+ pump is functionally altered in dystrophic muscle, we examined Ca2+ uptake by vesicles derived from skeletal muscle sarcoplasmic reticulum of normal and dystrophic (mdx) mice. The Hill coefficient and the Ca2+ sensitivity of the Ca2+- ATPase were the same in both cases. The maximum velocity of Ca2+ uptake, however, normalized to the ATPase content of the vesicles, was less for mdx muscle.
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PMID:The sarcoplasmic reticulum calcium pump is functionally altered in dystrophic muscle. 864 5

Due to its restricted localisation to the neuromuscular junction and based on sequence homology to cytoskeletal proteins, the dystrophin-related protein utrophin is thought to be an important constituent of the membrane cytoskeleton of the postsynaptic muscle membrane and may be involved in the clustering of acetylcholine receptors at the neuromuscular junction. However, due to the low density of utrophin in microsomal muscle membranes, it is difficult to analyse the biochemical properties of the skeletal muscle isoform of utrophin. To overcome these technical difficulties, we used here immunoblot analysis of highly purified muscle surface membranes enriched even in sarcolemma markers of very low density such as ecto-5' nucleotidase and the calmodulin-sensitive Ca(2+)-ATPase. This enabled us to analyse the membrane biochemical properties of this dystrophin isoform of extremely low abundance. Since alkaline treatment released utrophin from the bilayer while it stayed associated with the insoluble pellet following detergent extraction, utrophin exhibits biochemical properties typical of a membrane cytoskeletal protein. Therefore, utrophin appears to be a specialised isoform which performs the membrane cytoskeletal function(s) of dystrophin at the postsynaptic membrane of the neuromuscular junction.
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PMID:Characterisation of the dystrophin-related protein utrophin in highly purified skeletal muscle sarcolemma vesicles. 880 2


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