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)

Studies in animal models have suggested that alterations affecting phospholamban-mediated stimulation of Ca2+ uptake by sarcoplasmic reticulum are involved in the pathophysiology of heart disease. A monoclonal antibody that binds to phospholamban and stimulates Ca2+ uptake was used to characterize phospholamban-mediated effects in human cardiac sarcoplasmic reticulum and to compare these effects in tissue from normal and failing hearts. Stimulation of Ca2+ uptake by anti-phospholamban monoclonal antibody simulated the effect of phosphorylation of phospholamban by cAMP-dependent protein kinase. Binding of anti-phospholamban antibody reduced the K0.5 of the Ca2(+)-transporting ATPase from 0.53 microM [( Ca2+]) to 0.29 microM [( Ca2+]), without affecting Vmax or nHill. At 0.2 microM Ca2+, stimulation was 1.93-fold in sarcoplasmic reticulum prepared from normal human left ventricular myocardium and 1.94-fold in sarcoplasmic reticulum prepared from the left ventricular myocardium of patients with heart failure resulting from idiopathic dilated cardiomyopathy. Stimulation of Ca2+ uptake in canine cardiac sarcoplasmic reticulum under identical conditions was 1.89-fold. Phospholamban-mediated stimulation of Ca2+ uptake in human cardiac sarcoplasmic reticulum is thus comparable in magnitude to that observed in other species and results from an increase in the apparent affinity of the Ca2(+)-transporting ATPase for Ca2+. The pathogenesis of heart failure in idiopathic dilated cardiomyopathy does not, however, appear to involve intrinsic alterations of this mechanism.
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PMID:Phospholamban-mediated stimulation of Ca2+ uptake in sarcoplasmic reticulum from normal and failing hearts. 213 70

A new P-type ATPase gene, cta3, has been identified in Schizosaccharomyces pombe. The deduced amino acid sequence presents a 45% identity with the Saccharomyces cerevisiae putative Ca2(+)-ATPase encoded by the PMR2 gene. The cta3 protein contains 7 out of the 8 amino acid residues involved in high affinity Ca2+ binding in the sarcoplasmic reticulum Ca2(+)-ATPase from muscles. It also contains a region similar to the phospholamban-binding domain that characterizes this Ca2+ pump. A null mutation of cta3 leads to higher levels of cytosolic free Ca2+ and to lower amounts of sequestered and bound Ca2+. Cellular Ca2+ efflux and rates of uptake into intracellular compartments are reduced by the loss of cta3 function. The sequence analysis and the physiological results strongly support the conclusion that the cta3 gene encodes a Ca2(+)-ATPase, probably located in intracellular membranes.
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PMID:Calcium homeostasis and transport are affected by disruption of cta3, a novel gene encoding Ca2(+)-ATPase in Schizosaccharomyces pombe. 214 81

Phospholamban is the regulator of the Ca(2+)-ATPase in cardiac sarcoplasmic reticulum (SR). The mechanism of regulation appears to involve inhibition by dephosphorylated phospholamban, and phosphorylation may relieve this inhibition. Fast-twitch skeletal muscle SR does not contain phospholamban, and it is not known whether the Ca(2+)-ATPase isoform from this muscle may be also subject to regulation by phospholamban in a similar manner as the cardiac isoform. To determine this we reconstituted the skeletal isoform of the SR Ca(2+)-ATPase with phospholamban in phosphatidylcholine proteoliposomes. Inclusion of phospholamban was associated with significant inhibition of the initial rates of Ca2+ uptake at pCa 6.0, and phosphorylation of phospholamban by the catalytic subunit of cAMP-dependent protein kinase reversed the inhibitory effects on the Ca2+ pump. Similar effects of phospholamban were also observed using phosphatidylcholine:phosphatidylserine proteoliposomes, in which the Ca2+ pump was activated by the negatively charged phospholipids (24). Regulation of the Ca(2+)-ATPase appeared to involve binding with the hydrophilic portion of phospholamban, as evidenced by cross-linking experiments, using a synthetic peptide that corresponded to amino acids 1-25 of phospholamban. These findings suggest that the fast-twitch isoform of the SR Ca(2+)-ATPase may be also regulated by phospholamban, although this regulator is not expressed in fast-twitch skeletal muscles.
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PMID:Regulation of the skeletal sarcoplasmic reticulum Ca2+ pump by phospholamban in reconstituted phospholipid vesicles. 215 30

Intracellular Ca2+ concentrations in cardiac cells are dependent on trans-sarcolemmal Ca2+ fluxes and the ability of sarcoplasmic reticulum to release and take up Ca2+. Ca2+ accumulation by sarcoplasmic reticulum membranes causes muscle to relax, whereas Ca2+ release from sarcoplasmic reticulum initiates contraction. Ca2+ transport by the sarcoplasmic is mediated by a Ca2+-dependent ATPase enzyme. Ca2+ release from sarcoplasmic reticulum may be mediated by a ligant-gated Ca2+ channel. The physiological role of sarcoplasmic reticulum in developing muscle is not well established. In this report we investigated the composition and function of sarcoplasmic reticulum membranes during cardiac myogenesis. Phospholamban, a major phosphoprotein in mature sarcoplasmic reticulum membranes was present during early stages of cardiac myogenesis. The embryonic form of phospholamban was phosphorylated by cAMP-dependent protein kinase but not in the presence of Ca2+ and calmodulin. Ca2+ uptake and Ca2+-dependent ATPase activity were low in fetal sarcoplasmic reticulum compared to adult control membranes, although the apparent affinities of the enzyme for Ca2+ were similar. Sarcoplasmic reticulum vesicles used in these studies had very low levels of plasma membrane and mitochondrial contamination. The amounts of both 110-kDa Ca2+-ATPase and 55-kDa calsequestrin in the sarcoplasmic reticulum membrane were lower in fetal sarcoplasmic reticulum vesicles compared to mature membranes. Ca2+-ATPase and calsequestrin were identified in the isolated sarcoplasmic reticulum vesicles using specific antibodies produced against these membrane proteins. Age-related differences in Ca2+ transport properties of cardiac sarcoplasmic reticulum and in the amount of Ca2+-ATPase and calsequestrin may explain alterations in the regulation of intracellular Ca2+ concentrations in fetal heart muscle. This may relate to the developmental changes observed in myocardial function.
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PMID:Sarcoplasmic reticulum membrane and heart development. 244 May 34

The effects of different periods of myocardial ischemia on sarcoplasmatic reticulum function were studied in porcine hearts in which successive occlusions of branches of the left anterior descending coronary artery yielded myocardium ischemic for 0.5, 1 or 2 h. Sarcoplasmatic reticulum vesicles were isolated from transmural biopsies of control and ischemic segments. Ca2+ pumping ATPase was already impaired after 0.5 h of ischemia (77 +/- 9% of control, n = 5) and had decreased to 44 +/- 9% of control (n = 4) after 1 h of ischemia. The functional damage caused by ischemia may be related to an altered second messenger control of the Ca2+ pump because the in vitro phosphorylation of phospholamban by catalytic subunit was also reduced.
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PMID:Sarcoplasmatic reticulum function in the ischemic myocardium. 244 93

Smooth muscle cells contain two distinct Ca2+-transport ATpases with a different subcellular localization. The plasmalemmal Ca2+ pump has a relative molecular weight (Mr) of 140k and its phospho-intermediate level is increased by La3+. Its resemblance to the erythrocyte Ca2+ pump is further confirmed by its calmodulin-binding capacity and its antigenic properties. A 100k Ca2+-transport ATPase is localized in the endoplasmic reticulum. Its phospho-intermediate level is decreased by La3+, and it is antigenically related to the cardiac sarcoplasmic reticulum Ca2+-transport ATPase. These two different Ca2+-transport ATPases are present in both visceral and vascular smooth muscle, but tissue- and species-dependent differences in their relative amount have been observed. The endoplasmic-reticulum Ca2+-transport ATPase is regulated via phospholamban. Phosphorylation of this regulatory protein by cAMP-dependent as well as by cGMP-dependent protein kinase stimulates the endoplasmic-reticulum Ca2+ pump. The activity of the plasmalemmal Ca2+-transport ATPase can be modulated by calmodulin, negatively charged phospholipids, and by receptor-binding agonists. cGMP-dependent protein kinase also exerts a stimulatory effect on the plasmalemmal Ca2+ pump, but this effect is not mediated via a direct phosphorylation of the Ca2+ pump.
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PMID:The (Ca2+-Mg2+)-ATPases of the plasma membrane and of the endoplasmic reticulum in smooth muscle cells and their regulation. 246 79

Calcium uptake and (Ca2+ + Mg2+)-ATPase activity in canine cardiac microsomes were found to be stimulated by heparin and various other polyanions. Prior treatment of the microsomes with the ionophores alamethicin or A23187 produced no change in the extent of stimulation of the ATPase activity by heparin yet eliminated net calcium uptake. This finding and a lack of change in the stoichiometric ratio of mol of calcium transported/mol of ATP hydrolyzed (calcium:ATP) suggest that the effect of heparin is on the calcium pump rather than on a parallel calcium efflux pathway. Certain polycationic compounds including poly-L-arginine and histone inhibited both cardiac and fast skeletal muscle microsomal calcium uptake and also produced no change in the stoichiometric ratio of calcium to ATP. Several lines of evidence indicate that the polyanionic compounds tested stimulate calcium uptake by interacting with phospholamban, the putative phosphorylatable regulator of the cardiac sarcoplasmic reticulum calcium pump, whereas polycationic compounds appear to interact with the pump. (i) Heparin stimulated calcium uptake to the same extent as protein kinase A or trypsin, whereas prior phosphorylation or tryptic cleavage of phospholamban from the membrane abolished the stimulatory effect of heparin. (ii) Calcium uptake and (Ca2+ + Mg2+)-ATPase activity in fast skeletal muscle microsomes, which lack phospholamban, were unaffected by heparin. (iii) Purified cardiac (Ca2+ + Mg2+)-ATPase activity was no longer stimulated by heparin yet was still inhibited by polycationic compounds. The heparin-induced stimulation of calcium uptake was dependent on the pH and ionic strength of the heparin-containing preincubation medium, hence electrostatic interactions appear to play a significant role in heparin's stimulatory action. The data are consistent with an inhibitory role of the positively charged cytoplasmic domain of phospholamban with respect to calcium pump activity and the relief of the inhibition upon reduction in phospholamban's positive charge by phosphorylation or binding of polyanions.
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PMID:Modulation by polyelectrolytes of canine cardiac microsomal calcium uptake and the possible relationship to phospholamban. 247 44

The present study was designed to examine the relation between the loss of Ca2+ uptake activity and the change of protein phosphorylation in sarcoplasmic reticulum from ischemic myocardium. Ischemic (0.5, 1 and 2 h duration) and non-ischemic tissue samples were taken from the coronary-ligated porcine left ventricle and sarcoplasmic reticulum fractions were isolated. The membranes were tested for Ca2+ uptake and ATPase activities and phosphorylation of phospholamban. The in vitro 32P incorporation into phospholamban in the presence of cAMP plus the catalytic subunit of cyclic AMP dependent protein kinase became markedly reduced depending on the duration of ischemia. The activities of the Ca2+ pump (Ca2+ uptake and ATPase) were also decreased. The 32P incorporation into the myofibrillar component troponin I, which is also a specific substrate for catalytic subunit, was not affected by ischemia. The reduction of the Ca2+ pump activity correlated with the reduction of 32P incorporation into phospholamban. It is postulated that the ischemia induced inactivation of the Ca2+ pump is not only a consequence of specific loss of enzyme activity, but it is also caused by altered characteristics of phospholamban.
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PMID:Calcium transport and phospholamban in sarcoplasmic reticulum of ischemic myocardium. 252 77

The rapid removal of Ca2+ ions from the cytosol, necessary for the efficient relaxation of cardiac muscle cells, is performed by the Ca2+-pumping ATPase of the sarcoplasmic reticulum. The calcium pump is activated by cyclic AMP- and calmodulin-dependent phosphorylation of phospholamban, an integral membrane protein of the sarcoplasmic reticulum. Using a heterobifunctional crosslinking agent which can be cleaved and photoactivated, we provide evidence for a direct interaction between the two proteins. Only the non-phosphorylated form of phospholamban interacts with the ATPase, demonstrating that phospholamban is an endogenous inhibitor that is removed from the ATPase by phosphorylation. Non-phosphorylated phospholamban interacts only with the calcium-free conformation of the ATPase and is released when it is converted to the calcium-bound state. We localized the site of interaction to a single peptide isolated after cyanogen bromide cleavage of the ATPase. The peptide derives from a domain just C-terminal to the aspartyl phosphate of the active site. This domain is unique to ATPases of the sarcoplasmic reticulum in that it has no homology with any other phosphorylation-type ion pump. The domain occurs in both slow- and fast-twitch isoforms of the ATPase, even though phospholamban is not expressed in fast-twitch muscles.
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PMID:Nature and site of phospholamban regulation of the Ca2+ pump of sarcoplasmic reticulum. 253 Apr 54

The Ca2+-transport ATPases of smooth muscle were studied. It was concluded that smooth muscle expresses at least two different Ca2+-transport ATPases. One is present in the plasma membrane with an Mr of 140-130 kDa it is stimulated by calmodulin and it could be purified by affinity chromatography on immobilized calmodulin. This ATPase could be reconstituted in artificial membrane vesicles that were then able to catalyze an ATP-dependent Ca2+-uptake. This Ca2+-transport ATPase could also be stimulated by partial proteolysis and by negatively charged phospholipids. Polyclonal and monoclonal antibodies were found to inhibit this ATPase and concomitantly the Ca2+-transport specifically in plasma membranes and not in the endoplasmic reticulum. This plasma-membrane Ca2+ pump from smooth muscle is controlled by cGMP via phosphorylation of a phosphatidylinositol kinase which phosphorylates phosphatidylinositol to phosphatidylinositol-monophosphate for which a specific binding site exists on the Ca2+-transport ATPase. The catalytic phosphoprotein intermediate of this ATPase can be easily demonstrated and this forms a highly sensitive method to detect the presence of the ATPase in different smooth muscles and even in non-muscle sources as the kidney. A second type of Ca2+ pump with an Mr of 100 kDa is found in smooth-muscle endoplasmic reticulum. By means of its catalytic phosphointermediate this pump could be characterized as similar to the cardiac/slow muscle isoform of the sarcoplasmic reticulum Ca2+ pumps, but different from the fast skeletal-muscle isoform. Immunological studies confirmed this conclusion. This endoplasmic reticulum Ca2+ pump in smooth muscle is regulated by cAMP and cGMP via phosphorylation of phospholamban. Once Ca2+ is accumulated in the lumen of the endoplasmic reticulum, it can be bound to calsequestrin. The calsequestrin of smooth muscle appears to be a similar isoform as that found in cardiac muscle. The Ca2+-transport ATPases were found to be inhibited by fluoroaluminate complexes without the involvement of GTP-binding proteins.
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PMID:Ca2+ transport in muscle. A study of the Ca2+-transport ATPases in smooth muscle. 253 11


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