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)

Membrane-bound enzyme activities and cardiac glycoside binding were determined in red blood cell membrane preparations from patients with myotonic dystrophy and in age matched controls. Na+-K+-activated ATPase activity was significantly increased in myotonic patients. [3H]Ouabain binding to erythrocyte membranes was also significantly increased in myotonic dystrophy patients. The Mg2+-ATPase (ouabain-insensitive) was, however, unchanged. The K+-stimulated paranitrophenyl phosphatase (KPNPPase) activity was markedly enhanced in myotonic patients as compared to controls. The kinetic analysis showed a marked change in Vmax of Na+-K+ ATPase with respect to the activation by Na+, K+ and ATP. However, the Km values were the same in control as well as in myotonic groups. The increased erythrocyte membrane Na+-K+-ATPase activity, KPNPPase and [3H]ouabain binding in myotonic patients supports the hypothesis that generalized membrane abnormality may be involved in pathogenesis of the human myotonic dystrophy.
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PMID:Erythrocyte membrane abnormalities in human myotonic dystrophy. 624 57

The activity of [Na+ + K+] Mg2+-ATPase of muscle surface membrane was investigated in 20 cases of the Duchenne type of progressive muscular dystrophy; it was found to be diminished and to have a changed reactivity to ouabain. There was nothing like it in cases of limb-girdle dystrophy and neurogenic muscular atrophies investigated for the purpose of comparisons, whereas in some cases of myotonic dystrophy and myotonia congenita the activity of the ATPase was indeed depressed, but the response to ouabain invariably remained normal.
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PMID:[Na+ + K+] Mg2+-ATPase of muscle plasma membranes in Duchenne muscular dystrophy. 625 58

Since defective regulation of ion transport could initiate or contribute to the abnormal cellular function in myotonic dystrophy (MyD), Na+/K(+)-ATPase and sarcoplasmic reticulum (SR) Ca(2+)-ATPase were examined in skeletal muscle and cultured skeletal muscle cells of controls and MyD patients. Na+/K(+)-ATPase was investigated by measuring ouabain binding and the activities of Na+/K(+)-ATPase and K(+)-dependent 3-O-methylfluorescein phosphate (3-O-MFPase). SR Ca(2+)-ATPase was analysed by e.l.i.s.a., Ca(2+)-dependent phosphorylation and its activities with ATP and 3-O-methylfluorescein phosphatase (3-O-MFP). In MyD muscle the K(+)-dependent 3-O-MFPase activity and the activity and concentration of SR Ca(2+)-ATPase were decreased by 40%. In cultured muscle cells from MyD patients the activities as well as the concentration of both Na+/K(+)-ATPase and SR Ca(2+)-ATPase were reduced by about 30-40%. The ouabain-binding constant and the molecular activities, i.e. catalytic-centre activities with ATP or 3-O-MFP, of Na+/K(+)-ATPase and SR Ca(2+)-ATPase were similar in muscle as well as in cultured cells from both controls and MyD patients. Thus the decreased activity of both ATPases in MyD muscle is caused by a reduction in the number of their molecules. To check whether the deficiency of ATP-dependent ion pumps is a general feature of the pathology of MyD, we examined erythrocytes from the same patients. In these cells the Ca2+ uptake rate and the Ca(2+)-ATPase activity were lower than in controls, but the Ca(2+)-ATPase concentration was normal. Thus the reduced Ca(2+)-ATPase activity is caused by a decrease in the molecular activity of the ion pump. The Na+/K(+)-ATPase activity is also lower in erythrocytes of MyD patients. It is concluded that the observed alterations in ion pumps may contribute to the pathological phenomena in the muscle and other tissues in patients with MyD.
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PMID:Deficiency of Na+/K(+)-ATPase and sarcoplasmic reticulum Ca(2+)-ATPase in skeletal muscle and cultured muscle cells of myotonic dystrophy patients. 839 37

After excitation of skeletal muscle, the disturbed ion homeostasis is restored by Na+, K+ ATPase of the sarcolemma and Ca2+ ATPase of the sarcoplasmic reticulum (SR). Contrary to Na+, K+ ATPase, the concentration and isoenzyme distribution of SR Ca2+ ATPase in human skeletal muscle depend on fibre type and age. In cultured human muscle cells the concentration and activity of Na+, K+ ATPase and SR Ca2+ ATPase increase with maturation. In skeletal muscle and cultured muscle cells of patients suffering from myotonic dystrophy (MyD), the activity and the concentration of both Na+, K+ ATPase and SR Ca2+ ATPase are decreased by about 40%. In addition, we measured in cultured MyD muscle cells at rest an increased cytosolic Ca2+ concentration ([Ca2+]i) caused by active voltage-operated Ca2+ channels, which are inactive in resting control cells. However, the restoration of a stimulus-induced Ca2+ transient is unaffected. A differentiation-related disturbance of membranes or a modulation defect of membrane proteins may play a role in MyD. In skeletal muscle and cultured muscle cells of patients suffering from Brody's disease, which is characterized by impaired muscle relaxation, the SR Ca2+ ATPase activity is reduced by about 50%, but the concentrations of total SR Ca2+ ATPase and the predominant SERCA1 isoform are normal. Diseased muscle cells show a delayed restoration of [Ca2+]i after stimulation, which might be explained by structural modifications of SERCA1. Reduction of the Ca2+ release by drugs balances the excitation-relaxation cycle of the pathological cells.
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PMID:Ion transport in human skeletal muscle cells: disturbances in myotonic dystrophy and Brody's disease. 872 96

In this study we investigated the sarcoplasmic reticulum (SR), alongside myofibrillar phenotype, in muscle samples from five Myotonic Dystrophy (DM) patients and five control individuals. DM muscles exhibited as a common feature, a decrease in the slow isoform of myosin heavy chain (MHC) and of troponin C in myofibrils. We observed a match between myofibrillar changes and changes in SR membrane markers specific to fiber type, i.e. the fast (SERCA1) Ca(2+)-ATPase isoform increased concomitantly with a decrease of protein phospholamban (PLB), which in native SR membranes colocalizes with the slow (SERCA2a) SR Ca(2+)-ATPase, and regulates its activity depending on phosphorylation by protein kinases. Our results outline a cellular process selectively affecting slow-twitch fibers, and non-degenerative in nature, since neither the total number of Ca(2+)-pumps or of ryanodine receptor/Ca(2+)-release channels, or their ratio to the dihydropyridine receptor/voltage sensor in junctional transverse tubules, were found to be significantly changed in DM muscle. The only documented, apparently specific molecular changes associated with this process in the SR of DM muscle, are the defective expression of the slow/cardiac isoform of Ca(2+)-binding protein calsequestrin, together with an increased phosphorylation activity of membrane-bound 60 kDa Ca(2+)-calmodulin (CaM) dependent protein kinase. Enhanced phosphorylation of PLB by membrane-bound Ca(2+)-CaM protein kinase also appeared to be most pronounced in biopsy from a patient with a very high CTG expansion, as was the overall 'slow-to-fast' transformation of the same muscle biopsy. Animal studies showed that endogenous Ca(2+)-CaM protein kinase exerts a dual activatory role on SERCA2a SR Ca(2+)-ATPase, i.e. either by direct phosphorylation of the Ca(2+)-ATPase protein, or mediated by phosphorylation of PLB. Our results seem to be consistent with a maturational-related abnormality and/or with altered modulatory mechanisms of SR Ca(2+)-transport in DM slow-twitch muscle fibers.
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PMID:Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy. 884 17

Myotonic dystrophy (DM), the most prevalent muscular disorder in adults, is caused by (CTG)n-repeat expansion in a gene encoding a protein kinase (DM protein kinase; DMPK) and involves changes in cytoarchitecture and ion homeostasis. To obtain clues to the normal biological role of DMPK in cellular ion homeostasis, we have compared the resting [Ca2+]i, the amplitude and shape of depolarization-induced Ca2+ transients, and the content of ATP-driven ion pumps in cultured skeletal muscle cells of wild-type and DMPK[-/-] knockout mice. In vitro-differentiated DMPK[-/-] myotubes exhibit a higher resting [Ca2+]i than do wild-type myotubes because of an altered open probability of voltage-dependent l-type Ca2+ and Na+ channels. The mutant myotubes exhibit smaller and slower Ca2+ responses upon triggering by acetylcholine or high external K+. In addition, we observed that these Ca2+ transients partially result from an influx of extracellular Ca2+ through the l-type Ca2+ channel. Neither the content nor the activity of Na+/K+ ATPase and sarcoplasmic reticulum Ca2+-ATPase are affected by DMPK absence. In conclusion, our data suggest that DMPK is involved in modulating the initial events of excitation-contraction coupling in skeletal muscle.
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PMID:Myotonic dystrophy protein kinase is involved in the modulation of the Ca2+ homeostasis in skeletal muscle cells. 929 9

1. The Na+,K+-ATPase or Na+,K+-pump, mediating the active transport of Na+ and K+, which was first identified 40 years ago, is a central target for acute and long-term regulation, as well as for therapeutic intervention. Acute stimulation of the Na+,K+-pump in skeletal muscle by insulin, catecholamines, beta2-agonists or theophylline increases the intracellular uptake of K+ and accounts for the hypokalaemia elicited by these agents. Conversely, digitalis intoxication elicits hyperkalaemia via acute inhibition of the Na+, K+-pump. 2. Simple and accurate methods have been developed for the quantification of the total concentration of Na+,K+-pumps in small (0.5-5 mg) fresh or frozen biopsies of human skeletal muscle, myocardium or other tissues. This has allowed the identification of several long-term regulatory changes in the concentration of this transport system in human tissues. In skeletal muscle, upregulation is induced by training, thyroid hormones or glucocorticoids. Downregulation is seen in hypothyroidism, cardiac insufficiency, myotonic dystrophy, McArdle disease, K+ deficiency and after muscle inactivity. 3. Since the skeletal muscles contain one of the major pools of Na+,K+-pumps, these changes are important for the ability to counterregulate the hyperkalaemia elicited by exercise or the ingestion of K+. Moreover, downregulation or inhibition of the Na+, K+-pumps in skeletal muscle interferes with contractile performance. Since digitalis glycosides bind to the Na+,K+-pump, the muscles constitute a large distribution volume for these agents and are therefore an important determinant for their plasma level. 4. In cardiac insufficiency, the decrease in the concentration of Na+, K+-pumps in the myocardium is over a wide range correlated to the concomitant reduction in ejection fraction. The regulatory and pathophysiological changes in the activity and concentration of Na+, K+-pumps are important for the contractile function of skeletal muscle and heart as well as for K+ homoeostasis and the response to digitalization.
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PMID:Clinical and therapeutic significance of the Na+,K+ pump*. 966 81

SIX5 (previously known as myotonic dystrophy associated homeodomain protein - DMAHP ) is a member of the SIX [ sine oculis homeobox (Drosophila ) homologue ] gene family which encodes proteins containing a SIX domain adjacent to a homeo-domain. To investigate the DNA binding specificities of these two domains in SIX5, they were expressed as GST fusion proteins, both separately and together. Affinity purified recombinant proteins and cell lysates from bacteria expressing the recombinant proteins were used in gel retardation assays with double stranded oligonucleotides representing putative DNA binding sites. The putative sites included two in the promoter region of DMPK (dystrophia myotonica protein kinase ) and the previously characterised murine Six4 DNA binding site in the Na(+)/K(+) ATPase alpha 1 subunit gene ( ATP1A1 ) regulatory element (ARE). None of the recombinant proteins showed any affinity for the two putative sites in DMPK. However, the two recombinant proteins containing the homeodomain both formed at least one specific complex with the ARE. The recombinant protein containing both domains formed a second specific complex with the ARE, assumed to be a dimer complex. Finally, a whole genome PCR-based screen was used to identify genomic DNA sequences to which SIX5 binds, as an initial stage in the identification of genes regulated by SIX5.
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PMID:Functional analysis of the homeodomain protein SIX5. 1075 85

Myotonic dystrophy (DM) is an autosomal dominant disorder characterized by skeletal muscle wasting, myotonia, cardiac arrhythmia, hyperinsulinaemia, mental retardation and ocular cataracts. The genetic defect in DM is a CTG repeat expansion located in the 3' untranslated region of DMPK and 5' of a homeodomain-encoding gene, SIX5 (formerly DMAHP; refs 2-5). There are three mechanisms by which CTG expansion can result in DM. First, repeat expansion may alter the processing or transport of the mutant DMPK mRNA and consequently reduce DMPK levels. Second, CTG expansion may establish a region of heterochromatin 3' of the repeat sequence and decrease SIX5 transcription. Third, toxic effects of the repeat expansion may be intrinsic to the repeated elements at the level of DNA or RNA (refs 10,11). Previous studies have demonstrated that a dose-dependent loss of Dm15 (the mouse DMPK homologue) in mice produces a partial DM phenotype characterized by decreased development of skeletal muscle force and cardiac conduction disorders. To test the role of Six5 loss in DM, we have analysed a strain of mice in which Six5 was deleted. Our results demonstrate that the rate and severity of cataract formation is inversely related to Six5 dosage and is temporally progressive. Six5+/- and Six5-/- mice show increased steady-state levels of the Na+/K+-ATPase alpha-1 subunit and decreased Dm15 mRNA levels. Thus, altered ion homeostasis within the lens may contribute to cataract formation. As ocular cataracts are a characteristic feature of DM, these results demonstrate that decreased SIX5 transcription is important in the aetiology of DM. Our data support the hypothesis that DM is a contiguous gene syndrome associated with the partial loss of both DMPK and SIX5.
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PMID:Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts. 1080 68

Myotonic dystrophy (DM) is caused by a CTG expansion in the 3'-untranslated region of a protein kinase gene (DMPK). Cardiovascular disease is one of the most prevalent causes of death in DM patients. Electrophysiological studies in cardiac muscles from DM patients and from DMPK(-/-) mice suggested that DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity. However, there are no data regarding the molecular signaling pathways involved in DM heart failure. Here we show that DMPK expression in cardiac myocytes is highly enriched in the sarcoplasmic reticulum (SR) where it colocalizes with the ryanodine receptor and phospholamban (PLN), a muscle-specific SR Ca(2+)-ATPase (SERCA2a) inhibitor. Coimmunoprecipitation studies showed that DMPK and PLN can physically associate. Furthermore, purified wild-type DMPK, but not a kinase-deficient mutant (K110A DMPK), phosphorylates PLN in vitro. Subsequent studies using the DMPK(-/-) mice demonstrated that PLN is hypo-phosphorylated in SR vesicles from DMPK(-/-) mice compared with wild-type mice both in vitro and in vivo. Finally, we show that Ca(2+) uptake in SR is impaired in ventricular homogenates from DMPK(-/-) mice. Together, our data suggest the existence of a novel regulatory DMPK pathway for cardiac contractility and provide a molecular mechanism for DM heart pathology.
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PMID:Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum. 1559 48


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