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)

Toxicosis by monensin, a Na(+)-selective ionophore, induces skeletal and cardiac muscle necrosis. Cultured neonatal rat cardiac myocytes were killed by monensin (greater than 0.2 micrograms/ml) beginning at 30 min and completing by 60-90 min. Other cultured cell types presumably lacking excitable membranes were not killed by monensin under these conditions. Cardiac myocytes were also killed by nigericin and nonactin (monovalent cation-carrying ionophores with low ion selectivity), but not by valinomycin, which has a high selectivity for K+. Monensin-induced killing was associated with formation of blebs in cell membranes and subsequent swelling of the cells during the early phases of killing, whereas surface membranes of cells permeabilized to trypan blue dye contained discrete small holes visible by scanning electron microscopy. Monensin-induced killing occurred at extracellular Na+ concentrations greater than or equal to 10 mM, but not when Li+, K+, Cs+, Rb+, or choline ions replaced Na+ at concentrations up to 0.15 M. Killing was prevented at extracellular pH values less than or equal to 6.4 and was enhanced by ouabain, an inhibitor of Na+/K(+)-ATPase-mediated Na+ transport. Several characteristics of monensin-induced cardiac myocyte killing were similar to those observed during killing induced by the Ca(2+)-carrying ionophore, A23187 plus Ca2+, including a requirement for extracellular Ca2+ concentrations greater than 0.5 mM, inhibition by Mn2+ and Ni2+, and an associated stimulation of arachidonic acid release. The cell killing characteristics are consistent with a monensin-induced Na+ influx which admits toxic levels of extracellular Ca2+ to the cytoplasm of cells with excitable membranes, possibly via Na+/Ca2+ antiporter protein(s).
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PMID:Sodium- and calcium-dependent steps in the mechanism of neonatal rat cardiac myocyte killing by ionophores. I. The sodium-carrying ionophore, monensin. 152 51

Superfused cattle coronary artery rings contracted with endothelin or with a thromboxane A2 mimetic respond to transmural stimulation with relaxation. These relaxations are not reduced by denudation of the endothelium, or by combined pretreatment with quanethidine, atropine and propranolol, nor do they involve free radicals. Stimulation at 0.5 Hz with an increasing number of pulses, from 1 to 50, each of 500 microseconds in duration, produced progressively greater and more prolonged relaxations. Human coronary arteries, denuded and pretreated with guanethidine or tetrodotoxin, also showed prominent relaxations of both spontaneous and induced contractions with minimal transmural stimulation at 0.5 Hz. The delivery of 10 pulses briefly depressed near-maximal contractions to combinations of two or even three spasmogens in the cattle preparations. Reduction of extracellular potassium to near zero did not reduce stimulation-induced relaxations, but decreases in extracellular calcium did. The participation of ATP-sensitive potassium channels in stimulation-induced relaxations was unlikely because glibencamide did not reduce them, although it antagonized the relaxation produced by the potassium channel opener pinacidil. Tetraethylammonium blocked the relaxations to stimulation, indicating the involvement of calcium-dependent potassium channels, but block of small to moderate conductance SK channels with apamin was ineffective in antagonizing relaxations, making it likely that activation of large conductance SK channels or maxi-K channels was involved. Blockade of stimulation-induced relaxation in low sodium Krebs', but not by vanadate (1 mM), indicated the likely involvement of the Na+/Ca++ exchanger rather than a Ca(++)-ATPase as the calcium extrusion component of the relaxation process. Restoration of prestimulation tone required calcium influx through nifedipine-sensitive channels. It is concluded that a highly effective relaxation cascade is initiated by the delivery of one to five 0.5-msec pulses at 0.5 Hz, whose effects long outlast the stimulation parameters. The significance of this finding for coronary pathophysiology and as a means of selectively activating a relaxation cascade in an intact coronary artery segment is discussed.
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PMID:Activation of a relaxation cascade in isolated coronary arteries by brief electrical pulses. 156 Mar 67

In both types of striated muscle (skeletal and cardiac), calcium flux across the plasma membrane (sarcolemma) is regulated by at least three distinct membrane proteins; a voltage-dependent Ca2+ channel, Ca2+ pump (Ca2+ ATPase), and the Na+/Ca2+ antiporter. Each of these proteins is subject to regulation by intracellular second messengers. The magnitude and the role of this transsarcolemmal calcium flux are quite different between cardiac and skeletal muscle. In cardiac muscle, the influx is large, precedes, and is obligatory for contraction. There is general agreement that this influx is the trigger for Ca2+ release from the sarcoplasmic reticulum (SR) in the heart according to the Ca2+-induced Ca2+ release hypothesis. Variations in the transsarcolemmal Ca2+ influx have a profound effect on the strength of cardiac contraction, and it appears that this is the primary physiological strategy for regulation of contractility. In skeletal muscle, on the other hand, the T-tubules represent the richest source of dihydropyridine (DHP)-sensitive calcium channels known to exist, yet the influx of Ca2+ is proportionally much smaller and a significant portion enters the fiber following the twitch. While the majority of the Ca2+ influx is twitch dependent, it is quite clear that contraction in skeletal muscle is not predicated on this influx. It has been proposed that these DHP channels act as voltage sensors in order to initiate release of SR Ca2+; however, the link between the sensors and the opening of the SR Ca2+ (ryanodine-sensitive) channel is unknown. Transsarcolemmal Ca2+ transport appears to be subject to intense regulation to modify the acute response and demonstrates some plasticity in the adaptation to chronic perturbations.
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PMID:Ca2+ transport across the plasma membrane of striated muscle. 255 Jul 15

The purpose of this survey is to describe the importance of cyclic AMP and Ca2+-calmodulin as mediators of the effects of beta-adrenergic agonists on cardiac sarcolemma. First, the basic characteristics of the three sarcolemmal Ca2+-transporting systems, the slow Ca2+ channel, the Ca2+-pumping ATPase and the Na+/Ca2+ antiporter, are described. These different pathways for in- and outflux of Ca2+ play a crucial role in the excitation-contraction coupling and relaxation of heart muscle. Catecholamines in the myocardium cause an increase in the rate and extent of tension development during systole, and in the rate of relaxation during diastole. These functional changes may largely be brought about by cyclic AMP-induced phosphorylation of membrane proteins that increases both the probability of opening the slow Ca2+ channels and the rate of Ca2+ pumping ATPase. It is generally believed that the effects on Ca2+ transport systems are due to direct actions of beta-adrenergic agonists leading to an increased cytosolic Ca2+ level during systole. Indirectly, an increase in systolic Ca2+ can amplify the primary effect of catecholamine on the Ca2+ pumping ATPase and probably also on the Na+/Ca2+ antiporter through Ca2+-calmodulin-dependent phosphorylation of membrane proteins. The intimate involvement of calmodulin in the operation of several sarcolemmal Ca2+-transporting systems is discussed in the light of the unknown mechanism of action of the so-called Ca2+ channel blockers, a class of drugs that have a very important potential to provide information on the fundamental reaction steps in excitation-contraction coupling. Some of these drugs are potent inhibitors of Ca2+-calmodulin-regulated enzymes.
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PMID:Calcium transport systems in cardiac sarcolemma and their regulation by the second messengers cyclic AMP and calcium-calmodulin. 299 98

Experiments were carried out to test the hypothesis that membrane injury associated with Ca2+ depletion of the heart is involved in the development of Ca2+ overload during the Ca2+ paradox phenomenon. Biochemical properties of sarcolemma (SL) and sarcoplasmic reticulum (SR) isolated from the rabbit heart after 10 min of Ca2+-free perfusion were examined. This treatment predisposes hearts to the Ca2+ paradox as assessed by perfusate creatine kinase (CK) activity and heart contractility during reperfusion with Ca2+. Homogenates prepared from Ca2+ depleted heart were examined for their capacity to accumulate Ca2+ in the presence of ATP, which is mainly a property of the SR Ca2+ pump. The initial rate of Ca2+ pumping was 55% less in the Ca2+ depleted heart. The activities of 5'-nucleotidase, Na+/K+-ATPase and Na+/Ca2+ antiporter, and the Ca2+ permeability were studied in isolated SL vesicles. Na+/K+-ATPase activity was 75% less in SL isolated from Ca2+ depleted hearts, no significant changes were observed with the other parameters studied. Calmodulin (CaM) content in SL, assayed by radioimmunoassay, was unchanged. However, a 98% increase was observed in homogenates prepared from Ca2+ depleted hearts. The possible involvement of CaM in the Ca2+ paradox phenomenon is discussed. The data provide evidence that the net Ca2+ gain of myocardial cells in Ca2+ repletion may in part be associated with a loss of the ability of the SL and SR to remove Ca2+ from the cytosol.
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PMID:Diminished Na+/K+ and Ca2+ pump activities in the Ca2+ depleted heart: possible role in the development of Ca2+ overload during the Ca2+ paradox. 631 44

The present study aimed to clarify the existence of a Na+/Ca2+ antiport device in kidney tubular epithelial cells discussed in the literature to represent the predominant mechanistic device for Ca2+ reabsorption in the kidney. Inside-out oriented plasma membrane vesicles from tubular epithelial cells of guinea-pig kidney showed an ATP-driven Ca2+ transport machinery similar to that known to reside in the plasma membrane of numerous cell types. It was not affected by digitalis compounds which otherwise are well-documented inhibitors of Ca2+ reabsorption. The vesicle preparation contained high, digitalis-sensitive (Na+ + K+)-ATPase activities indicating its origin from the basolateral portion of plasma membrane. The operation of a Na+/Ca2+ antiport device was excluded by the findings that steep Ca2+ gradients formed by ATP-dependent Ca2+ accumulation in the vesicles were not discharged by extravesicular Na+, and did not drive 45Ca2+ uptake into the vesicles via a Ca2+-45Ca2+ exchange. The ATP-dependent Ca2+ uptake into the vesicles became increasingly depressed with time by extravesicular Na+. This was not due to an impairment of the Ca2+ pump itself, but caused by Na+/Ca2+ competition for binding sites on the intravesicular membrane surface shown to be important for high Ca2+ accumulation in the vesicles. Earlier observations on Na+-induced release of Ca2+ from vesicles pre-equilibrated with Ca2+, seemingly favoring the existence of a Na+/Ca2+ antiporter in the basolateral plasma membrane, were likewise explained by the occurrence of Na+/Ca2+ competition for binding sites. The weight of our findings disfavors the transcellular pathway of Ca2+ reabsorption through tubule epithelium essentially depending on the operation of a Na+/Ca2+ antiport device.
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PMID:Evidence against parallel operation of sodium/calcium antiport and ATP-driven calcium transport in plasma membrane vesicles from kidney tubule cells. 632 Aug 85

Sodium taurocholate (NaTC), at concentrations below the critical micellar concentration, caused a transient relaxation of isolated guinea-pig ileum smooth muscle strips. The relaxation was not inhibited by previous incubation with either 10 microM ouabain, 0.4 mM d-tubocurarine or 0.5 microM apamin, ruling out the participation of hyperpolarization of the plasma membrane induced by either stimulation of Na+/K+ ATPase or by opening of Ca(++)-dependent K+ channels. In guinea-pig ileum smooth muscle cultured cells, addition of NaTC (1 mM) stimulated Na+ uptake and Ca++ efflux. The relaxation induced by NaTC was inhibited by 3',4'-dichlorobenzamil, a blocker of the Na+/Ca++ exchanger. Preincubation with NaTC, or its addition during the early stage of the tonic response of the ileum to acetylcholine, enhanced that response, whereas a relaxation was observed when NaTC was added at the late stage of the acetylcholine response. In cultured cells, NaTC potentiated the stimulation of Ca2+ influx by acetylcholine. Our results suggest that NaTC acts on the smooth muscle cell membrane causing a stimulation of the Na+/Ca++ exchange mechanism.
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PMID:Role of Na+/Ca++ exchange in the relaxant effect of sodium taurocholate on the guinea-pig ileum smooth muscle. 823 9

Plasma membrane Ca(2+)-ATPase (PMCA) and the Na+/Ca2+ exchanger participate in regulating cell function by maintaining proper intracellular Ca2+ concentrations ([Ca2+]i). In renal epithelial cells these proteins have been additionally implicated in cellular calcium absorption. The purpose of the present studies was to determine the Ca2+ extrusion mechanisms in cells derived from the proximal tubule. Homology-based RT-PCR was used to amplify PMCA transcripts from RNA isolated from mouse cell lines originating from the S1, S2, and S3 proximal tubule segments. S1, S2, and S3 cells exhibited only PMCA1 and PMCA4 products. PCR product identity was confirmed by sequence analysis. Northern analysis of proximal tubule cell RNAs revealed appropriate transcripts of 7.5 and 5.5 kb for PMCA1 and 8.5 and 7.5 kb for PMCA4, but were negative for PMCA2 and PMCA3. Western analysis with a monoclonal antibody to PMCA showed that all proximal cell lines expressed a reacting plasma membrane protein of 140 kD, the reported PMCA molecular mas. Na+/Ca2+ exchanger (NCX1) mRNA expression, analyzed by RT-PCR, protein expression by Western analysis, and functional exchange activity were uniformly absent from all proximal tubule cell lines. These observations support the idea that immortalized cells derived from the proximal tubule express PMCA1 and PMCA4, which may serve as the primary mechanism of cellular Ca2+ efflux.
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PMID:Molecular dissection of Ca2+ efflux in immortalized proximal tubule cells. 904 50

cDNAs for the Na+/Ca2+ exchanger from Drosophila melanogaster (Dmel/Nck) have been cloned by homology screening using the human heart Na+/Ca2+ exchanger cDNA. The overall deduced protein structure for Dmel/Nck is similar to that of mammalian Na+/Ca2+ exchanger genes NCX1 and NCX2, having six hydrophobic regions in the amino terminus separated from six at the carboxy-terminal end by a large intracellular loop. Sequence comparison of the Drosophila exchanger cDNAs with NCX1 and NCX2 Na+/Ca2+ exchangers are approximately 46% identical at the deduced amino acid level. Consensus phosphorylation sites for both protein kinase C and protein kinase A are present on the intracellular loop region of the Dmel/Nck. Alternative splicing for the Dmel/Nck gene is suggested in the same intracellular loop region as demonstrated for NCX1. Functionally, the Drosophila Na+/ Ca2+ exchanger expressed in oocytes differs from expressed mammalian NCX1 with regard to Ca2+ transport in Ca2+/ Ca2+ exchange and the effect of monovalent-dependent Ca2+/ Ca2+ exchange. The Dmel/Nck gene maps to chromosome 3 (93A-B) using in situ hybridization to polytene chromosomes, the same position as the Na(+)-K(+)-ATPase, a related transporter. We conclude that, although extracellular Na+ concentration-dependent Ca2+ transport is subserved by both human and Drosophila Na+/Ca2+ exchangers, there are clear and important differences in the transporters, which should be useful in deducing how the Na+/Ca2+ exchanger protein function depends on its structure.
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PMID:Na+/Ca2+ exchanger in Drosophila: cloning, expression, and transport differences. 925 64

Outward current oscillations associated with transient membrane hyperpolarizations were induced in murine macrophage polykaryons by membrane depolarization in the absence of external Na+. Oscillations corresponded to a cyclic activation of Ca(2+)-dependent K+ currents (IKCa) probably correlated with variations in intracellular Ca2+ concentration. Addition of external Na+ (8 mM) immediately abolished the outward current oscillations, suggesting that the absence of the cation is necessary not only for their induction but also for their maintenance. Oscillations were completely blocked by nisoldipine. Ruthenium red and ryanodine reduced the number of outward current cycles in each episode, whereas quercetin prolonged the hyperpolarization 2- to 15-fold. Neither low molecular weight heparin nor the absence of a Na+ gradient across the membrane had any influence on oscillations. The evidence suggests that Ca2+ entry through a pathway sensitive to Ca2+ channel blockers is elicited by membrane depolarization in Na(+)-free medium and is essential to initiate oscillations, which are also dependent on the cyclic release of Ca2+ from intracellular Ca(2+)-sensitive stores; Ca2+ ATPase acts by reducing intracellular Ca2+, thus allowing slow deactivation of IKCa. Evidence is presented that neither a Na+/Ca2+ antiporter nor Ca2+ release from IP3-sensitive Ca2+ stores participate directly in the mechanism of oscillation.
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PMID:Outward potassium current oscillations in macrophage polykaryons: extracellular calcium entry and calcium-induced calcium release. 953 46


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