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 is a regulator of the Ca(2+) affinity of the cardiac sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and of cardiac contractility. In vitro expression studies have shown that several mutant phospholamban monomers are superinhibitory, suggesting that monomeric phospholamban is the active species. However, a phospholamban Asn(27) --> Ala (N27A) mutant, which maintained a normal pentamer to monomer ratio, was shown to act as a superinhibitor of SERCA2a Ca(2+) affinity. To determine whether the pentameric N27A mutant is superinhibitory in vivo, transgenic mice with cardiac-specific overexpression of mutant phospholamban were generated. Quantitative immunoblotting revealed a 61 +/- 6% increase in total phospholamban in mutant hearts, with 90% of the overexpressed protein being pentameric. The EC(50) value for Ca(2+) dependence of Ca(2+) uptake was 0.69 +/- 0.07 microM in mutant hearts, compared with 0.29 +/- 0.02 microM in wild-type hearts or 0. 43 +/- 0.03 microM in hearts overexpressing wild-type PLB by 2-fold. Myocytes from phospholamban N27A mutant hearts also exhibited more depressed contractile parameters than wild-type phospholamban overexpressing cells. The shortening fraction was 52%, rates of shortening and relengthening were 46% and 38% respectively, and time for 80% decay of the Ca(2+) signal was 146%, compared with wild-types (100%). Langendorff-perfused mutant hearts also demonstrated depressed contractile parameters. Furthermore, in vivo echocardiography showed a depression in the ratio of early to late diastolic transmitral velocity and a 79% prolongation of the isovolumic relaxation time. Isoproterenol stimulation did not fully relieve the depressed contractile parameters at the cellular, organ, and intact animal levels. Thus, pentameric phospholamban N27A mutant can act as a superinhibitor of the affinity of SERCA2a for Ca(2+) and of cardiac contractility in vivo.
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PMID:Cardiac-specific overexpression of a superinhibitory pentameric phospholamban mutant enhances inhibition of cardiac function in vivo. 1074 47

We determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles. Atrial and ventricular trabecular muscles were obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass surgery. Isometric contraction variables were recorded before and after propofol was added to the bath in concentrations between 0.056 and 560 microM. The effects of propofol were compared with its commercial vehicle intralipid. To test beta-adrenergic effects in the presence of propofol, 1 microM isoproterenol was added at the end of each experiment. To determine the cellular mechanisms responsible for the actions of propofol, we examined its effects on actomyosin ATPase activity and sarcoplasmic reticulum (SR) Ca(2+) uptake in nonfailing atrial tissues. Propofol caused a concentration-dependent decrease in maximal developed tension in all muscles, which became significant (P < 0.05) at concentrations exceeding the clinical range (> or =56 microM). Isoproterenol restored contractility to the level achieved before exposure to propofol (P > 0.05 compared with baseline). Failing ventricular muscle exposed to propofol exhibited somewhat diminished ability to recover contractility in response to isoproterenol (P < 0.05 versus failing muscle exposed to intralipid only). Propofol induced a concentration-dependent decrease in the uptake of Ca(2+) into SR vesicles. At the same time, in the presence of 56 microM propofol, the Ca(2+)-activated actomyosin ATPase activity was shifted leftward, demonstrating an increase in myofilament sensitivity to Ca(2+). We conclude that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with beta-adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by decreased Ca(2+) uptake into the SR; however, the net effect of propofol on contractility is insignificant at clinical concentrations because of a simultaneous increase in the sensitivity of the myofilaments to activator Ca(2+).
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PMID:The effects of propofol on the contractility of failing and nonfailing human heart muscles. 1152 17

The renal effects of dopamine are mainly mediated via the dopamine-1 receptor (D1 receptor). This receptor is recruited from intracellular compartments to the plasma membrane by dopamine and atrial natriuretic peptide (ANP), via adenylyl cyclase activation. We have studied whether isoproterenol, a beta-adrenoceptor (beta-AR) agonist that may interact with dopamine in the regulation of rat renal Na+, K+-adenosine triphosphatase (ATPase) activity, can recruit D1 receptors to the plasma membrane. The spatial regulation of D1 receptors was examined using confocal microscopy techniques in LLCPK cells and the functional interaction between dopamine and isoproterenol was examined by studying their effects on Na+, K+-ATPase activity in microdissected single proximal tubular segments from rat. Isoproterenol was found to translocate the D1 receptors from the interior of the cell towards the plasma membrane. The recruitment of dopamine 1 receptors was found to be cyclic adenosine phosphate (cAMP) dependent, while protein kinase C (PKC) activation was not involved. The functional studies on Na+, K+-ATPase activity showed that the effect of isoproterenol was abolished by a D1-like receptor antagonist (SCH 23390), and mediated via protein kinase A (PKA) and PKC dependent pathways. The results provide an explanation for the interaction between G protein-coupled receptors. The effects of isoproterenol on Na+, K+-ATPase activity can be explained by a heterologous recruitment of D1 receptors to the plasma membrane.
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PMID:beta-Adrenoceptor agonist sensitizes the dopamine-1 receptor in renal tubular cells. 1216 72

Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a overexpression and phospholamban depletion have been shown to have beneficial effects on contractility in heart failure. However, the high sympathetic tone during development of failure may interact with increases in SERCA2a activity in potentially deleterious ways. We used adenoviral vectors to overexpress SERCA2a or partially downregulate phospholamban in adult rabbit ventricular myocytes in culture and studied the responses of these cells to beta-adrenoceptor stimulation. SERCA2a overexpression and phospholamban depletion had quantitatively similar effects on basal contraction amplitude and in accelerating relaxation. Increasing SERCA2a activity by either strategy had little effect on the increase in contraction amplitude or incidence of arrhythmias with increasing isoproterenol. Maximum acceleration of relaxation by beta-adrenoceptor stimulation was similar to that produced by SERCA2a overexpression. Isoproterenol treatment of SERCA2a-overexpressing or phospholamban-deficient myocytes produced a further modest decrease in relaxation time, with similar final values in both groups. We find no evidence for Ca(2+) overload induced by SERCA2a overexpression alone or in combination with catecholamines.
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PMID:Interaction between increased SERCA2a activity and beta -adrenoceptor stimulation in adult rabbit myocytes. 1238 7

Isoproterenol stimulates H-K-ATPase activity in rat cortical collecting duct beta-intercalated cells through a PKA-dependent pathway. This study aimed at determining the signaling pathway underlying this effect. H-K-ATPase activity was determined in microdissected collecting ducts preincubated with or without specific inhibitors or antibodies against intracellular signaling proteins. Transient cell membrane permeabilization with streptolysin-O allowed intracellular access to antibodies. Isoproterenol increased phosphorylation of ERK in a PKA-dependent manner, and inhibition of the ERK phosphorylation prevented the stimulation of H-K-ATPase. Antibodies against the monomeric G protein Ras or the kinase Raf-1 curtailed the stimulation of H-K-ATPase by isoproterenol, whereas antibodies against the related proteins Rap-1 and B-Raf had no effect. Pertussis toxin and inhibition of tyrosine kinases with genistein also curtailed isoproterenol-induced stimulation of H-K-ATPase. It is proposed that activation of PKA by isoproterenol induces the phosphorylation of beta-adrenergic receptors and the switch from G(s) to G(i) coupling. In turn, betagamma-subunits released from G(i) would activate a tyrosine kinase-Ras-Raf-1 pathway, leading to the activation of ERK1/2 and of H-K-ATPase.
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PMID:Mechanism of activation of ERK and H-K-ATPase by isoproterenol in rat cortical collecting duct. 1267 35

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca(2+) was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca(2+) transients and peak tensions were reduced, whereas decay times of Ca(2+) transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.
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PMID:Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) activity and impairs cardiac function in mice. 1520 33

Cardiac function is known to be impaired in diabetes. Alterations in intracellular calcium handling have been suggested to play a pivotal role. This study aimed to test the hypothesis that beta-adrenergic activation can reveal the functional derangements of intracellular calcium handling of the 4-week diabetic heart. Langendorff perfused hearts of 4-week streptozotocin-induced diabetic rats were subjected to the beta-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca(2+)](i) levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca(2+)](i) transient the kinetic parameters of the sarcoplasmic reticulum Ca(2+)-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca(2+)](i) transient. Under unchallenged conditions, hemodynamic parameters were comparable between control and diabetic hearts. Isoproterenol administration stimulated hemodynamic function to a greater extent in control than in diabetic hearts, which was exemplified by more pronounced increases in rate of pressure development and decline. Under unchallenged conditions, [Ca(2+)](i) amplitude and rate of rise and decline of [Ca(2+)](i) as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under beta-adrenoceptor stimulation. Upon beta-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca(2+)](i) amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+)-release channel in response to beta-adrenoceptor challenge. Alterations in Ca(2+)(i) handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.
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PMID:beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes. 1562 May 73

Sorcin is a 21.6-kDa Ca(2+) binding protein of the penta-EF hand family. Several studies have shown that sorcin modulates multiple proteins involved in excitation-contraction (E-C) coupling in the heart, such as the cardiac ryanodine receptor (RyR2), L-type Ca(2+) channel, and Na(+)-Ca(2+) exchanger, while it has also been shown to be phosphorylated by cAMP-dependent protein kinase (PKA). To elucidate the effects of sorcin and its PKA-dependent regulation on E-C coupling in the heart, we identified the PKA-phosphorylation site of sorcin, and found that serine178 was preferentially phosphorylated by PKA and dephosphorylated by protein phosphatase-1. Isoproterenol allowed sorcin to translocate to the sarcoplasmic reticulum (SR). In addition, adenovirus-mediated overexpression of sorcin in adult rat cardiomyocytes significantly increased both the rate of decay of the Ca(2+) transient and the SR Ca(2+) load. An assay of oxalate-facilitated Ca(2+) uptake showed that recombinant sorcin increased Ca(2+) uptake in a dose-dependent manner. These data suggest that sorcin activates the Ca(2+)-uptake function in the SR. In UM-X7. 1 cardiomyopathic hamster hearts, the relative amount of sorcin was significantly increased in the SR fraction, whereas it was significantly decreased in whole-heart homogenates. In failing hearts, PKA-phosphorylated sorcin was markedly increased, as assessed using a back-phosphorylation assay with immunoprecipitated sorcin. Our results suggest that sorcin activates Ca(2+)-ATPase-mediated Ca(2+) uptake and restores SR Ca(2+) content, and may play critical roles in compensatory mechanisms in both Ca(2+) homeostasis and cardiac dysfunction in failing hearts.
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PMID:Sorcin interacts with sarcoplasmic reticulum Ca(2+)-ATPase and modulates excitation-contraction coupling in the heart. 1575 88

Desensitization of G-protein-coupled receptors (GPCR) includes receptor endocytosis. This phenomenon is suggested, at least for some receptors, to be associated with receptor resensitization. Here, we examined the role of receptor endocytosis for two different GPCR, the dopamine-1 (D1) receptor and the beta1-adrenoceptor (beta(1)-AR) in renal tissue. The functional role of receptor endocytosis was examined on Na+, K+ -ATPase activity in microdissected proximal tubules from rat kidney. The spatial regulation of endogenous D1 receptors and beta(1)-AR was examined by confocal microscopy techniques in LLCPK cells. Phenylarsine oxide (PAO) an endocytosis inhibitor, attenuated isoproterenol-induced decrease in Na+, K+ -ATPase activity but had no such effect on dopamine-induced decrease in Na+, K+ -ATPase activity. We have previously shown that isoproterenol sensitizes the renal dopamine system, by recruiting silent D1 receptors from the interior of the cell towards the plasma membrane. This effect was attenuated by PAO as well as by cytochalasin D while these substances had no effect on dopamine-induced D1 receptor recruitment. The beta(1)-AR was localized to the plasma membrane in control cells. Isoproterenol induced a rapid internalization of the beta(1)-AR; which was prevented by PAO. The results suggest that endocytosis of beta(1)-AR in renal proximal tubular cells is an important step in signal generation, while endocytosis of proximal tubular D1 receptor is not.
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PMID:The role of endocytosis in renal dopamine D1 receptor signaling. 1621 57

In the present study, chronic treatment of atorvastatin was evaluated on isoproterenol-induced myocardial infarction. Male Sprague-Dawley rats (200 +/- 25 g) were randomized into the following four groups: (1) control group, (2) isoproterenol-treated group, (3) atorvastatin-treated group, and (4) isoproterenol- and atorvastatin-treated group. Various serum and tissue parameters as well as histopathological studies were carried out in all groups. Isoproterenol administration produced severe myocardial damage and oxidative stress in rats. Atorvastatin treatment reduced myocardial infarction which has been reflected by improvement in serum parameters, ATPase activities and histopathological lesions. However, it could not reduce oxidative stress and hypertrophy induced by isoproterenol. Hence, it can be concluded that atorvastatin may protect myocardial infarction induced by isoproterenol independent of its antioxidant properties.
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PMID:Effect of atorvastatin treatment on isoproterenol-induced myocardial infarction in rats. 1656 50


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