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)

A quantitative reconstruction of [Ca2+]i transients is the desired goal, but that goal has yet to be reached. It will be reached by solving Equation 2., once an adequate mathematical description of all its terms is obtained. If computed [Ca2+]i transients match closely those recorded under many experimental conditions, then we can be confident that our understanding of the cellular processes that control [Ca2+]i is correct. The SL Ca2+ ATPase and the SL Ca2+ leak do not make an important contribution on a given beat. All the available data, physiologic and biochemical, indicate clearly that the Ca2+ fluxes via the SL Ca2(+)-ATPase and SL Ca2(+)-leak pathways are small in comparison to others. Over many beats, however, the fluxes through these pathways will contribute to loading of the SR with Ca2+. In the abnormal case of resting cardiac muscle, [Ca2+]i will be determined by the balance between Ca2+ influx via leak and Ca2+ efflux via Na/Ca exchange and SL Ca2+ ATPase. There is an emerging consensus that the amount of Ca2+ entering via Na/Ca exchange during normal activity is small. This consensus derives from direct observation of changes in [Ca2+]i attributable to Na/Ca exchange, from computations that utilize new quantitative data on the current-voltage relation of the exchanger and on the quantitative relationship of exchanger current to [Ca2+]i. Clearly, the efflux of Ca2+ via Na/Ca exchange on each beat is significant. From theory and the fact that SL Ca2+ pumping is small, the efflux of Ca2+ via the exchanger must equal the Ca2+ influx through SL Ca2+ channels, but experimental studies have not yet verified this quantitatively. All the studies, recent and older, indicate that the [Ca2+]i transient in all mammalian species is dominated by Ca2+ released from SR. Even in the rat, widely believed to be the species most dependent on SR, the Ca2+ current contributes measurable Ca2+ (24). Provided that the SR is not depleted by rest, it is the major cellular entity that determines the [Ca2+]i transient in mammalian ventricular tissue on a given beat. Quantitative knowledge of the flux of Ca2+ from it, required for evaluating theories of excitation-contraction coupling, still awaits determination.
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PMID:Cytoplasmic [Ca2+] in mammalian ventricle: dynamic control by cellular processes. 218 64

The idea of a PCr-circuit is supported by the fact that in fully differentiated and highly specialized cells with high sudden energy turnover, e.g., skeletal and cardiac muscle [Wallimann and Eppenberger, 1985], brain and retina photoreceptor cells [Wallimann et al, 1986a], spermatozoa [Tombes and Shapiro, 1985; Wallimann et al, 1986b] and Torpedo electrocytes [Wallimann et al, 1985] mitochondrial CK is generally found in conjunction with cytosolic CK's with a significant fraction of the latter being associated subcellularly in a compartmented fashion at intracellular sites of high energy turnover. It is also becoming apparent that some of the cytosolic CK is specifically associated with membranes possibly via membrane anchors, e.g., with the SR-membrane where CK was shown to be functional by supporting a significant portion of the maximal Ca2(+)-pumping rate [Rossi et al, 1988; submitted]. Similar membrane associations of CK have been shown with the post-synaptic acetylcholine-receptor-rich membrane, the invaginated, and non-innervated face membrane of electrocytes, rich in Na+/K+ ATPase as well as with synaptic vesicles [Wallimann et al, 1985], with the sperm-tail plasma membrane [Wallimann et al, 1986a], and recently also with rod outer segment plasma membranes of bovine photoreceptor cells [Quest et al, 1987; Hemmer et al, 1989]. Thus, for all the above cells the PCr-circuit seems to represent an efficient, flexible, and highly responsive accessory, crucial not only as an energy back-up system, but also as a regulator of energy flux (channeling) and as a fine-tuning device of local ATP-levels. The strength of such a regulated channeling circuit operating at relatively low adenine nucleotide levels compared to the high total PCr and Cr pools, which are metabolically inert, is its high sensitivity towards ADP [Wallimann et al, 1984] that is preventing in excitable cells the accumulation of ADP and AMP unless severe stress, such as hypoxia or ischaemia is imposed. Additional details concerning the PCr-circuit model in muscle and our current ideas about the structure-function relationships of mitochondrial have been described elsewhere [Wallimann and Eppenberger, 1985; Schlegel et al, 1988; Schnyder et al, 1988].(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The subcellular compartmentation of creatine kinase isozymes as a precondition for a proposed phosphoryl-creatine circuit. 220 65

1. The calcium sensitivity of force production of cardiac muscle fibres is altered by certain drugs. The sites of action of three such compounds (pimobendan, sulmazole, isomazole) within the myofibril have been investigated. Calmodulin antagonists, perhexilene and bepridil, which have been shown to alter the calcium dependence of myofibrillar ATPase activity and oxmetidine, an H2-receptor antagonist which binds to calmodulin, were also studied. 2. The rates of dissociation of calcium from both the regulatory and high affinity sites on bovine isolated cardiac troponin C (cTnC) were measured in a stopped-flow fluorimeter. The rates of dissociation were found to be 136.5 +/- 16 s-1 and 1.3 +/- 0.20 s-1 (mean +/- s.e.mean, n = 11 determinations; conditions: 100 mM KCl, 10 mM MOPS, 3 mM MgCl2, 0.1 mM dithriothreitol, pH 7.0, 15 degrees C). Sulmazole, isomazole and perhexiline (final concentration of 50 microM) had no effect on the rate of Ca2+ dissociation from the regulatory Ca2+ site, indicating that these compounds do not act on cTnC directly. 3. The rate of dissociation of Ca2+ from the regulatory site was slightly reduced (approximately 20%) by pimobendan (50 and 100 microM) and was somewhat increased by oxmetidine (28% at 100 microM). 4. Bepridil (25 microM) reduced the rate of dissociation by 50%, indicating a direct effect of bepridil on TnC. 5. Sulmazole, isomazole, perhexiline, pimobendan (50 microM) and bepridil (25 microM) were without effect on the rate of dissociation of Ca2+ from the high affinity Ca2+/Mg2+ sites. Oxmetidine caused 24% decrease in the rate of Ca2+ dissociation from these sites. 6. The rate of dissociation of Ca2+ from the regulatory site on the complex of troponin-tropomyosin (TnTm) was measured. Sulmazole and pimobendan (50 microM) were without effect on the rate of dissociation of Ca2+ from the regulatory site in the protein complex, and isomazole (50 microM) caused only a slight reduction (23%). Perhexiline (50 microM) or bepridil (10 microM) reduced the rate of Ca2 dissociation by about 50%. The rate of dissociation of Ca2+ from the high affinity Ca2 +/Mg2 + sites was not altered by sulmazole, isomazole, or pimobendan (50 microM), but was decreased - 35% by perhexiline (50 microM) or bepridil (10 microM).
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PMID:The effects of reported Ca2+ sensitisers on the rates of Ca2+ release from cardiac troponin C and the troponin-tropomyosin complex. 220

Compelling evidence has existed for more than a decade for a sodium/calcium (Na-Ca) exchange mechanism in the surface membrane of mammalian heart muscle cells which exchanges about three sodium ions for each calcium ion. Although it is known that cardiac muscle contraction is regulated by a transient increase in intracellular calcium ([Ca2+]i) triggered by the action potential, the contribution of the Na-Ca exchanger to the [Ca2+]i transient and to calcium extrusion during rest is unclear. To clarify these questions, changes in [Ca2+]i were measured with indo-1 in single cardiac myocytes which were voltage clamped and dialysed with a physiological level of sodium. We find that Ca entry through the Na-Ca exchanger is too slow to affect markedly the rate of rise of the normal [Ca2+]i transient. On repolarization, Ca extrusion by the exchanger causes [Ca2+]i to decline with a time constant of 0.5 s at -80 mV. The rate of decline can be slowed e-fold with a 77-mV depolarization. Calcium extrusion by the exchanger can account for about 15% of the rate of decline of the [Ca2+]i transient (the remainder being calcium resequestration by the sarcoplasmic reticulum (SR]. The ability of the cell to extrude calcium was greatly reduced on inhibiting the exchanger by removing external sodium, which itself led to an increase in resting [Ca2+]i. This finding is in contrast to the suggestion that calcium extrusion at rest is mediated mainly by a sarcolemmal Ca-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Kinetics, stoichiometry and role of the Na-Ca exchange mechanism in isolated cardiac myocytes. 234 72

The evidence in favor of a direct role of active Na transport in the regulation of excitation-contraction coupling in vascular smooth muscle has been examined. The observations in vivo and those obtained in isolated tissues do not always lead to the same conclusions. The changes of the membrane potential obtained in vitro by slight reductions in, or increases of [K]o do not modify the resting potential of the cells sufficiently to make them contract. Applying K-free or Na-free medium on isolated tissues is a much more vigorous procedure than the limited changes of [K]o that can occur in vascular beds in situ. The Na-Ca exchange-mechanism does not seem to play a major role in those smooth-muscle cells that have been analyzed in detail, but even here the experimental procedures have neither given precise information about the composition of the intracellular compartment nor allowed sufficient control of the parameters studied. The comparison of membrane vesicles from smooth muscle and from cardiac muscle indicates that important differences exist in Na-Ca exchange and in activities of Na+-K+ ATPase and Ca2+-Mg2+ ATPase. These findings suggest a poor development of Na-Ca exchange in smooth muscle as compared to cardiac muscle. Finally, the changes in the Na metabolism of erythrocytes from hypertensives are mentioned, and the present difficulties of linking those changes to an increased reactivity of vascular smooth-muscle cells are briefly discussed.
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PMID:Na+-K+ ATPase, Na-Ca exchange, and excitation-contraction coupling in smooth muscle. 240 82

The direct effects of amiloride on myocardial contractility were examined in electrically stimulated left atrial muscle of guinea-pig heart. Amiloride (0.3 to 1.5 mM) produced a positive inotropic effect which, at higher concentrations, was followed by a decline in developed tension. These effects were not accompanied by contracture or arrhythmia and were not affected by a combination of phentolamine, nadolol, cimetidine, tripelennamine and atropine. The above concentrations of amiloride prolonged the action potential duration during the development of the positive inotropic effect; however, no further change in the action potential duration was observed during the decline in developed tension caused by high concentrations of amiloride. Myocardial membrane Na,K-ATPase, ouabain-sensitive 86Rb+ uptake and Na+-dependent Ca2+ efflux from sarcolemmal membrane vesicles were all inhibited by amiloride. The positive inotropic effect of the agent is reduced and the negative inotropic action is enhanced in low Na+ solutions, i.e., under conditions likely to favor Ca2+ influx via Na+/Ca2+ exchange. These results suggest that amiloride, under the present conditions, has a complex interaction with cardiac muscle fibers. Amiloride may produce its inotropic effects in guinea-pig atrial muscle by several mechanisms including sodium pump inhibition, Na+/Ca2+ exchange inhibition, prolongation of the action potential duration, and/or actions such as Na+/H+ exchange inhibition which were not directly addressed in this study.
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PMID:Amiloride: effects on myocardial force of contraction, sodium pump and Na+/Ca2+ exchange. 242 Sep 97

The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
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PMID:Pharmacological modulation of cardiac and vascular contractile protein function. 243 41

A philosophy and approach is described for including enzyme-mediated transport currents in reconstructions of ion regulation and electrical activity in cardiac muscle. Data from physiological and biochemical experiments on isolated transport systems are combined with the principles of physical chemistry to construct mechanistic descriptions of the systems. These descriptions are then combined (unmodified) together with the results of morphological measurements on cells to reconstruct the behavior of the ion regulation system. Some results from a preliminary model of this type are described: calcium regulation by the plasmalemma, including sodium-calcium exchange, the calcium pump (ATPase), and a calcium leak. This subsystem is stable at physiological values of ion concentrations and transmembrane potential and the net flux through the leak is within the range determined experimentally. Under these conditions, most of the calcium entering the cell through the leak is shown to be restored by the calcium pump. From calculations with an action potential of arbitrary waveform, it is shown that sodium-calcium exchange can make a small, but measurable contribution to repolarization in the cardiac cell.
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PMID:Reconstruction of transport currents during repolarization: biochemical basis. 243 73

In cardiac muscle isolated from most mammalian species, an elevation of extracellular K+ concentration decreases developed tension. This is explained from stimulation of the Na pump. In rat myocardium, however, developed tension increased when K+ concentration was raised from 3.5 to 9.5 mM, seemingly inconsistent with the above explanation. Activation of isolated Na+,K+-adenosinetriphosphatase by K+ was not different in rat and guinea pig heart. The K+-induced increase in developed tension observed in left atrial muscle preparations obtained from rat heart was not blocked by phentolamine and propranolol or by reserpine pretreatment but attenuated by stimulation at higher frequency, incubation at a lower temperature, or by veratridine, all of which have been shown to increase Na+ loading of myocardial cells. K+ slightly prolonged action potential duration and partially depolarized resting membrane potential; however, K+-induced changes in electrophysiological parameters or possible inactivation of early outward current observed in myocytes isolated from rat heart are unlikely to be the primary cause of the positive inotropic effect. Caffeine or Cd2+ eliminated the inotropic effect of K+ but ryanodine was ineffective. An increase in extracellular K+ from 1 to 3.5 mM decreased developed tension. These results indicate that K+ has dual effects on developed tension in rat myocardium: a negative inotropic effect resulting from Na pump stimulation and a positive inotropic effect. The latter effect is due to a process that is either unique or more strongly expressed in the rat myocardium and masks the former effect in the range of physiological K+ concentrations.
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PMID:Paradoxical positive inotropic effect of K+ in the rat heart. 243 7

The Ca2+ antagonist binding sites associated with the voltage dependent calcium channel in rabbit myocardium were found to distribute with the sarcolemmal Na+ + K+ ATPase and adenylate cyclase activities during subcellular fractionation on sucrose-density gradients. The equilibrium dissociation constants (KD) for the binding of [3H]nitrendipine and [3H]verapamil were 0.31 +/- 0.04 nM and 4.1 +/- 0.5 nM respectively, and displayed an average density of 0.55 +/- 0.05 pmol/mg and 0.4 +/- 0.03 pmol/mg protein respectively for the most enriched membrane fraction. The Ca2+ antagonist binding sites were solubilized from the membranes with the detergent 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate, and specific binding sites for [3H]PN200-110, [3H]verapamil and [3H]diltiazem were isolated on a wheat-germ lectin column. The binding sites for [3H]PN200-110 were enriched about 2,500 fold as compared with the original homogenate and displayed a density of 28.5 +/- 8 pmole/mg protein in the isolated fraction. Sodium dodecyl sulfate gel electrophoresis of the isolated drug binding proteins indicated enrichment of proteins of Mr 170,000, 140,000, 130,000, 100,000 and 53,000. The isolated receptor contained an intrinsic kinase activity that phosphorylated glycoproteins of Mr 170,000 and 53,000. Exogenously added cAMP-kinase stimulated phosphorylation of the 170,000, 100,000, 53,000 and 28,000 Mr glycoproteins in the receptor fraction. The results of this study indicate that the binding sites for [3H]nitrendipine, [3H]PN200-110, [3H]verapamil and [3H]diltiazem residue on glycoprotein(s) which are of sarcolemmal origin, and co-purify together on wheat germ lectin columns. The polypeptide composition of the Ca2+ antagonist binding sites from cardiac muscle appears to be very similar to that of the dihydropyridine receptor in skeletal muscle.
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PMID:Subcellular distribution and isolation of the Ca2+ antagonist receptor associated with the voltage regulated Ca2+ channel from rabbit heart muscle. 244 72


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