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)

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca(2+)-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0 +/- 2.2 versus 8.6 +/- 1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.
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PMID:Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. 894 45

To study the relationship between myocardial energetics and contractile reserve, we acutely and selectively inhibited creatine kinase (CK) activity in isolated perfused rat hearts, using increasing doses of iodoacetamide. 31P nuclear magnetic resonance spectroscopy was used to measure intracellular pH and the concentrations of ATP, phosphocreatine, and inorganic phosphate. Contractile reserve was assessed as the increase of rate-pressure product (RPP) from baseline during high-calcium perfusion. Contractile reserve was reduced by 9, 35, and 72% in hearts with 26, 6, and 1% CK activity, respectively. An inverse linear relationship between RPP and the free energy release from ATP hydrolysis ([delta G approximately P[) was shown for all groups. Furthermore, the maximal RPPs of all hearts were achieved at the same level of [delta G approximately P[ (52-53 kJ/mol), which is equal to the free energy requirement of sarcoplasmic reticulum Ca2+ adenosine 5'-triphosphatase (ATPase). We suggest that inhibition of the CK reaction caused a decrease of [delta G approximately P[ which, in turn, limits the Ca(2+)-handling capacity of sarcoplasmic reticulum Ca2+ ATPase. In this way, the ability of the heart to increase its contractile performance is restricted.
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PMID:Energetic basis for reduced contractile reserve in isolated rat hearts. 896 58

The effect on intracellular Na+ ([Na+]i) and Rb+ fluxes if reduced [ATP]/ [ADP] and increased Pi has been investigated by 1 mM potassium cyanide (KCN) or KCl (control) infusion (24 min) in Langendorff perfused rat hearts. 87Rb, 23Na, or 31P nuclear magnetic resonance (NMR) spectra were acquired to measure intracellular Rb+ (a congener for K+, 20% substitution), Na+, and phosphates. KCN infusion (14-24 min) caused decreases in phosphocreatine (34 +/- 12% of initial), ATP (64 +/- 17), and Rb content (71 +/- 7) and increases in Pi (273 +/- 65) and [Na+]i (210 +/- 52). Dimethylamiloride (10 microM) did not change the rate of Na+ accumulation. The rate constant of unidirectional Rb+ efflux (min-1) increased during KCN treatment by 70% (0.061 +/- 0.006 vs. 0.036 +/- 0.004, P = 0.0001). KCN-stimulated Rb+ efflux was inhibited by glibenclamide (Glib, 10 microM. 0.042 +/- 0.009, P = 0.0001 vs. KCN) and alpha-cyano-4-hydroxycinnamate (0.5 mM, 0.047 +/- 0.008, P < 0.002 vs. KCN). KCN moderately decreased the Rb+ influx rate (to 82 +/- 17%, P = 0.01), which was depressed more significantly in the presence of Glib (47 +/- 17%, P = 0.03). We suggest that inhibition of Na(+)-K(+)-adenosinetriphosphatase (ATPase) by Pi is responsible for intracellular Na+ accumulation, whereas K+ loss is associated with both activation of ATP-sensitive K+ channels and the K(+)-lactate-cotransporter and inhibition of Na(+)-K(+)-ATPase.
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PMID:Cytoplasmic phosphates in Na(+)-K+ balance in KCN-poisoned rat heart: a 87Rb-, 23Na-, and 31P-NMR study. 896 70

The mechanism by which adenosine accumulates in the hippocampal slice during energy deprivation was investigated by examining the adenosine A1 receptor mediated depression of synaptically evoked field potentials in the CA1 area. Blocking of the mitochondrial electron transport chain with 200 microM sodium cyanide or mitochondrial uncoupling with 50 microM 2,4-dinitrophenol both produced a rapid depression of synaptic transmission that was antagonised by 1 microM 8-cyclopentyl-1, 3-dimethylxanthine, an adenosine A1 receptor antagonist. Cellular ATPase inhibition or elevation of cytosolic phosphocreatine failed to alter the 2,4-dinitrophenol induced depression of synaptic transmission. Attempts to block mitochondrial ATP synthesis with 3 microM oligomycin or 75 microM atractyloside did not cause depression of synaptic transmission. 100 microM iodotubercidin, an adenosine kinase inhibitor, alone produced a depression of synaptic transmission that was completely reversed by 1 microM 8-cyclopentyl-1,3-dimethylxanthine; however, a simultaneous or independent episode of hypoxia surmounted the adenosine A1 receptor antagonism and produced approximately 50% depression of synaptic transmission. Depression of synaptic transmission by hypoxia, cyanide or 2,4-dinitrophenol is a result of rapid adenosine accumulation and activation of extracellular adenosine A1 receptors. Although this early depression of synaptic transmission is a consequence of inhibition of normal mitochondrial function, it is not a result of depletion of cytosolic ATP, since attempts to preserve ATP did not maintain synaptic transmission during mitochondrial poisoning, and inhibitors of oxidative phosphorylation did not produce synaptic depression.
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PMID:Mechanism of adenosine accumulation in the hippocampal slice during energy deprivation. 901 69

Studies of skinned fibers suggest that the rate of ATP turnover in skeletal muscle is depressed by acidosis. To examine whether this occurs in intact muscles, the ATP cost of isometric contractions was measured in ex vivo, arterially perfused cat biceps (predominantly fast-twitch) and soleus (slow-twitch) muscles under normocapnic (5% CO2) and hypercapnic (70% CO2) conditions. Hypercapnia decreased extracellular pH from 7.4 to 6.7 and intracellular pH from 7.1 to 6.5 (soleus) or 6.6 (biceps) but had no significant effect on the phosphocreatine (PCr)-to-ATP ratio in muscles at rest. The ATP cost of contraction was estimated from PCr changes, measured by gating the acquisition of 31P-nuclear magnetic resonance spectra to times before and after brief tetani (1 s at 100 Hz and 2 s at 25 Hz for biceps and soleus, respectively) or 10-s trains of twitches (2 and 1 Hz, respectively). Peak isometric force and the ATP cost of tetanic contraction (PCr/force x time integral) were not significantly different under hypercapnic compared with normocapnic conditions in either muscle (mean: 7.97 and 2.44 micromol x kg(-1) x s(-1) for biceps and soleus, respectively). Twitch force and the ATP cost per twitch decreased by nearly 50% during hypercapnic perfusion in both muscle types. The results indicate that hypercapnic acidosis has no significant effect on the ATPase rate per active myosin head in intact mammalian skeletal muscle.
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PMID:Acidosis has no effect on the ATP cost of contraction in cat fast- and slow-twitch skeletal muscles. 912 91

The contribution of ATP-generating systems to Na+ pump (Na+-K+-ATPase) function was studied in Xenopus laevis A6 kidney epithelia apically permeabilized with digitonin. The ouabain-inhibitable Na+ pump current (I(P)) was measured in the presence of otherwise impermeant inhibitors and/or substrates at Na+ and K+ concentrations that allowed near-maximal pump function. Confocal fluorescence microscopy after apical addition of sulfosuccinimidobiotin (molecular weight of 443) showed that all cells were permeabilized. Less than 15% of the endogenous lactate dehydrogenase and creatine kinase (CK) were released into the apical medium. The I(P) was approximately 5 microA/cm2 in the presence of D-glucose. Blocking glycolysis with 2-deoxy-D-glucose or oxidative phosphorylation with antimycin A decreased it by > or = 50%. Exogenously added ATP prevented these decreases fully or partially, respectively. Two CK isoforms were detected, one likely being mitochondrial and the other corresponding to mammalian B isoform of CK. Phosphocreatine partially restored Na+ pump activity during inhibition of either ATP synthesis pathway. In conclusion, the ATP used by Na+ pumps of apically digitonin-permeabilized A6 epithelia is generated to a similar extent by glycolysis and oxidative phosphorylation. The CK system can partially support the ATP supply to the Na+ pumps.
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PMID:Metabolic support of Na+ pump in apically permeabilized A6 kidney cell epithelia: role of creatine kinase. 912 14

Vanadium compounds have been shown to cause a variety of biological and metabolic effects including inhibition of certain enzymes, alteration of contractile function, and as an insulin like regulator of glucose metabolism. However, the influence of vanadium on metabolic and ionic changes in hearts remains to be understood. In this study we have examined the influence of vanadate on glucose metabolism and sodium transport in isolated perfused rat hearts. Hearts were perfused with 10 mM glucose and varying vanadate concentrations (0.7-100 microM) while changes in high energy phosphates (ATP and phosphocreatine (PCr)), intracellular pH, and intracellular sodium were monitored using 31P and 23Na NMR spectroscopy. Tissue lactate, glycogen, and (Na+, K+)-ATPase activity were also measured using biochemical assays. Under baseline conditions, vanadate increased tissue glycogen levels two fold and reduced (Na+, K+)-ATPase activity. Significant decreases in ATP and PCr were observed in the presence of vanadate, with little change in intracellular pH. These changes under baseline conditions were less severe when the hearts were perfused with glucose, palmitate and beta-hydroxybutyrate. During ischemia vanadate did not limit the rise in intracellular sodium, but slowed sodium recovery on reperfusion. The presence of vanadate during ischemia resulted in attenuation of acidosis, and reduced lactate accumulation. Reperfusion in the presence of vanadate resulted in a slower ATP recovery, while intracellular pH and PCr recovery was not affected. These results indicate that vanadate alters glucose utilization and (Na+, K+)-ATPase activity and thereby influences the response of the myocardium to an ischemic insult.
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PMID:Influence of vanadate on glycolysis, intracellular sodium, and pH in perfused rat hearts. 914 18

The multiple ionic forms of metabolites were evaluated at 37 degrees C for four reactions important in muscle contraction and recovery: 1) ATPase, 2) creatine kinase, 3) the Lohmann reaction, and 4) the Lohmann reaction reversed by coupling to glycogenolysis and glycolysis. Solution of the system of equations defining the multiple equilibria of the proton and cation complexes gives the concentration of each ionic form and a value for the proton stoichiometry for each reaction. The proton stoichiometric coefficients are unique for each reaction and are a function of pH because of differential binding of Mg2+ and K+ to adenine nucleotides, phosphocreatine, and Pi and because of different acidic dissociation constants for the metabolites. These results show the need to consider the binding of K+ in addition to the previously documented effects of Mg2+ in the cytoplasmic milieu. Commercially available software was used to show that related problems can be calculated readily on personal computers in applications similar to those described here.
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PMID:Multiple equilibria of cations with metabolites in muscle bioenergetics. 917 67

The mathematical model of the compartmentalized energy transfer system in cardiac myocytes presented includes mitochondrial synthesis of ATP by ATP synthase, phosphocreatine production in the coupled mitochondrial creatine kinase reaction, the myofibrillar and cytoplasmic creatine kinase reactions, ATP utilization by actomyosin ATPase during the contraction cycle, and diffusional exchange of metabolites between different compartments. The model was used to calculate the changes in metabolite profiles during the cardiac cycle, metabolite and energy fluxes in different cellular compartments at high workload (corresponding to the rate of oxygen consumption of 46 mu atoms of O.(g wet mass)-1.min-1) under varying conditions of restricted ADP diffusion across mitochondrial outer membrane and creatine kinase isoenzyme "switchoff." In the complete system, restricted diffusion of ADP across the outer mitochondrial membrane stabilizes phosphocreatine production in cardiac mitochondria and increases the role of the phosphocreatine shuttle in energy transport and respiration regulation. Selective inhibition of myoplasmic or mitochondrial creatine kinase (modeling the experiments with transgenic animals) results in "takeover" of their function by another, active creatine kinase isoenzyme. This mathematical modeling also shows that assumption of the creatine kinase equilibrium in the cell may only be a very rough approximation to the reality at increased workload. The mathematical model developed can be used as a basis for further quantitative analyses of energy fluxes in the cell and their regulation, particularly by adding modules for adenylate kinase, the glycolytic system, and other reactions of energy metabolism of the cell.
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PMID:Compartmentalized energy transfer in cardiomyocytes: use of mathematical modeling for analysis of in vivo regulation of respiration. 919 6

Two noninvasive methods, calorimetry and 31P nuclear magnetic resonance (NMR), were used to further define energy-consuming and energy-providing reactions in endothelial cells. With 31P-NMR, cellular ATP content was measured; with calorimetry, heat flux as a result of ATP turnover was measured. For these measurements, pig aortic endothelial cells were cultured on microcarrier beads and perfused in a column at constant flow rate. Pig aortic endothelial cells synthesize ATP mainly through glycolysis and, as determined by NMR, contain no phosphocreatine. In such a system, calorimetry-measured heat flux reflects rate of cellular ATP turnover. By use of inhibitors of ATP-dependent processes, the following changes in basal heat flux (231 +/- 65.5 microW/mg protein) were obtained: 18% for 2,3-butanedione monoxime (inhibitor of actomyosin-ATPase), 17% for wortmannin (inhibitor of myosin light chain kinase), 10% for cytochalasin D (inhibitor of actin polymerization), 23% for cycloheximide (inhibitor of protein synthesis), 11% for thapsigargin (inhibitor of endoplasmic reticulum Ca(2+)-ATPase), and 6% for bafilomycin A1 (inhibitor of lysosomal H(+)-ATPase). Cytochalasin D, 2,3-butanedione monoxime, wortmannin, and thapsigargin caused changes in F-actin distribution, as revealed by rhodamine-phalloidin cytochemistry. In a separate experimental series, when cells were perfused with a medium containing no glucose, heat flux decreased by 40% while cellular ATP remained unchanged. Inhibition of glycolysis with 2-deoxy-D-glucose decreased heat flux by 73%, and ATP was no longer visible with 31P-NMR. Despite this massive ATP depletion, which was maintained for 3 h, cells fully recovered heat flux and ATP when 2-deoxy-D-glucose was removed. The results, together with previously published data for Na(+)-K(+)-ATPase [M. L. H. Gruwel, C. Alves, and J. Schrader. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H351-H358, 1995], demonstrate that > 70% of total ATP-consuming processes of endothelial cells can be attributed to specific cellular processes. Actomyosin-ATPase (18%) and protein synthesis (23%) comprise the largest fraction. At least three-fourths of ATP synthesized is provided by glycolysis. Endothelial cells exhibit the remarkable ability to coordinate downregulation of ATP synthesis and consumption when glycolysis is inhibited.
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PMID:Energy turnover of vascular endothelial cells. 925 58


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