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 pathogenesis of arrhythmogenic transient depolarizations (TDs) was studied by means of electrophysiological and cytochemical methods in normal and hypertrophied left ventricular myocardium of the rat. In hypertrophy induced by administration of 5 mg/kg isoprenaline once daily for 7 days, the myocardial membrane was depolarized, the action potential duration was prolonged and the Vmax was decreased, as compared with those of age-matched normal controls. TDs induced by a train of action potentials could be observed in hypertrophied myocardium, but not in normal control myocardium. Ryanodine completely abolished TDs, but the beta-adrenoceptor agonist noradrenaline and the adenylate cyclase activator forskolin were without effect. In cytochemical studies, the Na+,K(+)-ATPase activity was localized in the sarcolemma, and three times as much reaction product, which appeared on the inner side of the cell membrane, was found in the normal myocardium than in the hypertrophied myocardium. The results suggest that catecholamine-induced cardiac hypertrophy damages the membrane-bound Na+,K(+)-ATPase and causes a cAMP-independent intracellular Ca overload and TDs, thereby permitting abnormal impulse formation, which predisposes the diseased myocardium to develop arrhythmias.
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PMID:Sodium-pump injury and arrhythmogenic transient depolarizations in catecholamine-induced cardiac hypertrophy. 131 36

The objective of this study was to compare the properties of single smooth muscle cells enzymatically dispersed from the dog mesenteric arteries to the properties of similar cells functioning in tissue strips. The isolated cells remained relaxed in nominally Ca(2+)-free medium for about 1-2 h after exposure to 1 mM Ca2+ and like intact mesenteric artery rings did not contract spontaneously. Enzymatically dispersed cells maintained all the characteristic morphological features observed in strips of muscle prior to isolation except that the amorphous materials covering the smooth muscle cell surfaces (basal lamina) were absent after enzymatic dispersion. Addition of 100 mM KCl to these vascular muscle cells elicited maximal shortening in the presence but not in the absence of extracellular Ca2+ and KCl-induced cell shortening was prevented by 10(-7) M nifedipine indicating the presence of functional voltage-operated Ca2+ channels. However, in contrast to the vascular muscle strips, in which graded contractile responses were observed with increasing KCl concentrations, isolated vascular muscle cells underwent nearly maximal contraction at concentrations as low as 15 mM KCl. Both intact tissue and isolated cell preparations responded similarly to phenylephrine in a concentration-dependent manner and the responses were blocked by prazosin. In contrast to muscle strips, the isolated cells did not shorten in response to phenylephrine in Ca(2+)-free medium. Isolated muscle shortened in the presence of sarcoplasmic reticulum selective Ca2+ transport ATPase inhibitors, cyclopiazonic acid or thapsigargin. Ryanodine also caused contraction. We conclude that enzymatically dispersed smooth muscle cells from dog mesenteric arteries are potentially useful for studies of the regulation of smooth muscle contractility, but have significantly increased sensitivity to external K+, implying an altered membrane potential or voltage dependence of ion channels. Their impaired ability to contract to phenylephrine in Ca(2+)-free medium implies some alteration in intracellular Ca2+ stores of their coupling to cellular activation. These differences will affect how the data obtained from freshly isolated enzymatically dispersed vascular muscle cells may be extrapolated to cell studies in intact tissues.
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PMID:Morphological and functional characterization of vascular muscle cells enzymatically dispersed from dog mesenteric arteries. 148 91

The contribution of sarcoplasmic reticulum (SR) Ca2+ release to evoked tension in rat arterial rings was studied by comparing the effects of ryanodine (an SR Ca2+ channel opener) and thapsigargin and cyclopiazonic acid (CPA) (two Ca(2+)-ATPase inhibitors). Isometric tension was evoked by serotonin (5-HT), 30-50 mM external K+, and 10 mM caffeine in rings of aorta and a small (second-order) branch of the superior mesenteric artery (SMA). Resting tension was unaffected by 10 microM ryanodine or 1-5 microM thapsigargin, but 20 microM CPA raised resting tension in aortic rings and evoked spontaneous contractions in some SMA rings. Ryanodine (10 microM) or 1-5 microM thapsigargin partially depleted the SR Ca2+ stores (indicated by reduced caffeine-evoked contractions) and attenuated 5-HT- and high K(+)-evoked contractions in aortic rings but augmented 5-HT- and high K(+)-evoked contractions in SMA. Caffeine completely emptied the SR Ca2+ stores in the presence of ryanodine but not thapsigargin in both the aorta and SMA; thus, thapsigargin may selectively affect one component of a heterogeneous SR. When the aortic Ca2+ stores were empty (i.e., caffeine contractions were abolished), the 5-HT- and high K(+)-evoked contractions in the aorta were also augmented. CPA rapidly emptied the SR Ca2+ stores in both the aorta and SMA. CPA augmented the 5-HT-evoked contractions in the SMA and in five of nine aortic rings but attenuated evoked contractions in the remaining aortic rings. The attenuation or abolition of the caffeine contractions implies that ryanodine, thapsigargin, and CPA all deplete the SR Ca2+ stores. The attenuated responses to 5-HT and high K+ observed when the aortic SR Ca2+ stores were only partially depleted are consistent with the idea that evoked SR Ca2+ release is a large component of the Ca2+ transient in the aorta. The augmentation of 5-HT- and high K(+P)-evoked responses after partial (SMA) or complete (aorta) depletion of the SR Ca2+ stores suggests that evoked release of SR Ca2+ normally regulates Ca2+ entry by negative feedback and/or that the SR normally buffers the evoked rise in cytosolic Ca2+.
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PMID:Modulation of evoked contractions in rat arteries by ryanodine, thapsigargin, and cyclopiazonic acid. 153 81

Ryanodine, a highly toxic alkaloid known to react specifically with the Ca2+ release channels in sarcoplasmic reticulum (SR), was employed to study Ca2+ sequestration in the liver. Ryanodine at a 200 microM concentration increased cytosolic free Ca2+ levels and phosphorylase a activity in isolated hepatocytes. These effects may involve microsomal Ca2+ sequestration, because ryanodine, in the presence of inhibitors of mitochondrial Ca2+ uptake, at concentrations of 1 nM, 1 microM, 50 microM and 100 microM decreased 45Ca2+ retention in permeabilized hepatocytes. This inhibition of Ca2+ retention by ryanodine was not due to inhibition of the microsomal Ca(2+)-ATPase. Dantrolene, a compound shown previously to inhibit ryanodine binding in the liver, also decreased 45Ca2+ retention in permeabilized hepatocytes, and activated phosphorylase a. These results show that ryanodine administration alters calcium sequestration in liver. The possibility of the existence of a ryanodine-sensitive Ca(2+)-release channel in liver is discussed.
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PMID:Effects of ryanodine on calcium sequestration in the rat liver. 165 99

Repetitive stimulation of the smooth muscle with acetylcholine (ACh) in the continuous presence of nifedipine resulted in a progressive decrease in the developed tension. This was associated with a decrease in the content of the agonist-sensitive intracellular Ca2+ stores. Agonist-sensitive internal Ca2+ stores appeared to be readily depleted by successive or prolonged agonist stimulation in Ca(2+)-free medium. The refilling of the empty stores when the muscle is at rest required extracellular Ca2+, was decreased by nifedipine, and was increased by BAY K 8644 and by increased external Ca2+ concentration. Refilling of stores during ACh stimulation in Ca(2+)-containing medium was decreased by nifedipine and by cyclopiazonic acid (CPA), an inhibitor of the sarcoplasmic reticulum (SR) Ca2+ pump, and was potentiated by BAY K 8644. BAY K 8644 reversed the inhibitory effect of CPA on stores Ca2+ refilling. Ryanodine in normal Krebs increased muscle resting tension, an effect not observed in Ca(2+)-free medium, blocked by nifedipine and enhanced by BAY K 8644. We propose that the refilling of ACh-sensitive internal Ca2+ stores involves two distinct pathways, one dependent on the uptake of cytosolic Ca2+ via a CPA-sensitive SR Ca(2+)-adenosinetriphosphatase, and the other pathway dependent on extracellular Ca2+ influx via a dihydropyridine-sensitive Ca2+ channel and is CPA insensitive. The refilling pathway between plasmalemma and SR may involve a plasmalemma L-type Ca2+ channel (dihydropyridine sensitive) and the SR Ca2+ release channel (ryanodine sensitive).
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PMID:Acetylcholine Ca2+ stores refilling directly involves a dihydropyridine-sensitive channel in dog trachea. 171 53

The microsomal Ca-ATPase inhibitor thapsigargin induces in rat salivary acinar cells [Ca2+]i oscillations which, though similar to those activated by agonists, are independent of inositol phosphates or inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores (Foskett, J. K., Roifman, C., and Wong, D. (1991) J. Biol. Chem. 266, 2778-2782). To examine whether the oscillation mechanism resides in another, thapsigargin- and IP3-insensitive intracellular store, we examined the effects of caffeine and ryanodine, known modulators of Ca2+ release from sarcoplasmic reticulum in excitable cells. Oscillations were induced by caffeine (1-20 mM) in nonoscillating thapsigargin-treated acinar cells, which required the continued presence of caffeine, whereas caffeine was without effect or reduced oscillation amplitude in oscillating cells. Ryanodine (10-50 microM) inhibited oscillations in most of the cells. These results suggest that Ca2+ oscillations in parotid acinar cells are driven by periodic Ca2+ release from an IP3-insensitive Ca2+ store with properties similar to sarcoplasmic reticulum of excitable cells.
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PMID:Free cytoplasmic Ca2+ concentration oscillations in thapsigargin-treated parotid acinar cells are caffeine- and ryanodine-sensitive. 183 May 87

The effect of the plant alkaloid ryanodine on the cardiac sarcoplasmic reticulum (SR) function, which plays a major role in the regulation of intracellular calcium and thereby in the generation of force, was studied by determining oxalate-supported calcium uptake, steady-state calcium load, calcium permeability, intravesicular-free calcium and Ca,Mg-adenosine triphosphatase (ATPase) activity of "heavy" vesicles in the presence or absence of the oxygen-free radical-generating system. In vitro generation of oxygen-free radicals by xanthine oxidase (0.09 u/ml), acting on xanthine (25 microM) as a substrate, increased the permeability of the vesicles to calcium, determined by measuring net efflux of calcium after stopping pump-mediated fluxes, and decreased oxalate-supported calcium uptake and steady-state calcium load with no effect on Ca,Mg-ATPase activity. This effect of oxygen-free radicals was inhibited completely by superoxide dismutase, which eliminated completely superoxide anion radical production and caused an anticipated increase in hydrogen peroxide from the xanthine-xanthine oxidase reaction in our system. The xanthine-xanthine oxidase reaction decreased intravesicular-free calcium. The diminished level of intravesicular-free calcium, which was reflected by the decreased steady-state calcium load induced by oxygen-free radicals, was prevented by specific closure of the SR calcium release channel by ryanodine under established optimal conditions; under the same conditions, ryanodine also prevented superoxide dismutase-inhibitable reduction of calcium uptake induced by oxygen-free radicals in the presence or absence of oxalate. Ryanodine was without effect on Ca,Mg-ATPase activity by itself and had no effect on any of the changes in calcium permeability mediated by the generation of oxygen-free radicals under the experimental conditions used.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of ryanodine on oxygen free radical-induced dysfunction of cardiac sarcoplasmic reticulum. 184 30

Ryanodine binds to the transducer calcium channel complex that links depolarization of the transverse tubule to calcium release from the terminal cisternae during excitation-contraction coupling of skeletal muscle. Ryanodine exerts a bimodal action on the transducer calcium channel complex depending upon membrane potential and concentration. When the transmembrane potential is at resting level (-90 mV inside cell vs outside), low concentrations of ryanodine 10(-10) M to 10(-8) M favor calcium influx from outside which in turn causes calcium release from the terminal cisternae via calcium operated calcium channels. The leak from the terminal cisternae is insufficient to cause contraction but does cause a large increase in aerobic energy utilization by the Ca-ATPase of the sarcoplasmic reticulum. When the transmembrane potential is made more positive (-40 mV) the transducer channel is opened to the terminal cisternae of sarcoplasmic reticulum and is maintained in an open state by ryanodine allowing calcium efflux from the terminal cisternae to the sarcoplasm. At higher concentrations of ryanodine the transducer-calcium channel becomes open to the terminal cisternae and its store of ionized calcium leaks from the terminal cisternae in sufficient quantities to cause a contracture. The ryanodine-sensitive calcium transducer calcium channel operates in a bimodal manner. At low concentrations less than 10(-4) M the ryanodine-sensitive transducer calcium channel is open to the lumen of the T-tubule and allows calcium to flow in and trigger further calcium release. At higher concentrations the ryanodine-sensitive transducer channel opens to allow a calcium efflux from the terminal cisternae in sufficient quantities to cause contracture.
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PMID:Bimodal operation of the ryanodine-sensitive transducer calcium channel. 217 57

Junctional terminal cisternae are a recently isolated sarcoplasmic reticulum fraction containing two types of membranes, the junctional face membrane with morphologically intact "feet" structures and the calcium pump membrane [Saito, A., Seiler, S., Chu, A., & Fleischer, S. (1984) J. Cell Biol. 99, 875-885]. In this study, the Ca2+ fluxes of junctional terminal cisternae are characterized and compared with three other well-defined fractions derived from the sarcotubular system of fast-twitch skeletal muscle, including light and heavy sarcoplasmic reticulum, corresponding to longitudinal and terminal cisternae regions of the sarcoplasmic reticulum, and isolated triads. Functionally, junctional terminal cisternae have low net energized Ca2+ transport measured in the presence or absence of a Ca2+-trapping anion, as compared to light and heavy sarcoplasmic reticulum and triads. Ca2+ transport and Ca2+ pumping efficiency can be restored to values similar to those of light sarcoplasmic reticulum with ruthenium red or high [Mg2+]. In contrast to junctional terminal cisternae, heavy sarcoplasmic reticulum and triads have higher Ca2+ transport and are stimulated less by ruthenium red. Heavy sarcoplasmic reticulum appears to be derived from the nonjunctional portion of the terminal cisternae. Our studies indicate that the decreased Ca2+ transport is referable to the enhanced permeability to Ca2+, reflecting the predominant localization of Ca2+ release channels in junctional terminal cisternae. This conclusion is based on the following observations: The Ca2+, -Mg2+ -dependent ATPase activity of junctional terminal cisternae in the presence of a Ca2+ ionophore is comparable to that of light sarcoplasmic reticulum when normalized for the calcium pump protein content; i.e., the enhanced Ca2+ transport cannot be explained by a faster turnover of the pump. Ruthenium red or elevated [Mg2+] enhances energized Ca2+ transport and Ca2+ pumping efficiency in junctional terminal cisternae so that values approaching those of light sarcoplasmic reticulum are obtained. Rapid Ca2+ efflux in junctional terminal cisternae can be directly measured and is blocked by ruthenium red or high [Mg2+]. Ryanodine at pharmacologically significant concentrations blocks the ruthenium red stimulation of Ca2+ loading. Ryanodine binding in junctional terminal cisternae, which appears to titrate Ca2+ release channels, is 2 orders of magnitude lower than the concentration of the calcium pump protein. By contrast, light sarcoplasmic reticulum has a high Ca2+ loading rate and slow Ca2+ efflux that are not modulated by ruthenium red, ryanodine, or Mg2+.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Functional characterization of junctional terminal cisternae from mammalian fast skeletal muscle sarcoplasmic reticulum. 243 26

Physiologic studies suggest that the myocardium from fetal and newborn sheep functions at a higher contractile state with decreased contractile reserve when compared to the myocardium of adult sheep. To investigate the role of Ca2+ transport by the sarcoplasmic reticulum (SR) in this phenomenon, we studied functional properties and protein composition of cardiac SR vesicles isolated from fetal and maternal sheep. Active accumulation of Ca2+ and the density of the Ca2+ pump protein were decreased 60% (p less than 0.01) in fetal SR vesicles; however Ca2+-dependent ATPase activity was decreased only 30% (p less than 0.01). This decreased difference in Ca2+-dependent ATPase activities was accounted for by the higher turnover number measured for the Ca2+ pump of fetal SR vesicles (1.6-fold increased, p less than 0.01). Ryanodine, an alkaloid which blocks Ca2+ efflux from cardiac SR vesicles, stimulated Ca2+ uptake more effectively in fetal SR vesicles, suggesting that these vesicles had a higher passive Ca2+ permeability during conditions of active Ca2+ transport. Protein compositional studies showed that the content of phospholamban was decreased in fetal SR vesicles and was correlated with the decrease in the density of Ca2+ pumps. In contrast, the content of calsequestrin and the density of [3H]nitrendipine-binding sites were increased approximately 2-fold in fetal SR vesicles. These functional and compositional differences between SR vesicles isolated from fetal and maternal sheep may indicate that there is relatively more junctional SR in fetal hearts. Since the SR regulates muscle contraction by modulating intracellular Ca2+ concentration, it is possible that developmental alterations in cardiac SR may contribute to the decreased myocardial contractile reserve noted in fetal sheep.
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PMID:Developmental changes in cardiac sarcoplasmic reticulum in sheep. 302 68


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