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)

The basic cellular mechanisms involved in the regulation of (Na + K)-ATPase are discussed. Various ligands seem to be responsible for the short-term modulation of this enzyme activity (intracellular messengers). Cytosolic Ca2+ has a key role in mediating changes induced by hormones or receptor agonist; but, in turn, intracellular Ca(2+)-dependent proteins like calmodulin, calnaktin or others, are also needed for these changes. Phosphorylation of effector proteins, following the activation of PKC, PKA or CaM-kinase II, may result in changes of (Na + K)-ATPase activity either by a direct effect on the catalytic subunit or by modulating the Na(+)-H+ exchanger thereby resulting in an effect on intracellular sodium, whose concentration is known to be rate-limiting for the enzyme activity. Despite the ubiquity of (Na + K)-ATPase in various organs and tissues, its response to modulators partly depends on the heterogeneity of the alpha-subunit that give rise to the existence of different isoforms. The relative abundance of alpha 1, alpha 2, alpha 3 or other isoforms is tissue-specific and represents another way of regulation among different cell types. While these cellular mechanisms occur in various cell types the kidney shows an opposite response respect to other tissues such as liver or brain. The functional relevance of the mechanisms of acute adaptation of (Na + K)-ATPase, discussed in this review, is becoming increasingly recognized for the renal enzyme, what may contribute to stimulate new approaches to the study of the short-term regulation of the pump activity in molecular terms.
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PMID:Is the renal (Na + K)-ATPase modulated by intracellular messengers? 133 18

The relationship of structural and functional moieties on calmodulin is important in all venues of cell activity. In this study, we investigate the effect of lysine modification on calmodulin function. Azidosalicylate reagents containing different "linker arm" lengths, between the photoactive terminus and an amine-reactive N-hydroxysuccinimidyl ester moiety were used to modify calmodulin lysines at three different positions in a calcium-dependent manner. The short cross-linker, (ASNE-2 (where ASNE represents azidosalicylate N-hydroxysuccinimidyl ester), modifies Lys-75, whereas the longer reagent, ASNE-6, modifies lysines 21, 75, and 94. The modification of these different lysines is shown to be calcium-dependent. At 1-100 microM levels of calcium, only Lys-94 is modified, suggesting that modification of this residue is directed by both the binding of calcium to calcium-binding loops III and IV and the hydrophobic pocket exposed between these two loops as a result of calcium binding. At higher calcium concentrations (> 200 microM), where sites I and II become filled, modification of Lys-21 or Lys-75 also was observed. All the modified calmodulins were able to stimulate 3',5'-cyclic-nucleotide phosphodiesterase fully although the Kact for the Lys-75 and Lys-21 derivatives increased 10- and 50-fold, respectively. None of the modifications affected the activation of erythrocyte plasma membrane Ca(2+)-ATPase. Only the ASNE-6 Lys-75 derivative showed efficient (40%) photocross-linking to the Ca(2+)-ATPase. The ASNE-2 Lys-75 derivative as well as the ASNE-6 Lys-21 and Lys-94 derivatives did not show efficient calcium-dependent photocross-linking to this enzyme.
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PMID:The effects of calcium site occupancy and reagent length on reactivity of calmodulin lysyl residues with heterobifunctional aryl azides. Mapping interaction domains with specific calmodulin photoprobe derivatives. 134 68

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

We have recently identified a novel 190-kD calmodulin-binding protein (p190) associated with the actin-based cytoskeleton from mammalian brain (Larson, R. E., D. E. Pitta, and J. A. Ferro. 1988. Braz. J. Med. Biol. Res. 21:213-217; Larson, R. E., F. S. Espindola, and E. M. Espreafico. 1990. J. Neurochem. 54:1288-1294). These studies indicated that p190 is a phosphoprotein substrate for calmodulin-dependent kinase II and has calcium- and calmodulin-stimulated MgATPase activity. We now have biochemical and immunological evidence that this protein is a novel calmodulin-binding myosin whose properties include (a) Ca2+ dependent action activation of its Mg-ATPase activity, which seems to be mediated by Ca2+ binding directly to calmodulin(s) associated with p190 (maximal activation by actin requires the presence of Ca2+ and is further augmented by addition of exogenous calmodulin); (b) ATP-sensitive cross-linking of skeletal muscle F-actin, as demonstrated by the low-speed actin sedimentation assay; and (c) cross-reactivity with mAbs specific for epitopes in the head of brush border myosin I. We also show that p190 has properties distinct from conventional brain myosin II and brush border myosin I, including (a) separation of p190 from brain myosin II by gel filtration on a Sephacryl S-500 column; (b) lack by p190 of K(+)-stimulated EDTA ATPase activity characteristic of most myosins; (c) lack of immunological cross-reactivity of polyclonal antibodies which recognize p190 and brain myosin II, respectively; (d) lack of immunological recognition of p190 by mAbs against an epitope in the tail region of brush border myosin I; and (e) distinctive proteolytic susceptibility to calpain. A survey of rat tissues by immunoblotting indicated that p190 is expressed predominantly in the adult forebrain and cerebellum, and could be detected in embryos 11 d post coitus. Immunocytochemical studies showed p190 to be present in the perikarya and dendritic extensions of Purkinje cells of the cerebellum.
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PMID:Biochemical and immunological characterization of p190-calmodulin complex from vertebrate brain: a novel calmodulin-binding myosin. 137 47

The alpha-adrenergic agonist oxymetazoline increased Na+,K(+)-ATPase activity of single proximal convoluted tubules dissected from rat kidney. Activation of the enzyme by oxymetazoline was prevented by either the alpha 1-adrenergic antagonist prazosin or the alpha 2-adrenergic antagonist yohimbine and was mimicked by the calcium ionophore A23187. The effect of oxymetazoline on Na+,K(+)-ATPase activity was prevented by a specific peptide inhibitor of calcineurin, as well as by FK 506, an immunosuppressant agent known to inhibit calcineurin; these results indicate that the action of oxymetazoline is mediated via activation of calcineurin (a calcium/calmodulin-dependent protein phosphatase). Activation of the Na+,K(+)-ATPase by either oxymetazoline or A23187 was associated with a greater than 2-fold increase in its affinity for Na+. The results provide a biochemical mechanism by which norepinephrine, released from renal nerve terminals, stimulates Na+ retention.
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PMID:Calcineurin mediates alpha-adrenergic stimulation of Na+,K(+)-ATPase activity in renal tubule cells. 138 Jan 57

Paramecium generates a Ca2+ action potential and can be considered a one-cell animal. Rises in internal [Ca2+] open membrane channels that specifically pass K+, or Na+. Mutational and patch-clamp studies showed that these channels, like enzymes, are activated by Ca(2+)-calmodulin. Viable CaM mutants of Paramecium have altered transmembrane currents and easily recognizable eccentricities in their swimming behavior, i.e. in their responses to ionic, chemical, heat, or touch stimuli. Their CaMs have amino-acid substitutions in either C- or N-terminal lobes but not the central helix. Surprisingly, these mutations naturally fall into two classes: C-lobe mutants (S101F, I136T, M145V) have little or no Ca(2+)-dependent K+ currents and thus over-react to stimuli. N-lobe mutants (E54K, G40E+D50N, V35I+D50N) have little or no Ca(2+)-dependent Na+ current and thus under-react to certain stimuli. Each mutation also has pleiotropic effects on other ion currents. These results suggest a bipartite separation of CaM functions, a separation consistent with the recent studies of Ca(2+)-ATPase by Kosk-Kosicka et al. [41, 55]. It appears that a major function of Ca(2+)-calmodulin in vivo is to orchestrate enzymes and channels, at or near the plasma membrane. The orchestrated actions of these effectors are not for vegetative growth at steady state but for transient responses to stimuli epitomized by those of electrically excitable cells.
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PMID:In vivo Paramecium mutants show that calmodulin orchestrates membrane responses to stimuli. 138 Apr 4

Sublethal doses of methyl parathion (O,O-dimethyl-O-nitrophenyl- thiophosphate) injected intraperitoneally to 15 and 21 day old rat pups induced regional alterations in the central nervous system (CNS) in the levels of total RNA, total proteins, modulatory protein Calmodulin (CaM), in the activity levels of membrane bound enzyme Ca(2+)-ATPase and phospholipids. Levels of RNA and total proteins increased considerably in 15 days old methyl parathion treated (MPT) rat pups. Contrary to this the RNA and total protein content exhibited remarkable decrease in 21 day old methyl parathion treated animals. Calmodulin level showed an increase in cerebral cortex and brain stem and decrease in cerebellum and spinal cord in 15 day old methyl parathion treated rat pups. Whereas the level of Calmodulin decreased in cerebral cortex and cerebellum and increased in brain stem and spinal cord in 21 day old methyl parathion treated rat pups. Activity levels of calcium dependent ATPase showed significant inhibition in all the regions of Central Nervous System (CNS) of 15 and 21 day old methyl parathion treated rat pups. Phospholipids showed a general increase in all the regions of Central Nervous System on methyl parathion exposure. In the light of these observations, it has been suggested that the molecular regulatory mechanisms involving Ca2+/CaM are rendered inefficient due to toxic impact of methyl parathion.
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PMID:Methyl parathion induced regional alterations in the regulatory proteins during critical stage of central nervous system development in albino rat pups. 138 Apr 92

The nucleotide dependence of the Ca(2+)-ATPase purified from cardiac sarcolemma by calmodulin-affinity chromatography was investigated for preparations either in the basal state or activated by three procedures: (i) addition of calmodulin; (ii) addition of phosphatidylserine and (iii) controlled proteolysis. Upon activation, the maximal velocity of ATP hydrolysis increases by a factor of 4-5, while the curves of ATP dependence of ATP hydrolysis change from hyperbolic to biphasic, revealing the presence of two Kmapp for ATP. A tight coupling between Ca2+ and ATP binding sites was also observed. At high ATP concentration, the ATPase activity of the basal state shows a complex dependence on Ca2+ concentration, increasing sharply at millimolar Ca2+. Our results indicate that this increase in ATPase activity is paralleled by the appearance of a second, low affinity Kmapp for ATP. When only the high affinity site for ATP is occupied the ATPase activity of the basal state displays a simple, hyperbolic dependence on the Ca2+ concentration. In addition, increasing Ca2+ concentration appears to decrease the ATP binding at the low affinity site of the enzyme. The effect of ADP on ATP hydrolysis was also examined. The finding that ADP is a potent inhibitor of the purified Ca(2+)-ATPase from heart suggests that the stimulatory action of ADP observed in cardiac sarcolemmal vesicles is not an intrinsic property of the enzyme.
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PMID:Regulation of the nucleotide dependence of the cardiac sarcolemma Ca(2+)-ATPase. 138 33

Although there is extensive data available on Ca2+ effects in normal tissues, comparatively little is known about its effects or regulation in tumor cells. The present studies were undertaken to investigate whether various extracellular calcium concentrations could modulate the expression of the tumor-associated antigen (TAA) recognized by monoclonal antibody (MAb) 44-3A6. It is highly expressed by the human lung adenocarcinoma cell line A549 and has been shown to be a 40-kD integral plasma membrane protein. Treatment of the A549 cell line with various concentrations of exogenous calcium showed a dose-dependent rise in the internal free calcium levels up to 2.4-2.9 mM (external calcium treatment). At higher concentrations, the internal calcium level showed a decline, indicating a higher calcium efflux. The calmodulin-dependent Ca(2+)-ATPase enzyme involved in calcium homeostasis was assayed under these same conditions. The enzyme activity increased with increasing external calcium concentrations showing a 5-fold increase in cells treated with 4.05 mM calcium. These data suggest that as the internal calcium approaches toxic levels, the Ca(2+)-regulated ATPase activity increases to reduce the calcium overload within the cell. Employing Western blot analysis and immunoperoxidase staining studies, this report shows that the antigen recognized by MAb 44-3A5 on A549 cells increased with an increase in calcium concentration. Evidence that this antigen is phosphorylated is presented using Western blot analysis of a radiolabeled antigen-enriched plasma membrane fraction. The previously reported subcellular localization, and now the phosphorylation and responsiveness to calcium by this TAA, gives it the properties predicted to be seen in a calcium 'pump-like' molecule. Thus, these studies support the hypothesis that this TAA may be important in intracellular calcium concentration control or that it is regulated via some calcium-mediated process.
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PMID:Changes in the expression of the tumor-associated antigen recognized by monoclonal antibody 44-3A6 in A549 cells due to calcium. 138 56

Caldesmon is an actin-binding protein present in smooth muscle cells that also inhibits actin-activated myosin ATPase activity. To assess the possible role of caldesmon in the regulation of smooth contraction, we investigated the effects of synthetic peptides on force directly recorded from single hyperpermeable smooth muscle cells of ferret aorta and portal vein. GS17C, a peptide that contains the residues from Gly651 to Ser667 of the caldesmon sequence plus an added cysteine at the C terminus, binds calmodulin in a Ca(2+)-dependent manner and also binds to F-actin but does not inhibit actomyosin ATPase activity (Zhan, Q., Wong, S.S., and Wang, C.-L.A. (1991) J. Biol. Chem. 266, 21810-21814). In cells in which Ca2+ was clamped at pCa 7.0, GS17C induced a dose-dependent contraction (EC50 = 0.92 microM) in aorta cells, whereas it evoked little or no contraction in portal vein cells. The GS17C-induced contraction in aorta cells was inhibited at higher Ca2+ concentrations (above pCa 6.6) and by pretreatment with calmodulin. Another peptide, C16AA, which contains the residues from Ala594 to Ala609 and does not bind actin or calmodulin, did not induce contraction. Our results strongly suggest that GS17C induces contraction by the displacement of the inhibitory region of endogenous caldesmon and, furthermore, that caldesmon present in these smooth muscle cells regulates contraction by providing a basal resting inhibition of vascular tone.
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PMID:Regulation of vascular smooth muscle tone by caldesmon. 138 78


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