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)

Recent studies have implicated angiotensin II (angiotensin) in the pathogenesis of cardiac hypertrophy and heart failure. Heart failure is associated with alterations in intracellular Ca2+ movements mediated by sarcolemmal (SL) and sarcoplasmic reticular (SR) membranes in cardiac myocytes. As it was suspected that alteration gene expression of proteins responsible for controlling transmembrane Ca2+ fluxes may contribute to loss of Ca2+ homeostasis in failing hearts, we undertook a study of the effect of angiotensin on the expression of some target genes in the myocardium. Specifically, we tested the effect of angiotensin on mRNA abundance of cardiac Ca(2+)-transport genes including SL Na+/Ca2+ exchange (EX), SR ryanodine receptor (RYR), and sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). The mRNA abundance of target gene was assessed by Northern blot assay in (i) direct hormonal stimulation of cultured isolated neonatal and adult rat myocytes and (ii) adult rat hearts after implantation of osmotic mini-pumps for delivery of hormone. In all experiments, Northern blot data were normalized using cDNA (Glyceraldehyde 3-phosphate dehydrogenase signal, GAPDH) hybridization to RNA samples. The results indicate that the ratios of EX/GAPDH, RYR/GAPDH, and SERCA2/GAPDH signals were decreased by 51.6%, 55.0%, and 49.4% respectively after neonatal cardiac myocytes were treated (24 h) with 10(-7) M angiotensin. These decreases were blocked completely by treatment with angiotensin subtype 1 (AT1) receptor antagonist (losartan), whereas angiotensin subtype 2 (AT2) receptor antagonist (PD123319) treatment had no effect on the angiotensin-mediated decrease in target gene mRNA abundance. In contrast, angiotensin had no effect on EX, RYR nor SERCA2 gene mRNA abundance in cultured adult myocytes. In a separate series of experiments wherein adult male Sprague-Dawley rats were infused with different dose of angiotensin for 3 days via osmotic mini-pump, we did not detect any alterations in mRNA abundance of cardiac EX/GAPDH, RYR/GAPDH or SERCA/GAPDH genes in either left or right ventricular samples. Thus our results indicate that, in neonatal rat myocytes, angiotensin affects SL and SR calcium transport gene expression by direct agonism of AT1-receptors. As the infusion of low and high dose angiotensin did not affect the expression of target genes in adult hearts, we suggest that the mechanisms for transduction of the angiotensin signaling in neonatal and adult myocytes may be different and may depend on the stage of development. We conclude that regulation of myocardial Ca(2+)-transport gene mRNA abundance by angiotensin may differ among neonatal and adult animals. Nonetheless, our finding with respect to neonatal preparation led us to believe that in neonatal myocytes, the mRNA abundance of SL Na+/Ca2+ exchange, SR ryanodine receptor, and SR Ca(2+)-ATPase are all decreased in response to stimulation by angiotensin.
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PMID:Altered mRNA abundance of calcium transport genes in cardiac myocytes induced by angiotensin II. 876 48

In cardiac muscle, a Ca2+/calmodulin-dependent protein kinase (CaM kinase) associated with the sarcoplasmic reticulum (SR) is known to phosphorylate the membrane proteins phospholamban, Ca(2+)-ATPase, and Ca(2+)-release channel (ryanodine receptor). Phosphorylation of phospholamban and Ca(2+)-ATPase is recognized to stimulate Ca2+ sequestration by the SR but the functional consequence of Ca2+ channel phosphorylation has not been clearly established. In this study, we investigated the effects of the SR Ca(2+)-release inhibitor, ruthenium red (RR), and the SR Ca(2+)-release activator, ryanodine (at submicromolar concentrations), on CaM kinase-mediated phosphorylation of the Ca(2+)-cycling proteins in rabbit cardiac SR. Incubation of SR with RR (5-30 microM) for 3 min at 37 degrees C resulted in marked (up to 85%) inhibition of Ca2+ channel phosphorylation (50% inhibition with 15 +/- 2 microM RR) by the endogenous membrane-associated CaM kinase. Phosphorylation of the Ca2+ channel by exogenously added multifunctional alpha CaM kinase II was also inhibited similarly by RR. Phosphorylation of the Ca(2+)-ATPase by endogenous and exogenous CaM kinase was inhibited only modestly (25-30%) by RR, and phospholamban phosphorylation was unaffected by RR. The magnitude of RR-induced inhibition of Ca2+ channel phosphorylation did not differ appreciably at saturating or subsaturating concentrations of Ca2+ or calmodulin, and in the absence or presence of protein phosphatase inhibitors. In contrast to the effects of RR, low concentrations of ryanodine (0.25-1 microM) caused significant stimulation (up to approximately 50%) of Ca2+ channel phosphorylation but had no effect on Ca(2+)-ATPase and phospholamban phosphorylation. These findings suggest that interaction of RR with the ryanodine receptor induces a "nonphosphorylatable state" of the Ca(2+)-release channel, likely through a conformational change involving occlusion of the CaM kinase phosphorylation site. On the other hand, ryanodine binding to the receptor may serve to maintain an open, "phosphorylatable state" of the channel.
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PMID:Divergent effects of ruthenium red and ryanodine on Ca2+/calmodulin-dependent phosphorylation of the Ca2+ release channel (ryanodine receptor) in cardiac sarcoplasmic reticulum. 880 75

1. Effects of xanthone and its derivative, 1,3,6,7-tetrahydroxyxanthone (norathyriol), on Ca2+ release and ryanodine binding were studied in isolated sarcoplasmic reticulum (SR) vesicles from rabbit skeletal muscle. 2. Both xanthone and norathyriol dose-dependently induced Ca2+ release from the actively loaded SR vesicles which was blocked by ruthenium red, a specific Ca2+ release inhibitor, and Mg2+. 3. Xanthone and norathyriol also dose-dependently increased apparent [3H]-ryanodine binding. Norathyriol, but not xanthone, produced a synergistic effect on binding activation when added concurrently with caffeine. 4. In the presence of Mg2+, which inhibits ryanodine binding, both caffeine and norathyriol, but not xanthone, could restore the binding to the level observed in the absence of Mg2+. 5. Xanthone activated the Ca(2+)-ATPase activity of isolated SR vesicles dose-dependently reaching 70% activation at 300 microM. 6. When tested in mouse diaphragm, norathyriol potentiated the muscle contraction followed by twitch depression and contracture in either a Ca(2+) -free bathing solution or one containing 2.5 mM Ca2+. These norathyriol-induced effects on muscle were inhibited by pretreatment with ruthenium red or ryanodine. 7. These data suggest that xanthone and norathyriol can induce Ca2+ release from the SR of skeletal muscle through a direct interaction with the Ca2+ release channel, also known as the ryanodine receptor.
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PMID:Induction of calcium release from sarcoplasmic reticulum of skeletal muscle by xanthone and norathyriol. 884 39

In this study we investigated the sarcoplasmic reticulum (SR), alongside myofibrillar phenotype, in muscle samples from five Myotonic Dystrophy (DM) patients and five control individuals. DM muscles exhibited as a common feature, a decrease in the slow isoform of myosin heavy chain (MHC) and of troponin C in myofibrils. We observed a match between myofibrillar changes and changes in SR membrane markers specific to fiber type, i.e. the fast (SERCA1) Ca(2+)-ATPase isoform increased concomitantly with a decrease of protein phospholamban (PLB), which in native SR membranes colocalizes with the slow (SERCA2a) SR Ca(2+)-ATPase, and regulates its activity depending on phosphorylation by protein kinases. Our results outline a cellular process selectively affecting slow-twitch fibers, and non-degenerative in nature, since neither the total number of Ca(2+)-pumps or of ryanodine receptor/Ca(2+)-release channels, or their ratio to the dihydropyridine receptor/voltage sensor in junctional transverse tubules, were found to be significantly changed in DM muscle. The only documented, apparently specific molecular changes associated with this process in the SR of DM muscle, are the defective expression of the slow/cardiac isoform of Ca(2+)-binding protein calsequestrin, together with an increased phosphorylation activity of membrane-bound 60 kDa Ca(2+)-calmodulin (CaM) dependent protein kinase. Enhanced phosphorylation of PLB by membrane-bound Ca(2+)-CaM protein kinase also appeared to be most pronounced in biopsy from a patient with a very high CTG expansion, as was the overall 'slow-to-fast' transformation of the same muscle biopsy. Animal studies showed that endogenous Ca(2+)-CaM protein kinase exerts a dual activatory role on SERCA2a SR Ca(2+)-ATPase, i.e. either by direct phosphorylation of the Ca(2+)-ATPase protein, or mediated by phosphorylation of PLB. Our results seem to be consistent with a maturational-related abnormality and/or with altered modulatory mechanisms of SR Ca(2+)-transport in DM slow-twitch muscle fibers.
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PMID:Skeletal muscle sarcoplasmic reticulum phenotype in myotonic dystrophy. 884 17

Changes in contractile and relaxation properties of heart muscle in the cardiac hypertrophy induced by pressure overload have been attributed to alterations in intracellular Ca2+ transport as well as the phenotypic and quantitative changes in contractile protein. However, contradictory data have been reported regarding Ca2+ uptake, release and storage by the sarcoplasmic reticulum (SR). The purpose of this study was to evaluate the changes in SR Ca(2+)-ATPase, ryanodine receptor, calsequestrin and alpha-actin gene expression, and the changes in Ca2+ uptake capacity in various degrees of hypertrophied hearts due to pressure overload. Cardiac hypertrophy was produced in rats by placing a constricting clip (0.80 mm) around the suprarenal abdominal aorta for 8 days. The mRNA levels and Ca2+ uptake capacity were then measured as a function of the severity of cardiac hypertrophy. Ca(2+)-ATPase and ryanodine receptor mRNA levels were increased in mildly hypertrophied hearts but were diminished in severely hypertrophied hearts, showing a bimodal response to pressure overload, Ca2+ uptake capacity showed similar changes along with a positive correlation with Ca(2+)-ATPase mRNA level (r = 0.67, P < 0.001). In contrast, the level of calsequestrin mRNA expression was unaltered and that of alpha-actin was markedly increased over a range of severity of cardiac hypertrophy. These findings suggest that the expression of sarcoplasmic reticulum genes for Ca2+ uptake and release is up- or downregulated dependent on the degree of pressure overload. The gene for the SR Ca2+ storage protein, calsequestrin, might be under different control from these genes in pressure overload. Our findings suggest that the decrease in ratio of mRNAs encoding Ca2+ uptake and release proteins to those encoding contractile proteins could significantly contribute to the slowed contractile and relaxation properties seen in pressure-overloaded hearts.
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PMID:Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload. 887 69

1. The effects of digoxin and ouabain on the calcium release flux from the sarcoplasmic reticulum (SR), isometric tension and intramembrane charge movement were studied in voltage clamped skeletal muscle fibres of the frog. 2. Both cardiac glycosides increased both calcium transients and simultaneously recorded tension at all membrane potentials, showing different effects on the peak and on the steady components of the calcium release flux. These effects were attained at an extracellular digoxin concentration of 5 nM and an estimated intracellular ouabain concentration of 1-2 nM. Digoxin and ouabain thus exerted their effects at the same concentration on calcium release in skeletal muscle as previously observed in isolated cardiac-type ryanodine receptor (RyR) calcium release channels. 3. The peak of SR calcium release increased at all voltages, with the largest potentiation at intermediate membrane potentials. This increase in calcium release flux was attained despite an unchanged SR calcium content. The attenuated release rate therefore reflected an increased number of open RyR channels rather than increased SR loading. 4. These effects could be attributed to an increase in calcium release activation and not a decrease in the rate of inactivation. Rather, the rate of inactivation was enhanced at all voltages as expected from the increased calcium concentration in the triadic junction. 5. In contrast, CMA (17 alpha-acetoxy-6-chloro-4, 6-pregnadiene-3,20-dione; 5 microM), a Na(+)-K(+)-ATPase inhibitor with no positive inotropic effects on the heart, neither influenced SR calcium release nor antagonized the effects of ouabain. 6. Both digoxin and ouabain preserved total intramembrane charge apart from a small negative shift in the mid-point voltage and increase in slope factor. 7. Both digoxin and ouabain induced calcium release from heavy SR vesicles at rates comparable to that induced by ryanodine or caffeine. 8. It is concluded that at least part of the inactivating component of SR calcium release involves distinct RyR calcium release channels that resemble the cardiac RyR isoform in its specific sensitivity to cardiac glycosides.
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PMID:Effects of cardiac glycosides on excitation-contraction coupling in frog skeletal muscle fibres. 888 70

The impact of aging on the Ca2+ pump function of skeletal muscle sarcoplasmic reticulum (SR) was investigated using SR-enriched membrane vesicles isolated from the slow-twitch soleus muscle (SM) and the relatively fast-twitch gastrocnemius muscle (GM) isolated from adult (6-8 mo old) and aged (26-28 mo old) Fischer 344 rats. In addition, isometric twitch characteristics of SM and GM were determined in situ in adult and aged rats under anesthesia. The rates of ATP-supported Ca2+ uptake by SM SR was markedly lower ( approximately 50%) in the aged compared with adult at varying Ca2+ (0.11-8.24 microM) concentrations. Kinetic analysis of the data revealed age-associated decrease in maximum activity reached (Vmax) and increase in the concentration of Ca2+ giving half of Vmax. In contrast, no significant age-related difference was observed in ATP-supported Ca2+ uptake activity of GM SR. The Ca(2+)-stimulated adenosinetriphosphatase (ATPase) activities and the amount of Ca(2+)-ATPase protein did not vary significantly with aging in SM or GM SR. Also, no significant age-related difference was observed in the content of the ryanodine receptor (Ca(2+)-release channel) or the Ca2+ binding protein, calsequestrin in SM and GM SR. In isometrically contracting SM, the time to peak force, half-relaxation time, and contraction duration were significantly prolonged in the aged compared with adult, whereas there was no age-related difference in maximum developed force. None of these isometric twitch parameters differed significantly with age in the GM. These results demonstrate that the effects of aging on skeletal muscle contractile properties and SR function are muscle specific. Furthermore, the data strongly suggest that impairment in SR Ca2+ pump function, apparently due to uncoupling of ATP hydrolysis from Ca2+ transport, contributes to the age-associated slowing of relaxation in the soleus muscle.
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PMID:Effects of aging on sarcoplasmic reticulum function and contraction duration in skeletal muscles of the rat. 889 7

Previous studies on sarcoplasmic reticulum calcium release channel (ryanodine receptor) demonstrated that protein levels are unchanged in myocardium from hearts with end-stage failing dilated cardiomyopathy. In ischemic cardiomyopathy, ryanodine receptor mRNA levels were shown to be decreased but no data on protein levels are available. Accordingly, protein levels of ryanodine receptor, calsequestrin, and sarcoplasmic reticulum calcium-ATPase (SR-Ca(2+)-ATPase) were measured by Western blot analysis in nonfailing human myocardium (n = 7) and in end-stage failing myocardium due to ischemic cardiomyopathy (n = 14). Protein levels of calsequestrin which is the major sarcoplasmic reticulum calcium storage protein were similar in nonfailing myocardium and in myocardium from end-stage failing hearts with ischemic cardiomyopathy. Ryanodine receptor protein levels, normalized to total protein or calsequestrin were also unchanged in ischemic cardiomyopathy. In contrast, protein levels of SR-Ca(2+)-ATPase normalized to total protein or calsequestrin were decreased by 31 and 30%, respectively (p < 0.05). The data indicate that (1) sarcoplasmic reticulum calcium uptake sites are decreased relative to the release sites in ischemic cardiomyopathy, and (2) alterations of sarcoplasmic proteins are similar in ischemic and dilated cardiomyopathy.
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PMID:Unaltered ryanodine receptor protein levels in ischemic cardiomyopathy. 890 86

1. Ca2+ signaling elicited by ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (iGluR) and metabotropic (mGluR) glutamate receptor agonists was studied in the somatic and dendritic regions of cultured cerebellar Purkinje neurons using microscopic video imaging and the Ca2+ sensitive dye fura-2. 2. iGluR and mGluR agonists and K+ depolarization applied by brief micropressure pulses evoked Ca2+ signals in both the somatic and dendritic regions of all Purkinje neurons studied. The Ca2+ signals were generated simultaneously in both cellular regions. The Ca+ signals to these stimulants were similar in general form, consisting of an initial peak and slow recovery phase, but differed in details of amplitude, time course, and complexity. 3. Removal of extracellular Ca2+ abolished the Ca2+ signal to the iGluR agonist AMPA, indicating that Ca2+ influx was essential to the generation of Ca2+ signals by iGluR agonists. The Ca2+ channel blocker lanthanum almost completely eliminated the Ca2+ signals to AMPA, indicating that Ca2+ influx through voltage-sensitive Ca2+ channels was the main pathway for Ca2+ influx. Omega-agatoxin IVA, a P-type Ca2+ channel blocker, significantly reduced the Ca2+ signals to AMPA suggesting that Ca2+ influx was predominately through P-type Ca2+ channels. 4. Pharmacological manipulation of intracellular Ca2+ stores significantly reduced the Ca2+ signals to AMPA, indicating that release of Ca2+ from intracellular Ca2+ stores also plays a prominent role in the generation of the Ca2+ signals to iGluR agonists. These manipulations included blocking Ca2+ release from intracellular stores with dantrolene, an antagonist at the ryanodine receptor that controls Ca2+ release from one pool of intracellular Ca2+ stores, and depletion of intracellular Ca2+ stores with caffeine or ryanodine. 5. Ca2+ influx through voltage-sensitive Ca2+ channels did not appear to be involved in the Ca2+ signals to mGluR activation, because neither lanthanum nor omega-agatoxin IVA altered Ca2+ signals to mGluR agonists. Manipulation of intracellular stores with Ca(2+)-ATPase inhibitors and dantrolene significantly reduced the Ca2+ signal to mGluR agonists, indicating that Ca2+ signals were derived from both the inositol trisphosphate (IP3) and the ryanodine receptor-controlled intracellular Ca2+ stores. 6. Ca2+ signals to the iGluR agonist AMPA correlated temporally with the prolonged, multiphasic membrane responses elicited by similar agonist application in parallel electrophysiological studies. Pharmacological manipulation of Ca2+ influx and release of Ca2+ from intracellular stores significantly influenced components of the membrane response to AMPA, indicating a potential modulator or mediator role for Ca2+ in the membrane response to iGluR activation.
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PMID:Ca2+ signaling pathways linked to glutamate receptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons. 893 Feb 76

Phospholamban ablation is associated with significant increases in the sarcoplasmic reticulum Ca(2+)-ATPase activity and the basal cardiac contractile parameters. To determine whether the observed phenotype is due to loss of phospholamban alone or to accompanying compensatory mechanisms, hearts from phospholamban-deficient and age-matched wild-type mice were characterized in parallel. There were no morphological alterations detected at the light microscope level. Assessment of the protein levels of the cardiac sarcoplasmic reticulum Ca(2+)-ATPase, calsequestrin, myosin, actin, troponin I, and troponin T revealed no significant differences between phospholamban-deficient and wild-type hearts. However, the ryanodine receptor protein levels were significantly decreased (25%) upon ablation of phospholamban, probably in an attempt to regulate the release of Ca2+ from the sarcoplasmic reticulum, which had a significantly higher diastolic Ca2+ content in phospholamban-deficient compared with wild-type hearts (16.0 +/- 2.2 versus 8.6 +/- 1.0 mmol Ca2+/kg dry wt, respectively). The increases in Ca2+ content were specific to junctional sarcoplasmic reticulum stores, as there were no alterations in the Ca2+ content of the mitochondria or A band. Assessment of ATP levels revealed no alterations, although oxygen consumption increased (1.6-fold) to meet the increased ATP utilization in the hyperdynamic phospholamban-deficient hearts. The increases in oxygen consumption were associated with increases (2.2-fold) in the active fraction of the mitochondrial pyruvate dehydrogenase, suggesting increased tricarboxylic acid cycle turnover and ATP synthesis. 31P nuclear magnetic resonance studies demonstrated decreases in phosphocreatine levels and increases in ADP and AMP levels in phospholamban-deficient compared with wild-type hearts. However, the creatine kinase activity and the creatine kinase reaction velocity were not different between phospholamban-deficient and wild-type hearts. These findings indicate that ablation of phospholamban is associated with downregulation of the ryanodine receptor to compensate for the increased Ca2+ content in the sarcoplasmic reticulum store and metabolic adaptations to establish a new energetic steady state to meet the increased ATP demand in the hyperdynamic phospholamban-deficient hearts.
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PMID:Compensatory mechanisms associated with the hyperdynamic function of phospholamban-deficient mouse hearts. 894 45


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