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)

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

Sarcoplasmic reticulum (SR) vesicles isolated from skeletal muscle of Sprague-Dawley rats ranging in age from 4 months to 28 months were studied and compared. A marked decline, with age, was observed in the amount of (total) SR proteins isolated per gram of muscle tissue used. This decline is in line with the known loss of muscle fiber mass and size with advancing age; however, whether the magnitudes of these two effects are indeed identical, remains to be studied. In contrast, no analogous age-related change was detected in the amount of SR protein per unit mass of rat cardiac muscle. The calcium contents, per mg protein, in SR vesicles isolated from rats of all age groups studied did not differ significantly, and represented only a small fraction of the total capacity of the vesicles for this cation. This capacity was found to decline at old age and this effect, combined with the age-related decrease in the concentration of SR proteins in the tissue, indicate a significant decline in calcium sequestration ability in old muscle. Both basal (Ca2+ independent) and calcium stimulated ATPase activities were found not to be affected by age. In contrast, the efficiency of Ca2+ transport across the SR membrane, as reflected by the number of calcium ions pumped into the vesicles per ATP cleaved, declined from a value of 0.37 at 3-4 months to 0.15 at 24 months. This change may represent an age-related reduction in the fraction of coupled SR vesicles, possibly due to alterations in the membrane. SR vesicle preparations from both young and old rats displayed strongly biphasic inactivation kinetics when incubated at 37 degrees C. This may reflect the heterogeneity of muscles in the tissue used, or be due to the presence of a mixture of coupled and uncoupled vesicles in the SR preparations. The rate of the first step in the ATPase inactivation, in which about 75% of the activity is lost, was found to be affected by age, the old SR vesicles being markedly more labile than their young counterparts. In contrast, no difference was detected between the inactivation kinetics of young and old ATPase proteins dissolved in Triton X-100 and the inactivation was monophasic down to less than 6% of the original activity. These results indicate that the age-related modifications in the stability of the SR calcium pump system involve the membrane but not the ATPase protein. The inactivation of the SR ATPase is believed to proceed via dissociation of the dimeric enzyme to (unstable) subunits. It is therefore likely that changes in the SR membrane in old muscle render the ATPase more dissociable.
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PMID:A comparative study of the Ca2+-Mg2+ dependent ATPase from skeletal muscles of young, adult and old rats. 252

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 effects of aromatic compounds in sarcoplasmic reticulum Ca2+-ATPase were investigated. The solubility of the drugs in various organic solvents and water was measured. The ratio between the solubility in organic solvents and that in water (distribution coefficient) was used as an index of their hydrophobicity. The order found was triphenylphosphine greater than diphenylamine greater than 3-nitrophenol greater than 4-nitrophenol greater than 1,3-dihydroxybenzene. The effects observed on the Ca2+-ATPase were correlated with hydrophobicity of the drugs, activation and inhibition being obtained at a lower concentration the greater the distribution coefficient of the drug into organic solvent. In leaky vesicles, the effects of each compound on the ATPase activity varied depending on the Ca2+ concentration in the medium: it inhibited in the presence of 5 microM Ca2+ and activated when the Ca2+ concentration was raised to 2 mM. In intact vesicles, 3- and 4-nitrophenol, diphenylamine, and triphenylphosphine enhanced both the rate of ATP hydrolysis and the amount of Ca2+ accumulated by the vesicles. These four drugs inhibited Ca2+ uptake when ITP was used as substrate. 1,3-Dihydroxybenzene enhanced the amount of Ca2+ accumulated by the vesicles regardless of whether ATP or ITP was the substrate. All five compounds inhibited the phosphorylation of the enzyme by Pi, the efflux of Ca2+, and the synthesis of ATP measured during the reversal of the Ca2+ pump. The results indicate that the hydrophobic character of various organic compounds determines their access to sensitive domains of the membrane-bound calcium pump. Additional specific effects are then produced, depending on the structure of each compound.
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PMID:Activation of Ca2+ uptake and inhibition of reversal of the sarcoplasmic reticulum Ca2+ pump by aromatic compounds. 253 Nov 44

The Ca2+-transporting ATPase of rabbit skeletal muscle sarcoplasmic reticulum was site-specifically labeled with either N-(1-anilinonaphth-4-yl)maleimide (ANM) or 5-[[(iodoacetamido)-ethyl]amino]naphthalene-1-sulfonate (IAEDANS), and the segmental motion of submolecular domains of the ATPase molecule was examined by means of time-resolved and steady-state fluorescence anisotropy measurements. The ANM-binding domain showed wobbling with a rotational relaxation time phi = 69 ns in the absence of free Ca2+ without any independent wobbling of the ANM moiety. The IAEDANS-binding domain showed a significantly slower wobbling with phi = 190 ns in the absence of Ca2+. The present results demonstrated for the first time that the ATPase molecule is composed of distinct domains whose mobilities are considerably different from each other. The binding of Ca2+ to the transport site increased the segmental motion of ANM-labeled domain, leading to a phi value of 65 ns. Solubilization of the ANM-labeled SR membranes by deoxycholate led to a further increase in the segmental flexibility (phi = 48 ns in the absence of free Ca2+), indicating that the mobility of the ANM-binding domain was considerably restricted through interaction with the membrane. The mobility of the ANM-binding domain of solubilized ATPase was also increased to some extent upon binding of Ca2+.
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PMID:Independent flexible motion of submolecular domains of the Ca2+,Mg2+-ATPase of sarcoplasmic reticulum measured by time-resolved fluorescence depolarization of site-specifically attached probes. 253 32

The Ca2(+)-ATPase of plasma membranes from a variety of tissues is subject to stimulation in vitro, and apparently in vivo, by physiological concentrations of iodothyronines regarded as biologically active in other bioassay systems. This calmodulin-dependent action of thyroid hormone is nongenomic, that is, directly on the cell membrane and independent of the cell nucleus. In the case of human erythrocyte Ca2(+)-ATPase, this assay of thyroid hormone bioactivity is attractive as an in vitro, readily-studied model of hormone action in a human cell. Enzyme activity is paralleled, as expected, by changes in calcium pump activity. Thyroid hormone action in this system is subject to modulation by glucose and by a variety of compounds which, like iodothyronines, are hydrophobic. The mechanism of thyroid hormone action on membrane Ca2(+)-ATPase involves, at least in part, membrane lipids, including components of the phosphatidylinositol cycle. The physiologic role of thyroid hormone action on cell membrane Ca2(+)-ATPase is speculative. In plasma membranes of nonexcitable and excitable tissues, ambient thyroid hormone may set basal activity of Ca2(+)-ATPase or magnitude of the enzymatic response to calmodulin Ca2+.
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PMID:Thyroid hormone regulation of membrane Ca2(+)-ATPase activity. 253 10

Modelling of the in vivo and in vitro aging processes in the human red cell has stressed the following features of the active calcium uptake by inside-out vesicles: 1) it is higher in the outdated, in vitro aged, than in the fresh red cell (p less than 0.0005), and in the densest, in vivo aged fraction than in the lightest, young fraction (p = 0.08); 2) it increases following stimulation by excess calmodulin to values that are not significantly different; 3) it decreases to the same value in the absence of endogenous calmodulin and inhibitor, with and without exogenous calmodulin; 4) it is the target of a non-competitive inhibition, that is stronger in the fresh than in the outdated red cell. We conclude that the aging process does not involve neither membrane Ca-ATPase nor calmodulin, but rather the interaction of the calcium pump with the inhibitor of Ca-ATPase.
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PMID:The effect of in vitro and in vivo cellular aging on the active calcium transport in human inside-out red cell membrane vesicles. 253 9

Micromolar concentrations of HOCl, an oxidant produced by activated neutrophils, inhibited Ca2+ uptake and Ca2+ATPase of isolated dog heart sarcoplasmic reticulum (SR). DTT antagonized completely the HOCl effect only when it was given within 5 min after the addition of HOCl. When the pharmacological intervention was delayed, the recovery with DTT was not complete, and administration of DTT 30 min after the start of HOCl's reaction with SR resulted in only a small improvement in SR Ca2+ uptake. Although H2O2 and Fe ion-chelate (a free radical-generating procedure) also inhibited Ca2+ uptake and ATPase, the concentrations required were very large. The response of cardiac sarcolemmal and skeletal muscle SR calcium pumps to oxidants was similar to that of the cardiac SR calcium pump.
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PMID:Pharmacological intervention in oxidant-induced calcium pump dysfunction of dog heart. 254 58

We describe the characterization of a rat kidney cDNA that encodes a novel Ca2+-transporting ATPase. The cDNA, termed RK 8-13, was isolated previously using an oligonucleotide hybridization probe corresponding to part of the ATP binding site of the sarcoplasmic reticulum Ca-ATPases (Gunteski-Hamblin, A.-M., Greeb, J., and Shull, G. E. (1988) J. Biol. Chem. 263, 15032-15040). The complete nucleotide sequence of the 4.5-kilobase cDNA has been determined, and the primary structure of the protein has been deduced. The enzyme consists of 999 amino acids, has an Mr of 109,223, and contains all of the conserved domains found in transport ATPases of the E1-E2 class. It exhibits 75-77% amino acid identity with the fast-twitch and slow-twitch/cardiac isoforms of the sarcoplasmic reticulum Ca-ATPase, and the hydropathy plots of the three enzymes are virtually identical. High levels of ATP-dependent Ca2+ uptake were demonstrated in microsomes of COS-1 cells that had been transfected with a construct consisting of the entire coding sequence of the cDNA in the expression vector p91023(B). Northern blot analyses of poly(A)+ RNA revealed that the mRNA for this protein is expressed in heart, skeletal muscle, uterus, brain, lung, liver, kidney, testes, small intestine, large intestine, and pancreas. These data show that the enzyme is a Ca2+-transporting ATPase and that its mRNA is expressed in a broad variety of both muscle and non-muscle tissues.
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PMID:cDNA cloning, functional expression, and mRNA tissue distribution of a third organellar Ca2+ pump. 255 13

The different membrane systems and proteins involved in the control of intracellular calcium movements in the skeletal muscle cell are described. These include the sarcoplasmic reticulum, that Ca(++)-ATPase sarcoplasmic reticular calcium pump, transverse tubules, calcium channels, and the ryanodine receptor protein. The significance of these systems is shown clearly in the myopathies, where the main errors involved do not concern the contractile system, but the command and control mechanisms.
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PMID:[Contraction of skeletal muscles: regulation of calcium intracellular movements]. 256 Jun 11


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