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)

Sodium/calcium (Na/Ca) exchange is thought to play a role in Ca2+ extrusion from the pancreatic B cell. The aim of the present study was to provide direct evidence for such a role. The effect of extracellular Na+ (Na0+) removal on cytosolic free Ca2+ ([Ca2+]i) in single pancreatic B cells was examined using fura 2 and dual wavelength microfluorimetry. Isosmotical replacement of Na0+ by sucrose increased [Ca2+]i in the presence of extracellular Ca2+ but failed to affect [Ca2+]i in the absence of the divalent cation. Thapsigargin (1 microM), an inhibitor of the endoplasmic reticulum Ca(2+)-ATPase, induced a transient increase in [Ca2+]i in the presence of Na0+. This increase was enhanced and more sustained in the absence of Na0+. In the absence of Na0+ and the presence of thapsigargin, reintroduction of Na0+ induced a rapid decrease in [Ca2+]i. A similar picture was observed when caffeine (10 mM) was used to release Ca2+ from the endoplasmic reticulum. The decrease in [Ca2+]i induced by Na0+ reintroduction was accompanied by an important increase in 45Ca outflow from perifused islets. In conclusion, this study provides direct evidence that Na/Ca exchange may regulate B cell [Ca2+]i within physiological range.
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PMID:A role for Na/Ca exchange in the pancreatic B cell. Studies with thapsigargin and caffeine. 842 25

Thapsigargin, previously reported to release Ca2+ from non-mitochondrial stores of different cell types, as well as nigericin, were found, when used at high concentrations, to release Ca2+ and collapse the membrane potential of Trypanosoma brucei bloodstream and procyclic trypomastigotes mitochondria in situ. At similarly high concentrations (> 10 microM), thapsigargin was also found to release Ca2+ and collapse the membrane potential of isolated rat liver mitochondria. These results indicate that care should be taken when attributing the effects of thapsigargin in intact cells to the specific inhibition of the sarcoplasmic and endoplasmic reticulum Ca(2+)-ATPase family of calcium pumps. In addition, we have found no evidence for an increase in intracellular Ca2+ by release of the ion from intracellular stores by nigericin, measuring changes in cytosolic Ca2+ by dual wavelength spectrofluorometry in fura-2-loaded T. brucei bloodstream trypomastigotes or measuring Ca2+ transport in digitonin-permeabilized cells.
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PMID:Thapsigargin causes Ca2+ release and collapse of the membrane potential of Trypanosoma brucei mitochondria in situ and of isolated rat liver mitochondria. 847 1

Teleocidin, a phorbol ester-type tumor promoter, enhanced actin redistribution, vacuole formation and c-fos expression of PLC/PRF/5 hepatoma cells. This tumor promoter also inhibited calcium mobilization induced by epidermal growth factor (EGF). Thapsigargin, a specific inhibitor of endoplasmic reticulum Ca(2+)-ATPase, elevated cytosolic calcium, enhanced c-fos expression and antagonized the vacuole formation induced by teleocidin without interfering with actin redistribution and Lucifer yellow uptake. On the other hand, a calcium ionophore ionomycin elevated both cytosolic Ca2+ and c-fos mRNA but could not antagonize the vacuole formation induced by teleocidin. From these results it was speculated that the Ca2+ leak from the endoplasmic reticulum rather than the elevation of cytosolic Ca2+ appeared to be responsible for the specific inhibition of vacuole formation by thapsigargin.
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PMID:Thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPase, enhances c-fos expression but antagonizes vacuole formation of human hepatoma cells induced by teleocidin. 848 67

The effect of 15 min of global, normothermic ischemia on 3H-ryanodine binding and the oxalate-supported Ca2+ uptake of cardiac sarcoplasmic reticulum (SR) was investigated in parallel using ventricular homogenates of isolated perfused rat hearts. Ischemia increased the Ca2+ efflux under the uptake assay conditions, as demonstrated by the greater stimulation of Ca2+ uptake by high concentrations of ryanodine (+RY) to close the SR Ca2+ channel. This effect was partially reversed by reperfusion. Ischemia depressed Ca2+ uptake rate -RY at free [Ca2+] of 0.4 microM and above, while the depression + RY was significant only above 10 microM Ca2+. We tested the hypothesis that inhibition of the Ca-ATPase alone, by adding thapsigargin or cyclopiazonic acid, could reproduce the effects of ischemia on the homogenate Ca2+ uptake rate. Thapsigargin or cyclopiazonic acid proportionally depressed Ca2+ uptake rate +RY and -RY and produced distinctly different effects of ischemia. Ischemia did not change the Bmax or Kd for equilibrium 3H-ryanodine binding, or the Hill coefficient or KCa for the [Ca2+]-dependence of equilibrium 3H-ryanodine binding. The rate of ryanodine binding, measured under the uptake conditions, was increased by ischemia and further increased by reperfusion. The effect of ischemia on the rate and extent of equilibrium binding to the high-affinity ryanodine binding site were unrelated to the highly reproducible effects on SR Ca2+ uptake rates measured in the homogenate.
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PMID:Effect of ischemia and ischemia--reperfusion on ryanodine binding and Ca2+ uptake of cardiac sarcoplasmic reticulum. 852 56

The mechanisms for Ca++ release from caffeine-sensitive stores were investigated in freshly dispersed porcine myometrial cells utilizing the fura-2 method. Because the caffeine-sensitive Ca++ store has not been detected in myometrium of mammals, we first determined the existence of this type of store in porcine myometrial cells. The evidence includes: 1) caffeine (1-33 mM)-induced concentration-dependent increase in the intracellular Ca++ concentration ([Ca++]i) in both the presence and absence of extracellular Ca++ and 2) although ryanodine alone (< or = 10 microM) failed to change [Ca++]i, it inhibited the response to caffeine in a use-, concentration- and time-dependent manner. In the cell suspension study, the amount of Ca++ released by 10 mM caffeine was found to be inversely proportional to the amount released by preadministration of caffeine (1-33 mM). In the single cell study, about 30% of cells responded to only a certain concentration of caffeine and the others responded to caffeine gradually. Thapsigargin, an inhibitor of Ca(++)-adenosine triphosphatase in sarcoplasmic reticulum, failed to increase [Ca++]i. Pretreatment with thapsigargin inhibited the response to caffeine in a time- and concentration-dependent manner. These results suggest that in porcine myometrial cells: 1) the Ca++ released from the caffeine- and ryanodine-sensitive store is in an all-or-none manner through compartments of stores or the entire store of a cell and 2) the release process is regulated by luminal Ca++ content of the stores.
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PMID:The caffeine- and ryanodine-sensitive Ca++ store in porcine myometrial cells: its heterogeneity of all-or-none Ca++ release. 853 Oct 66

1. Primary-cultured cerebellar Purkinje cells (PCs) from mouse embryos were whole cell voltage clamped, and L-glutamate (Glu) was applied iontophoretically to the dendrite. Long-term depression (LTD) of Glu-evoked currents was induced through the conjunction of repeated depolarizations and Glu applications. 2. Thapsigargin, a specific inhibitor of Ca(2+)-ATPase on the endoplasmic reticulum, and ryanodine and ruthenium red, inhibitors of the ryanodine receptor, blocked the induction of LTD. 3. Thapsigargin and ryanodine alone did not affect influx of Ca2+ through voltage-gated Ca2+ channels and inward currents evoked by Glu applications. 4. Our results suggest that Ca2+ release from internal stores, particularly from ryanodine-sensitive stores, is necessary for the induction of LTD in cultured PCs.
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PMID:Ca2+ release from Ca2+ stores, particularly from ryanodine-sensitive Ca2+ stores, is required for the induction of LTD in cultured cerebellar Purkinje cells. 859 7

Thermal uncoupling of the Ca2+ pump of skeletal muscle sarcoplasmic reticulum is specifically blocked by binding of Ca2+ to the high affinity sites, having identical characteristics to the Ca2+ transport sites (Berman, M.C., McIntosh, D.B. and Kench, J.E. (1977) J. Biol. Chem. 252, 994-1001). The present study has investigated the nature of the decreased net Ca2+ transport in the uncoupling process. Ca2+ uptake in the presence and absence of oxalate, Ca2+ retention following passive Ca2+ loading and Ca2+-dependent ATPase activity were inactivated at pH 7.0 and 37 degrees C, with rate constants of 0.12, 0.047, 0.053 and 0.001 min-1, respectively. Activation energies were in the range 72-76 kcal/mol, indicating a common irreversible protein conformational transition. A thermodynamic analysis of parallel or consecutive inactivation pathways revealed that loss of Ca2+ transfer and ATPase activity occurred on the same pump unit, making the existence of a predominant uncoupled intermediate unlikely. Decreased passive Ca2+ loading, an index of the number of intact vesicles, correlated with decreased active uptake in the absence of oxalate, indicating increased vesicle permeability. Thapsigargin, at a 1:1 stoichiometry, stabilised the Ca-ATPase against thermal inactivation, while previously inactivated Ca-ATPases appeared not to bind TG. Protection by TG suggests that the origin of inactivation is in the transmembrane and stalk regions of the ATPase. We propose that protein unfolding results in inefficient gating of a small percentage of ATPases with subsequent uncoupling of the entire vesicle.
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PMID:Mechanism of thermal uncoupling of Ca2+-ATPase of sarcoplasmic reticulum as revealed by thapsigargin stabilization. 860 Sep 72

The biochemical transductional events involved in NO synthesis are not fully understood. These studies, therefore, were undertaken to elucidate the role of intracellular calcium and protein kinase C (PKC) in the induction of nitric oxide (NO) synthesis in murine peritoneal macrophages. Thapsigargin (TG), Ca(2+)-ATPase inhibitor of endoplasmic reticulum, had modest activity on NO synthesis by itself, whereas phorbol ester, PKC activator, alone had no effect. When TG was used in combination with phorbol ester, there was a marked cooperative induction of NO synthesis in a dose-dependent manner. The optimal effect of phorbol ester was shown in the first 6 h after TG treatment. In addition, the ability of TG with phorbol ester on NO synthesis could be mimicked by another chemically unrelated inhibitor of Ca(2+)-ATPase, 2,5-di-(t-butyl)-1, 4-benzohydroquinone, and Ca2+ ionophore, A23187. This increase of NO synthesis was reflected as increased amount of NO synthase (NOS) mRNA, as determined by Northern blotting. Intracellular Ca2+ transient by TG was not affected in the presence or absence of extracellular Ca2+, indicating that TG must be effective on cytosolic Ca2+ pool. In addition, chelation of intracellular Ca2+ by acetoxymethyl ester of 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM), an intracellular Ca2+ chelating agent, blocked TG- or TG + PMA-induced NO production. PKC inhibitors such as staurosporine or polymyxin B reduced only the synergistic cooperative effect of TG with phorbol ester without affecting TG-induced NO production. In addition, when the cells were pretreated with phorbol ester before TG treatment, there was no synergy between TG and phorbol ester, indicating that PKC is not directly involved in the expression of NOS but involved in "triggering" signal. Secretion of NO corresponded with tumor cell killing, but TG plus phorbol ester-activated macrophages failed to kill tumor cell targets in the presence of Ng-monomethyl-L-arginine. Collectively, these data illustrate that mobilization of intracellular Ca2+ provides a "priming" signal for induction of NOS gene expression by itself and it also requires PKC as a "triggering" signal for macrophage tumoricidal activity.
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PMID:Synergistic cooperation between thapsigargin and phorbol ester for induction of nitric oxide synthesis in murine peritoneal macrophages. 872 23

We have investigated the effect of the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin and the calcium ionophore A23187 on the differentiation of 3T3-L1 preadipocytes. Treatment of 3T3-L1 preadipocytes with either agent resulted in a dose-dependent inhibition of adipocyte differentiation. The cells accumulated neither fat droplets nor the adipocyte-specific mRNAs encoding stearoyl-CoA desaturase 1 (SCD1) and adipocyte-P2 (aP2). These late markers of differentiation were specifically affected, because thapsigargin and A23187 did not inhibit the expression of beta-tubulin mRNA. No inhibition of differentiation or the expression of the mRNAs occurred when the drugs were added either prior to or 2 days after the initiation of differentiation. Thapsigargin and A23187 were also shown to dramatically block cell proliferation and DNA replication, which occur early in differentiation. Furthermore, during the first 48 h, thapsigargin and A23187 mediated an elevated and prolonged expression of the immediate-early gene corresponding to c-myc, and altered intracellular levels of calcium. Our results suggests that changes in intracellular calcium levels elicited by thapsigargin and A23187 prevent differentiation of 3T3-L1 preadipocytes into adipocytes by blocking the postconfluent mitotic phase of the differentiation process and also by mediating c-myc gene expression.
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PMID:Role of Ca2+ in the early stages of murine adipocyte differentiation as evidenced by calcium mobilizing agents. 876 94

The regulation and role of the intracellular Ca2+ pools were studied in rat peritoneal mast cells. Cytosolic free calcium concentration ([Ca2+]i) was monitored in fura-2 loaded mast cells. In the presence of Ca2+ and K+, compound 48/80 induced a biphasic increase in [Ca2+]i composed of a fast transient phase and an apparent sustained phase. The sustained phase was partially inhibited by the addition of Mn2+. DTPA, a cell-impermeant chelator of Mn2+, reversed this inhibition, suggesting that a quenching of fura-2 fluorescence occurs in the extracellular medium. In the absence of extracellular Ca2+, the transient phase, but not the sustained one, could be preserved, provided that mast cells were depolarized. The transient phase was completely abolished by thapsigargin, a microsomal Ca(2+)-ATPase inhibitor. Maximum histamine release induced by either compound 48/80 or antigen was obtained in the absence of added Ca2+ only when mast cells were depolarized. These histamine releases were inhibited by low doses (< 30 nM) of thapsigargin. Thapsigargin at higher doses induced histamine release which was unaffected by changing the plasma membrane potential, but was completely dependent on extracellular Ca2+, showing that a Ca2+ influx is required for thapsigargin-induced exocytosis. Together, these results suggest that the mobilization of Ca2+ from thapsigargin sensitive-intracellular pools induced by compound 48/80 or antigen is sufficient to trigger histamine release. The modulation of these pools by the plasma membrane potential suggest their localization is close to the plasma membrane.
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PMID:Mast cell activation involves plasma membrane potential- and thapsigargin-sensitive intracellular calcium pools. 880 73


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