Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human erythrocyte and bovine brain calmodulins were indistinguishable by tryptic peptide mapping, indicating that the primary sequence of the two proteins is either very similar or identical. Calcium binding determinations of human erythrocyte calmodulin, by equilibrium dialysis and fluorescence titration, were in close agreement with previous studies on other calmodulins. The calcium-activated adenosine triphosphatase which is stimulated by calmodulin was shown to be firmly associated with smooth erythrocyte plasma membranes devoid of spectrin and actin. Kinetic titration demonstrated that there are 4500 calmodulin binding sites per erythrocyte and that the turnover number of this calcium-activated adenosine triphosphatase is 3000 mumol of Pi . (mumol of site)-1 . min-1 which is similar to the turnover numbers of other transport adenosine triphosphatases. Furthermore, calmodulin stimulates calcium-activated adenosine triphosphatase by a simple enzyme-ligand association.
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PMID:Human erythrocyte calmodulin. Further chemical characterization and the site of its interaction with the membrane. 15 56

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacology of bepridil. 137 85

Dietary caloric restriction extends life span in the Fischer 344 rat. The interaction of aging and caloric restriction was examined at the level of the plasma membrane transport-associated enzymes, Ca(2+)-adenosine triphosphatase (ATPase) and Na,K-ATPase, in the Fischer rat. Animals were in four age groups, ranging from 6.1 to 25.0 months, and were specific pathogen-free (SPF, barrier-raised). Results from male and female animals raised on an ad libitum diet were compared with those from rats that received 60% of the age-specific caloric intake of their ad lib littermates. The responses of erythrocyte membrane Ca(2+)-ATPase activity in vitro to thyroid hormone (L-thyroxine [T4]; 3,5,3'-triiodothyronine [T3]) and to purified calmodulin, a Ca(2+)-binding protein activator of Ca(2+)-ATPase, were measured. Erythrocyte membrane Na,K-ATPase was also compared in the two diet groups, as was plasma glucose. Plasma membrane Ca(2+)-ATPase activity in the absence of added thyroid hormone and calmodulin was significantly reduced in calorically restricted rats (-39%, P less than .001), compared with ad lib-fed animals, and the response was similar in the four age groups aged 6.1, 12.7, 17.0, and 25.0 months. In contrast, pooled (all ages) Ca(2+)-ATPase response in vitro to T4 and to T3 in calorically restricted animals was enhanced compared with the ad lib group (+62% and +58%, P less than .001, respectively). Calmodulin responsiveness of the enzyme was increased by 45% (P less than .001) in calorie-deprived animals, similar to the change in T4 and T3 responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of caloric restriction and aging on erythrocyte membrane Ca(2+)-ATPase activity in specific pathogen-free Fischer 344 rats. 165 Apr 20

Red blood cell (RBC) calcium, calcium 45 influx, and calcium extrusion as indicated by Ca-stimulated, Mg-dependent adenosine triphosphatase (CaATPase) was determined in patients with chronic renal failure (CRF), patients with CRF receiving continuous ambulatory peritoneal dialysis (CAPD) treatment, and controls. Cell calcium, which in the controls was 5.5 mumol/L of cells, was elevated in patients with CRF--30.6 +/- 6.8 mumol/L of cells (p less than 0.002)--and in patients receiving CAPD-23.6 +/- 6.7 mumol/L of cells (p less than 0.02). Basal CaATPase activity in controls was 850.7 +/- 66.7 nmol inorganic phosphate per milligram of protein per hour. It was suppressed in patients with CRF and patients receiving CAPD: 504.9 +/- 34.4 nmol inorganic phosphate per milligram of protein per hour and 618.2 +/- 47.3 nmol inorganic phosphate per milligram of protein per hour, respectively (p less than 0.01). Calmodulin-stimulated CaATPase revealed a pattern similar to that of CaATPase basal activity. RBC calcium showed an inverse correlation with CaATPase activity (r = -0.935, p less than 0.005) in patients with CRF. Calcium influx was increased in patients with CRF and in patients receiving CAPD: 12.00 +/- 1.34 mumol/L of cells per hour and 13.60 +/- 1.70, respectively, compared with 4.61 +/- 0.39 mumol/L of cells per hour in controls (p less than 0.001). Patients with CRF have elevated RBC calcium levels mainly related to decreased extrusion and to increased influx. CAPD fails to improve substantially these abnormalities. Plasma vanadium levels were markedly elevated in patients undergoing hemodialysis and marginally in patients receiving CAPD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Red blood cell calcium level in chronic renal failure: effect of continuous ambulatory peritoneal dialysis. 214 69

To investigate potential mechanisms underlying the enhanced myocardial performance consequent to exercise training, the adrenergic receptors of myocardial tissue and Ca2+ uptake into sarcoplasmic reticulum-enriched fractions from exercise conditioned animals were compared with that of sedentary controls. Female Wistar rats were exercised by swimming 30 min (5 days/wk) for 12 wk. Exercise conditioning was effective in producing myocardial hypertrophy, as reflected by an increase in heart weight (1.179 +/- 0.022 vs. 1.031 +/- 0.020 g, P less than 0.001) and heart weight-to-body weight ratio (3.29 +/- 0.06 vs. 2.77 +/- 0.05 X 10(-3), P less than 0.001) but no difference in body weight. Despite the myocardial hypertrophy, neither the affinity nor the density of the alpha 1-adrenergic receptors or the beta-adrenergic receptors determined by Scatchard analysis of the ligands [3H]prazosin and [3H]dihydroalprenolol were significantly different between the two groups. The basal Ca2+ uptake into the sarcoplasmic reticulum was also similar (9.90 +/- 0.97 vs. 9.04 +/- 0.75 nmol/mg protein/min), but the addition of calmodulin produced a significantly greater increment in Ca2+ uptake into sarcoplasmic reticulum from the exercised-conditioned animals (1.90 +/- 0.23 vs. 1.21 +/- 0.19 nmol/mg protein/min, P less than 0.03). The adenosine triphosphatase (ATPase) activities of the sarcoplasmic reticulum-enriched fractions of the two groups were similar. We conclude that exercise conditioning produces an enhancement of calmodulin-mediated calcium uptake that is independent of any effect on Ca2+-ATPase.
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PMID:Exercise conditioning increases rat myocardial calcium uptake. 242 95

Monoclonal antibody PM4A2B was prepared by immunizing mice with calmodulin affinity purified Ca2+-Mg2+-adenosine triphosphatase from rabbit erythrocytes and screening the clones with a plasma membrane-enriched fraction (F1) from rabbit stomach smooth muscle. On Western blots, PM4A2B reacted with F1 and with ghosts, right-side-out vesicles, and inside-out vesicles prepared from erythrocytes giving one major band at 130 kDa and minor lower molecular weight bands whose intensity increased on freezing and thawing the membranes. On enzyme-linked immunosorbent assay, PM4A2B reacted with inside-out vesicles, but not with the right-side-out vesicles or ghosts prepared from erythrocytes. It activated the ATP-dependent Ca2+ uptake by F1 and by the inside-out vesicles prepared from the erythrocytes. PM4A2B should be useful in determining membrane sidedness as well as in investigating the mechanism of the sarcolemmal Ca2+ pump.
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PMID:Monoclonal antibody against an epitope on the cytoplasmic aspect of the plasma membrane calcium pump. 246 40

The new calmodulin antagonist, CGS-9343B, was found to inhibit both histamine plus 3-isobutyl-1-methylxanthine and carbachol-induced [14C]aminopyrine accumulation in dispersed, fundic mucosal cells of rats. The IC50 value for CGS-9343B inhibition of histamine plus 3-isobutyl-1-methylxanthine-induced [14C]aminopyrine accumulation was 306 nM. The drug was more potent than the H2-histamine receptor antagonist, cimetidine (1128 nM), less potent than the nonspecific calmodulin antagonists, trifluoperazine and fenoctimine (IC50 = 40 and 224 nM, respectively), and equipotent with the H+, K+-adenosine triphosphatase inhibitor, omeprazole (365 nM). CGS-9343B showed an IC50 of 369 nM for carbachol-induced [14C]aminopyrine accumulation in dispersed mucosal cells. CGS-9343B must be added to cells before or simultaneously with acid secretagogues in order to be effective. The drug did not reverse previously stimulated secretion. Unlike trifluoperazine and fenoctimine, CGS-9343B had anticamodulin activity for inhibition of calmodulin-activated (Type I) phosphodiesterase in the same range of potency as observed for the inhibition of aminopyrine accumulation. In anesthetized rats and dogs the i.v. infusion of CGS-9343B did not block histamine plus pentagastrin-stimulated acid secretion. However, i.a. administration of CGS-9343B to anesthetized rats produced a significant inhibition of acid secretion. In vivo the order of potency was omeprazole greater than cimetidine much greater than CGS-9343B. These data provide evidence for involvement of calmodulin in the acid secretory process and suggest that the pursuit of selective calmodulin antagonists such as CGS-9343B may prove useful for understanding the regulation of the hydrogen ion secretory process.
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PMID:Inhibition of gastric acid secretion in vivo and in vitro by a new calmodulin antagonist, CGS 9343B. 246 57

The generation of free oxygen radicals from the xanthine-xanthine oxidase system produced a decrease in the steady-state calcium load of canine cardiac sarcoplasmic reticulum (SR) vesicles and an increase in the SR passive calcium permeability. This effect of free oxygen radicals was completely inhibited by superoxide dismutase, a scavenger of superoxide anion radical (.O2-). Treatment of intact SR with a specific calmodulin antagonist, compound 48/80 or W-7, lead to the enhancement of the free oxygen radical-mediated reduction of steady-state calcium accumulation with little effect on passive calcium permeability and Ca,Mg-adenosine triphosphatase activity. The effects of free oxygen radicals and the calmodulin antagonists on steady-state calcium accumulation, but not on passive calcium permeability, were only observed in the presence of the endogenous calmodulin of SR vesicles. These results indicate that stimulation by .O2- and/or a closely related species of free oxygen radical of the passive calcium leak pathway is not calmodulin-dependent and is not a potent way of changing the steady-state calcium accumulation. Hence, we propose that calmodulin-dependent component of calcium fluxes in cardiac SR vesicles is modified directly by free oxygen radicals, and that free oxygen radicals can reduce steady-state calcium accumulation due to increased calcium release through a calcium efflux pathway which is inhibited by calmodulin, but not due to reduced catalytic activity of the pump.
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PMID:Calmodulin and free oxygen radicals interaction with steady-state calcium accumulation and passive calcium permeability of cardiac sarcoplasmic reticulum. 252 16

Upon irradiation with UV light, chlorpromazine binds irreversibly to calmodulin and inactivates it. To determine whether this chlorpromazine-calmodulin (CPZ-CaM) complex can inhibit the actions of native calmodulin, we examined its effects on the activity of calmodulin-sensitive cyclic nucleotide phosphodiesterase from rat brain and on the Ca++-adenosine triphosphatase (ATPase) of human erythrocyte membranes. The CPZ-CaM complex was prepared by irradiating purified bovine brain calmodulin in the presence of chlorpromazine and Ca++. The sample was then dialyzed extensively to remove reversibly bound chlorpromazine and then assayed for its ability to activate calmodulin-sensitive phosphodiesterase and Ca++-ATPase, and for its ability to block the stimulatory effects of native calmodulin on these enzymes. The CPZ-CaM complex had no effect on the basal activity of either enzyme; it neither activated nor inhibited the enzymes when assayed in the absence of calmodulin. However, it affected differentially the activation of the two enzymes by native calmodulin. The CPZ-CaM complex totally inhibited calmodulin-stimulated phosphodiesterase but had no effect on the activation of the ATPase by calmodulin. Other studies showed that CPZ-CaM increased the activation constant (Ka) for the interaction of calmodulin with phosphodiesterase but did not affect the maximal activation (Vmax) of the enzyme by calmodulin. Neither calmodulin nor CPZ-CaM altered the Km for the interaction between phosphodiesterase and cyclic AMP. These results suggest that CPZ-CaM inhibits the calmodulin-induced activation of phosphodiesterase by competing with calmodulin for regulatory sites on the enzyme and not by interacting with calmodulin itself or by blocking the interaction of cyclic AMP with the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential inhibition of calmodulin-sensitive phosphodiesterase and Ca++-adenosine triphosphatase by chlorpromazine-linked calmodulin. 282 96

The relaxant action of amiloride was investigated in the smooth muscles of guinea pig taenia ceci and chicken gizzard. Amiloride inhibited the contractions induced by high K+ (45.4 mM) and carbachol (10 microM) in the taenia with the concentrations needed to induce 50% inhibition (IC50) of approximately 41 microM. A prolonged incubation period (greater than 1 hr) was necessary to obtain the full inhibition of these contractions. The taenia gradually accumulated amiloride and the tissue/medium ratio exceeded 2.0 after a 120-min incubation period. Amiloride had no effect on the high K+-stimulated 45Ca++ uptake or the ATP content of the taenia. Amiloride inhibited the Ca++-induced contraction of the saponin-treated taenia with an IC50 of 186 microM. Amiloride (10-1000 microM) also inhibited superprecipitation and Mg++-adenosine triphosphatase activity of the gizzard native actomyosin as well as the phosphorylation of myosin light chain. The inhibition of the phosphorylation was antagonized competitively by ATP. Amiloride (1 mM) had no effect on the dephosphorylation of myosin light chain upon removal of Ca++ from reaction medium. Amiloride, at concentrations up to 1 mM, had not effect on calmodulin activity as monitored by the Ca++-calmodulin-activated erythrocyte membrane (Ca++ + Mg++)-adenosine triphosphatase and phosphodiesterase activities. In contrast to this, trifluoperazine inhibited the calmodulin activity at the concentration needed to inhibit the Ca++-induced contraction of the permeabilized taenia and the superprecipitation and the phosphorylation of myosin light chain of gizzard. We conclude that amiloride, unlike trifluoperazine, may inhibit directly the myosin light chain kinase activity to induce muscle relaxation.
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PMID:Inhibition by amiloride of contractile elements in smooth muscle of guinea pig taenia cecum and chicken gizzard. 282 5


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