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)

Previous studies have shown that hypocapnia results in fragmentation of nuclear DNA in the cerebral cortex of newborn piglets. We tested the hypothesis that hypocapnia results in decreased ATP and phosphocreatine (PCr) levels and increased nuclear high-affinity Ca++-ATPase activity, intranuclear Ca++ flux, and CaM kinase IV activity in neuronal nuclei of piglets. Three groups of piglets were ventilated as either hypocapnic (a PaCO2 of 20 mm Hg), normocapnic (a PaCO2 of 40 mm Hg), or corrected hypocapnic (ventilated as hypocapnic but with CO2 added to maintain normocapnia) for 1 h. Tissue ATP levels were lower in the hypocapnic than in the normocapnic group. PCr levels were lower and 45Ca++-influx, Ca++-ATPase activity and CaM kinase IV activity were higher in hypocapnic than in normocapnic or corrected hypocapnic piglets. We conclude that hypocapnia alters nuclear membrane Ca++ flux mechanisms and may alter neuronal phosphorylation mechanisms in the cerebral cortex of piglets.
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PMID:The effect of moderate hypocapnic ventilation on nuclear Ca2+-ATPase activity, nuclear Ca2+ flux, and Ca2+/calmodulin kinase IV activity in the cerebral cortex of newborn piglets. 1509 43

An increase in stimulation frequency causes an acceleration of myocardial relaxation (FDAR). Several mechanisms have been postulated to explain this effect, among which is the Ca(2+)-calmodulin-dependent protein kinase (CaMKII)-dependent phosphorylation of the Thr(17) site of phospholamban (PLN). To gain further insights into the mechanisms of FDAR, we studied the FDAR and the phosphorylation of PLN residues in perfused rat hearts, cat papillary muscles and isolated cat myocytes. This allowed us to sweep over a wide range of frequencies, in species with either positive or negative force-frequency relationships, as well as to explore the FDAR under isometric (or isovolumic) and isotonic conditions. Results were compared with those produced by isoprenaline, an intervention known to accelerate relaxation (IDAR) via PLN phosphorylation. While IDAR occurs tightly associated with a significant increase in the phosphorylation of Ser(16) and Thr(17) of PLN, FDAR occurs without significant changes in the phosphorylation of PLN residues in the intact heart and cat papillary muscles. Moreover, in intact hearts, FDAR was not associated with any significant change in the CaMKII-dependent phosphorylation of sarcoplasmic/endoplasmic Ca(2+) ATPase (SERCA2a), and was not affected by the presence of the CaMKII inhibitor, KN-93. In isolated myocytes, FDAR occurred associated with an increase in Thr(17) phosphorylation. However, for a similar relaxant effect produced by isoprenaline, the phosphorylation of PLN (Ser(16) and Thr(17)) was significantly higher in the presence of the beta-agonist. Moreover, the time course of Thr(17) phosphorylation was significantly delayed with respect to the onset of FDAR. In contrast, the time course of Ser(16) phosphorylation, the first residue that becomes phosphorylated with isoprenaline, was temporally associated with IDAR. Furthermore, KN-93 significantly decreased the phosphorylation of Thr(17) that was evoked by increasing the stimulation frequency, but failed to affect FDAR. Taken together, the results provide direct evidence indicating that CaMKII phosphorylation pathways are not involved in FDAR and that FDAR and IDAR do not share a common underlying mechanism. More likely, a CaMKII-independent mechanism could be involved, whereby increasing stimulation frequency would disrupt the SERCA2a-PLN interaction, leading to an increase in SR Ca(2+) uptake and myocardial relaxation.
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PMID:Frequency-dependent acceleration of relaxation in mammalian heart: a property not relying on phospholamban and SERCA2a phosphorylation. 1552 41

Cardioprotection by intermittent high-altitude (IHA) hypoxia against ischemia-reperfusion (I/R) injury is associated with Ca(2+) overload reduction. Phospholamban (PLB) phosphorylation relieves cardiac sarcoplasmic reticulum (SR) Ca(2+)-pump ATPase, a critical regulator in intracellular Ca(2+) cycling, from inhibition. To test the hypothesis that IHA hypoxia increases PLB phosphorylation and that such an effect plays a role in cardioprotection, we compared the time-dependent changes in the PLB phosphorylation at Ser(16) (PKA site) and Thr(17) (CaMKII site) in perfused normoxic rat hearts with those in IHA hypoxic rat hearts submitted to 30-min ischemia (I30) followed by 30-min reperfusion (R30). IHA hypoxia improved postischemic contractile recovery, reduced the maximum extent of ischemic contracture, and attenuated I/R-induced depression in Ca(2+)-pump ATPase activity. Although the PLB protein levels remained constant during I/R in both groups, Ser(16) phosphorylation increased at I30 and 1 min of reperfusion (R1) but decreased at R30 in normoxic hearts. IHA hypoxia upregulated the increase further at I30 and R1. Thr(17) phosphorylation decreased at I30, R1, and R30 in normoxic hearts, but IHA hypoxia attenuated the depression at R1 and R30. Moreover, PKA inhibitor H89 abolished IHA hypoxia-induced increase in Ser(16) phosphorylation, Ca(2+)-pump ATPase activity, and the recovery of cardiac performance after ischemia. CaMKII inhibitor KN-93 also abolished the beneficial effects of IHA hypoxia on Thr(17) phosphorylation, Ca(2+)-pump ATPase activity, and the postischemic contractile recovery. These findings indicate that IHA hypoxia mitigates I/R-induced depression in SR Ca(2+)-pump ATPase activity by upregulating dual-site PLB phosphorylation, which may consequently contribute to IHA hypoxia-induced cardioprotection against I/R injury.
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PMID:Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. 1563 15

Elevations in the intracellular Ca(2+) concentration activate the serine/threonine protein kinase Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II). We tested the hypothesis that increased sarco(endo)plasmic reticulum Ca(2+)-ATPase activity by phospholamban (PLB) phosphorylation contributes to smooth muscle relaxation by elevating the sarcoplasmic reticulum (SR) Ca(2+) load and increasing the frequency of Ca(2+) release events from the SR. We have previously shown that caffeine or sodium nitroprusside (SNP) relaxes murine gastric fundus smooth muscles and increases PLB phosphorylation by CaM kinase II. These findings suggest that an increased SR Ca(2+) load increases the frequency of Ca(2+) transients from the SR and results in PLB phosphorylation by CaM kinase II, contributing to caffeine- or SNP-induced relaxation. The aim of the present study was to investigate the effects of SNP on CaM kinase II and PLB phosphorylation in gastric antrum smooth muscles. SNP or 8-bromo-cGMP decreased the basal tone and amplitudes of spontaneous phasic contractions and activated CaM kinase II. SNP-induced relaxation and CaM kinase II activation were blocked by [1,2,4]oxadizolo-[4,3alpha]quinoxaline-1-one (ODQ) and inhibited by cyclopiazonic acid (CPA) or KN-93. SNP also increased PLBSer(16) and PLBThr(17) phosphorylation. Both PLBSer(16) and Thr(17) phosphorylation were ODQ sensitive. However, only PLBThr(17) phosphorylation was inhibited by CPA or KN-93. These results suggest that CaM kinase II activation and PLB phosphorylation participate in the relaxant effect of SNP on murine gastric antrum smooth muscles through a nitric oxide/guanylyl cyclase/cGMP pathway.
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PMID:CaM kinase II activation and phospholamban phosphorylation by SNP in murine gastric antrum smooth muscles. 1718 33

This study examined Ca(2+) handling mechanisms involved in cardioprotection induced by chronic intermittent hypoxia (CIH) against ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were exposed to 10% inspired O(2) continuously for 6 h daily from 3, 7, and 14 days. In isolated perfused hearts subjected to I/R, CIH-induced cardioprotection was most significant in the 7-day group with less infarct size and lactate dehydrogenase release, compared with the normoxic group. The I/R-induced alterations in diastolic Ca(2+) level, amplitude, time-to-peak, and the decay time of both electrically and caffeine-induced Ca(2+) transients measured by spectrofluorometry in isolated ventricular myocytes of the 7-day CIH group were less than that of the normoxic group, suggesting an involvement of altered Ca(2+) handling of the sarcoplasmic reticulum (SR) and sarcolemma. We further determined the protein expression and activity of (45)Ca(2+) flux of SR-Ca(2+)-ATPase, ryanodine receptor (RyR) and sarcolemmal Na(+)/Ca(2+) exchange (NCX) in ventricular myocytes from the CIH and normoxic groups before and during I/R. There were no changes in expression levels of the Ca(2+)-handling proteins but significant increases in the RyR and NCX activities were remarkable during I/R in the CIH but not the normoxic group. The augmented RyR and NCX activities were abolished, respectively, by PKA inhibitor (0.5 microM KT5720 or 0.5 microM PKI(14-22)) and PKC inhibitor (5 microM chelerythrine chloride or 0.2 microM calphostin C) but not by Ca(2+)/calmodulin-dependent protein kinase II inhibitor KN-93 (1 microM). Thus, CIH confers cardioprotection against I/R injury in rat cardiomyocytes by altered Ca(2+) handling with augmented RyR and NCX activities via protein kinase activation.
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PMID:Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion. 1726 48

The role of caveolins, signature proteins of caveolae, in arterial Ca(2+) regulation is unknown. We investigated modulation of Ca(2+) homeostasis by caveolin-1 and caveolin-3 using smooth muscle cells from rat cerebral resistance arteries. Membrane current and Ca(2+) transients were simultaneously measured with voltage-clamped single cells. Membrane depolarization triggered Ca(2+) current and increased intracellular Ca(2+) concentration ([Ca(2+)](i)). After repolarization, elevated [Ca(2+)](i) returned to the resting level. Ca(2+) removal rate was determined from the declining phase of the Ca(2+) transient. Application of caveolin-1 antibody or caveolin-1 scaffolding domain peptide, corresponding to amino acid residues 82-101 of caveolin-1, significantly slowed Ca(2+) removal rate at a measured [Ca(2+)](i) of 250 nM, with little effect at a measured [Ca(2+)](i) of 600 nM. Application of caveolin-3 antibody or caveolin-3 scaffolding domain peptide, corresponding to amino acid residues 55-74 of caveolin-3, also significantly slowed Ca(2+) removal rate at a measured [Ca(2+)](i) of 250 nM, with little effect at a measured [Ca(2+)](i) of 600 nM. Likewise, application of calmodulin inhibitory peptide, autocamtide-2-related inhibitory peptide, and cyclosporine A, inhibitors for calmodulin, Ca(2+)/calmodulin-dependent protein kinase II, and calcineurin, also significantly inhibited Ca(2+) removal rate at a measured [Ca(2+)](i) of 250 nM but not at 600 nM. Application of cyclopiazonic acid, a sarcoplasmic reticulum Ca(2+) ATPase inhibitor, also significantly inhibited Ca(2+) removal rate at a measured [Ca(2+)](i) of 250 nM but not at 600 nM. Our results suggest that caveolin-1 and caveolin-3 are important in Ca(2+) removal of resistance artery smooth muscle cells.
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PMID:Caveolin-1 and caveolin-3 regulate Ca2+ homeostasis of single smooth muscle cells from rat cerebral resistance arteries. 1733 1

Previously we showed that hypoxia results in increased neuronal nuclear Ca(2+) influx, Ca(2+)/calmodulin-dependent protein kinase IV activity (CaM KIV) and phosphorylation of c-AMP response element binding (CREB) protein. The aim of the present study was to understand the importance of neuronal nuclear Ca(2+) in the role of CaM KIV activation and CREB protein phosphorylation associated with hypoxia. To accomplish this the present study tests the hypothesis that clonidine administration will block increased nuclear Ca(2+) influx by inhibiting high affinity Ca(2+)/ATPase and prevent increased CaM KIV activity and CREB phosphorylation in the neuronal nuclei of the cerebral cortex of hypoxic newborn piglets. To accomplish this piglets were divided in three groups: normoxic, hypoxic, and hypoxic-treated with clonidine. The piglets that were in the Hx+Cl group received clonidine 5 min prior to hypoxia. Cerebral tissue hypoxia was confirmed biochemically by tissue levels of ATP and phosphocreatine (PCr). The data show that clonidine prevents hypoxia-induced increase in CaM KIV activity and CREB protein phosphorylation. We conclude that the mechanism of hypoxia-induced activation of CaM KIV and CREB phosphorylation is nuclear Ca(2+) influx mediated. We speculate that nuclear Ca(2+) influx is a key step that triggers CREB mediated transcription of apoptotic proteins and hypoxic mediated neuronal death.
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PMID:Mechanism of Ca(2+)/calmodulin-dependent protein kinase IV activation and of cyclic AMP response element binding protein phosphorylation during hypoxia in the cerebral cortex of newborn piglets. 1742 48

A conserved molecular cascade involving Nodal signaling that patterns the laterality of the lateral mesoderm in vertebrates has been extensively studied, but processes involved in the initial break of left-right (LR) symmetry are just beginning to be explored. Here we report that Na,K-ATPase alpha2 and Ncx4a function upstream of Nodal signaling to regulate LR patterning in zebrafish. Knocking down Na,K-ATPase alpha2 and Ncx4a activity in dorsal forerunner cells (DFCs), which are precursors of Kupffer's vesicle (KV), is sufficient to disrupt asymmetric gene expression in the lateral plate mesoderm and randomize the placement of internal organs, indicating that the activity of Na,K-ATPase alpha2 and Ncx4a in DFCs/KV is crucial for LR patterning. High-speed videomicroscopy and bead implantation experiments show that KV cilia are immobile and the directional fluid flow in KV is abolished in Na,K-ATPase alpha2 and Ncx4a morphants, suggesting their essential role in KV ciliary function. Furthermore, we found that intracellular Ca(2+) levels are elevated in Na,K-ATPase alpha2 and Ncx4a morphants and that the defects in ciliary motility, KV fluid flow and placement of internal organs induced by their knockdown could be suppressed by inhibiting the activity of Ca(2+)/calmodulin-dependent protein kinase II. Together, our data demonstrate that Na,K-ATPase alpha2 and Ncx4a regulate LR patterning by modulating intracellular calcium levels in KV and by influencing cilia function, revealing a previously unrecognized role for calcium signaling in LR patterning.
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PMID:Na,K-ATPase alpha2 and Ncx4a regulate zebrafish left-right patterning. 1744 98

The time course and magnitude of the Ca(2+) fluxes underlying spontaneous Ca(2+) waves in single permeabilized ventricular cardiomyocytes were derived from confocal Fluo-5F fluorescence signals. Peak flux rates via the sarcoplasmic reticulum (SR) release channel (RyR2) and the SR Ca(2+) ATPase (SERCA) were not constant across a range of cellular [Ca(2+)] values. The Ca(2+) affinity (K(mf)) and maximum turnover rate (V(max)) of SERCA and the peak permeability of the RyR2-mediated Ca(2+) release pathway increased at higher cellular [Ca(2+)] loads. This information was used to create a computational model of the Ca(2+) wave, which predicted the time course and frequency dependence of Ca(2+) waves over a range of cellular Ca(2+) loads. Incubation of cardiomyocytes with the Ca(2+) calmodulin (CaM) kinase inhibitor autocamtide-2-related inhibitory peptide (300 nM, 30 mins) significantly reduced the frequency of the Ca(2+) waves at high Ca(2+) loads. Analysis of the Ca(2+) fluxes suggests that inhibition of CaM kinase prevented the increases in SERCA V(max) and peak RyR2 release flux observed at high cellular [Ca(2+)]. These data support the view that modification of activity of SERCA and RyR2 via a CaM kinase sensitive process occurs at higher cellular Ca(2+) loads to increase the maximum frequency of spontaneous Ca(2+) waves.
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PMID:Measurement and modeling of Ca2+ waves in isolated rabbit ventricular cardiomyocytes. 1754 34

Defecation in the nematode worm Caenorhabditis elegans is a highly rhythmic behavior that is regulated by a Ca(2+) wave generated in the 20 epithelial cells of the intestine, in part through activation of the inositol 1,4,5-trisphosphate receptor. Execution of the defecation motor program (DMP) can be modified by external cues such as nutrient availability or mechanical stimulation. To address the likelihood that environmental regulation of the DMP requires integrating distinct cellular and organismal processes, we have developed a method for studying coordinate Ca(2+) oscillations and defecation behavior in intact, freely behaving animals. We tested this technique by examining how mutations in genes known to alter Ca(2+) handling [including egl-8/phospholipase C (PLC)-beta, kqt-3/KCNQ1, sca-1/sarco(endo)plasmic reticulum Ca(2+) ATPase, and unc-43/Ca(2+)-CaMKII] contribute to shaping the Ca(2+) wave and asked how Ca(2+) wave dynamics in the mutant backgrounds altered execution of the DMP. Notably, we find that Ca(2+) waves in the absence of PLCbeta initiate ectopically, often traveling in reverse, and fail to trigger a complete DMP. These results suggest that the normal supremacy of the posterior intestinal cells is not obligatory for Ca(2+) wave occurrence but instead helps to coordinate the DMP. Furthermore, we present evidence suggesting that an underlying pacemaker appears to oscillate at a faster frequency than the defecation cycle and that arrhythmia may result from uncoupling the pacemaker from the DMP rather than from disrupting the pacemaker itself. We also show that chronic elevations in Ca(2+) have limited influence on the defecation period but instead alter the interval between successive steps of the DMP. Finally, our results demonstrate that it is possible to assess Ca(2+) dynamics and muscular contractions in a completely unrestrained model organism.
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PMID:Intestinal Ca2+ wave dynamics in freely moving C. elegans coordinate execution of a rhythmic motor program. 1794 36


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