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)

Signal transduction in Dictyostelium for oriented movement and differentiation involves a fine tuning of the cytosolic Ca2+ concentration. We have previously shown that cAMP binding to the cell surface receptor elicits two cellular events: (i) to enhance Ca2+ entry across the plasma membrane; (ii) to increase Ca2+ uptake into Ca(2+)-sequestering organelles. Here we used permeabilised cells to show that cAMP-induced Ca2+ uptake in these cells was sensitive to the Ca2+ transport ATPase blocker 2,5-di-(tert-butyl)-1,4-hydroquinone (BHQ) and the vacuolar H(+)-ATPase inhibitor NBD-Cl. By contrast, bafilomycin A1 and vanadate, inhibitors of Ca2+ uptake into acidosomes in Dictyostelium, did not reduce the cAMP-induced Ca2+ uptake of permeabilised cells. GTP gamma S served as a tool to measure Ins(1,4,5)P3- (InsP3)-sensitive Ca2+ release. Following NBD-Cl or BHQ treatment Ca2+ release was reversibly inhibited. We conclude that the cAMP-controlled Ca2+ influx is directed into a NBD-Cl and BHQ-sensitive compartment, which comprises the InsP3-releasable pool. The acidosomal Ca2+ store seems to provide for additional Ca2+ if required.
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PMID:Evidence for two intracellular calcium pools in Dictyostelium: the cAMP-induced calcium influx is directed into a NBD-Cl- and 2,5-di-(tert-butyl)1,4-hydroquinone-sensitive pool. 822 1

The effect of modifying protein kinase and phosphatase activity on Ca2+ influx induced by inhibition of Ca(2+)-ATPase activity has been investigated in rabbit platelets. Activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) or inhibition of phosphatase type 1/2A (PP1/2A) activity with calyculin A caused a dose-dependent inhibition of cytosolic Ca2+ elevation in thapsigargin (Tg)-treated platelets and decreased Ca2+ influx into platelets at a time when Ca2+ channels had already been opened by pretreatment of cells with Tg. In addition, both activation of PKC and inhibition of PP1/2A activity caused a dose-dependent inhibition of bivalent cation (Mn2+) influx (acting as a surrogate for Ca2+ influx) in Tg-treated platelets. Inhibition of cyclo-oxygenase activity caused a small decrease in [Ca2+]i elevation in Tg-treated platelets, but had no effect on the ability of PMA or calyculin A to inhibit Tg-induced [Ca2+]i elevation Unexpectedly, PMA inhibited Tg-induced [Ca2+]i elevation in the absence of extracellular Ca2+, and in agreement calyculin A decreased [Ca2+]i elevation almost to basal levels. The results from this study were confirmed with another Ca(2+)-ATPase inhibitor, namely 2,5-di(tert-butyl)hydroquinone (tBHQ). These findings therefore suggest that modification of phosphorylation of target protein(s) on serine/threonine amino acid residues plays a role in the regulation of both Ca2+ influx and in the filling state of the intracellular Ca2+ pool in platelets treated with Tg.
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PMID:A role for protein phosphorylation in modulating Ca2+ elevation in rabbit platelets treated with thapsigargin. 854 14

The Ca2+ stores of Dictyostelium discoideum amoebae take part in control of homoeostasis of the cytosolic free Ca2+ concentration ([Ca2+]i) and the cyclic-AMP-induced [Ca2+]i-signalling cascade. In order to characterize regulatory mechanisms of these stores, we incubated cells with the calmodulin antagonist calmidazolium. Measurement of permeabilized and intact cells in suspension with a Ca(2+)-sensitive electrode revealed that calmidazolium induced Ca2+ release from intracellular stores, influx of Ca2+ across the plasma membrane and subsequent efflux. In single fura-2-loaded cells calmidazolium evoked rapid and global transient elevations of [Ca2+]i. Other calmodulin antagonists (trifluoperazine, chlorpromazine, fendiline and W7) also induced transient elevations of [Ca2+]i, which were, however, slower and observed in fewer cells. The calmidazolium-induced influx of extracellular Ca2+ was inhibited by preincubation with 2,5-di-(t-butyl)-1, 4-hydroquinone (BHQ) and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-Cl), both known to interact with pumps of the inositol 1,4,5-trisphosphate (IP3)-sensitive store, and by the V-type H(+)-ATPase inhibitor bafilomycin A1, which affects the acidosomal Ca2+ store. Incubation with pump inhibitors did not itself induce changes in [Ca2+]i. We conclude that the effects of calmidazolium are, at least in part, mediated by its calmodulin-antagonizing properties, that it acts by inducing Ca2+ release from filled storage compartments, and that its target of action is both the IP3-sensitive store and the acidosome; emptying of these stores leads to influx of extracellular Ca2+.
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PMID:Calmidazolium leads to an increase in the cytosolic Ca2+ concentration in Dictyostelium discoideum by induction of Ca2+ release from intracellular stores and influx of extracellular Ca2+. 857 7

We performed comparative studies to determine an acute toxicity of microsomal Ca(2+)ATPase inhibitor, 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) and its related analog, mono(tert-butyl)-1,4-hydroquinone (MTBHQ), which are both used as antioxodants. Wistar rats, 5 weeks old, male and female, were used. By a single dose of oral administration, DTBHQ-induced LD50 values (obtained by Lorke method) in male and female rats were estimated 295.1 and 234.4 mg/kg BW, respectively, whereas each LD50 value for MTBHQ was 711.6 and 400.0 mg/kg BW, respectively. MTBHQ-induced deaths occurred from 8 to 20 minutes after administration, however, DTBHQ-induced deaths occurred more delayed from 1 to 5 days after administration. The observed toxic signs of DTBHQ included diarrhea (jelly like), prone position, lacrimation, salivation and abnormal gait (such as reluctance to walk, limping). Localized purpura and loss of the tail (perhaps as a result of necrosis) were also observed. In comparison, MTBHQ elicited prone position, panting, staggering gait and spastic gait. Without loss of the tail montioned above, dead and sacrified rats showed no remarkable changes in macroscopic examination due to exposure to both compounds.
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PMID:[Comparative studies on a single dose toxicity of microsomal Ca(2+)ATPase inhibitor, 2,5-di(tert-butyl)-1,4-hydroquinone and its related analog, mono(tert-butyl)-1,4-hydroquinone, in rats]. 871 30

1. An apamin-sensitive Ca(2+)-activated K+ channel was characterized in turtle hair cells and utilized to monitor submembranous intracellular Ca2+ and to evaluate the concentration of the mobile endogenous calcium buffer. 2. Isolated hair cells were voltage clamped with whole-cell patch electrodes filled with a Cs(+)-based intracellular solution to block the large-conductance Ca(2+)-activated K+ (BK) channel. Ca2+ currents evoked by depolarization were followed by inward tail currents lasting several hundred milliseconds. Both the Ca2+ current and slow tail current were abolished by nifedipine. 3. The tail current was carried by K+ and Cs+ (relative permeabilities PCa/PK = 0.22), and was fully blocked by 0.1 microM apamin and half blocked by 5 mM external TEA. These properties suggest the tail current flows through a Ca(2+)-activated K+ channel distinct from the BK channels. 4. Intracellular Ca2+ was imaged with a confocal microscope in hair cells filled with the indicator Calcium Green-5N introduced via the patch pipette. Increases in Ca2+ evoked by depolarization were localized to hotspots on the basolateral surface of the cell. The time course of the tail current closely matched the fast component of the fluorescenece monitored at a hotspot. 5. Ca(2+)-ATPase pump inhibitors thapsigargin, 2,4-di-(t-butyl)hydroquinone (BHQ) and vanadate, which are known to influence calcium regulation in turtle hair cells, prolonged the time course of the tail current, supporting the idea that the channel monitors cytoplasmic Ca2+. 6. The mobile endogenous buffer was estimated by combining perforated-patch and whole-cell recordings on a single cell. After recording tail currents with an amphotericin-perforated patch, the patch was ruptured to obtain the whole-cell mode, thus allowing washout of soluble cytoplasmic proteins and exchange with pipette buffers. By varying the concentration of Ca2+ buffer in the pipette, the mobile endogenous buffer was found to be equivalent to about 1 mM BAPTA.
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PMID:Monitoring calcium in turtle hair cells with a calcium-activated potassium channel. 886 61

Two enzymes, protein kinase C and microsomal Ca(2+)-ATPase help regulate levels of Ca2+ in many types of cells. Since proteins that regulate Ca2+ often influence sensitivity to Pb2+, we determined the possible roles played by protein kinase C and microsomal Ca(2+)-ATPase for the Pb(2+)-evoked release of norepinephrine (NOR) in PC cells. NOR release was observed at 10 microM Pb2+ when PC 12 cells were stimulated with inhibitors of microsomal Ca(2+)-ATPase such as thapsigargin, cyclopiazonic acid, or 2,5-di-(t-butyl)-hydroquinone. At 5 microM, Pb2+ evoked the release of NOR in PC 12 cells stimulated with activators of protein kinase C such as phorbol 12-myristate 13-acetate (PMA) or (-)-7-octylindolactam. NOR release was observed at 1 microM Pb2+ in the presence of both PMA and thapsigargin. Ni2+ and Cd2+ blocked NOR release stimulated by Pb2+ in the presence of thapsigargin but not by PMA. NOR released by thapsigargin stimulation was not altered in PC 12 cells depleted of protein kinase C. Two proteins found in vesicles, chromogranin B and secretogranin-II were released with NOR. Our results indicate that in PC 12 cells, PB(2+)-evokes the release of neurotransmitters. Furthermore, thapsigargin and PMA increase the cell's sensitivity to Pb2+ by different pathways.
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PMID:Distinct mechanisms of neurotransmitter release from PC 12 cells exposed to lead. 897 2

The effects of three Ca(2+)-ATPase inhibitors, thapsigargin (TG), cyclopiazonic acid (CPA), and 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), on the Ca2+ response, degranulation, and leukotriene C4 (LTC4) release in RBL-2H3 cells were investigated. All three compounds elevated the intracellular free Ca2+ concentration ([Ca2+]i), and caused degranulation in the presence of 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C activator. The dose-dependency of each compound in the Ca2+ response was in good agreement with that in degranulation. TG and CPA also caused the release of LTC4 in a dose-dependent manner, and this effect was unaffected by TPA or calphostin C, a selective PKC inhibitor. DTBHQ, however, did not induce LTC4 release, and rather inhibited the antigen-induced release of LTC4. These results suggest [1] that both degranulation and LTC4 release caused by these compounds are dependent on their [Ca2+]i increasing effect, [2] that degranulation and LTC4 release are mediated via independent pathways following the Ca2+ response, and [3] that DTBHQ additionally prevents the synthesis of LTC4 possibly by inhibition of 5-lipoxygenase.
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PMID:Effects of three different Ca(2+)-ATPase inhibitors on Ca2+ response and leukotriene release in RBL-2H3 cells. 898 2

We report the synthesis and characterization of O[o-nitromandelyloxycarbonyl]-2,5-di(tert-butyl)hydroquinone (Nmoc-DBHQ), a new "caged" reagent for photoreleasing DBHQ, a membrane-permeant, reversible inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA). The Nmoc group is a new caging group developed for the current application. Photolysis of Nmoc-DBHQ proceeds with t1/2 = 126 +/- 2 micros, and t1/2 for subsequent release of DBHQ is estimated to be approximately 5 ms. Nmoc-DBHQ thus allows rapid and reversible modulation of SERCA activity in living cells. Through its acetoxymethyl ester, Nmoc-DBHQ can be loaded into cells easily by incubation. We demonstrate the use of Nmoc-DBHQ for photomodulating SERCA activity in fibroblasts and vagal sensory neurons. We further demonstrate the utility of pulsed DBHQ photorelease for probing and manipulating dynamic phenomena such as [Ca2+] oscillations in fibroblasts.
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PMID:Nmoc-DBHQ, a new caged molecule for modulating sarcoplasmic/endoplasmic reticulum Ca2+ ATPase activity with light flashes. 901 64

The present study was designed to examine the role of Ca2+ in the regulation of digestive enzyme synthesis, to determine whether changes in intracellular Ca2+ stores or cytosolic Ca2+ caused the observed effects, and to establish the steps in the pathway of protein synthesis where the regulation occurs. Protein synthesis, polysome size, and the ratio of completed to nascent polypeptides were measured as a function of Ca2+ in the intracellular stores and the cytoplasm of pancreatic acinar cells. Rat acini and rabbit pancreatic lobules were incubated in media containing 1 mM CaCl2 with the following additives: cholecystokinin (CCK) octapeptide; the inhibitors of microsomal Ca2+ ATPase, thapsigargin (THP) and 2,5-di(tertbutyl)-hydroquinone (BHQ); the intracellular Ca2+ chelator, 1,2-bis(O-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA); an inhibitor of translational initiation, 7-methylguanosine 5'-triphosphate; and an inhibitor of translation elongation, cyclohexamide. THP and BHQ depleted intracellular pools of Ca2+ and caused a sustained elevation in cytosolic [Ca2+]. Under these conditions, the polysome size diminished, and the ratio of completed proteins increased twofold relative to nascent polypeptides despite an overall decrease in net protein synthesis (55.3 +/- 2.7% of control). These effects paralleled those caused by incubation with 1 nM CCK. Incubation of pancreatic acini with BAPTA plus THP or BHQ depleted the pool [Ca2+] without changing the cytosolic [Ca2+]. In addition, these agents decreased the net protein synthesis (30.1 +/- 3.6% compared to control) and polysome size and increased the ratio of completed to nascent polypeptides to 2:1. These results suggest that depletion of intracellular stores of Ca2+ without changes in cytosolic [Ca2+] decreases protein synthesis at translational initiation.
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PMID:The role of calcium in the regulation of protein synthesis in the exocrine pancreas. 905 85

1. We have investigated interactions between intracellular pH (pHi) and the intracellular free calcium concentration ([Ca2+]i) in collagenase-isolated rat lacrimal acinar cells. The fluorescent dyes fura-2 and 2',7'-bis(carboxyethyl)-5-carboxyfluorescein (BCECF) were used to measure [Ca2+]i and pHi, respectively. 2. Application of the weak base NH4Cl alkalinized the cytosol and caused a dose-dependent increase in [Ca2+]i. Trimethylamine (TMA) also alkalinized the cytosol and increased [Ca2+]i. The increase in [Ca2+]i evoked by NH4Cl or TMA was much smaller than that evoked by the secretory agonist acetylcholine (ACh). 3. Application of NH4Cl also increased [Ca2+]i in cells bathed in Ca(2+)-free medium, indicating that NH4Cl released Ca2+ from an intracellular pool. 4. Ammonium chloride had no effect on [Ca2+]i in cells bathed in Ca(2+)-free medium if agonist-sensitive intracellular Ca2+ pools had been depleted with either ACh or the microsomal Ca(2+)-ATPase inhibitor 2,5-di(tert-butyl)hydroquinone. Treatment of cells with NH4Cl in Ca(2+)-free medium reduced the amount of Ca2+ released by ACh. These results suggest that NH4Cl released Ca2+ from the same intracellular pool released by ACh. 5. Calcium release from the agonist-sensitive pool was also triggered when the cytosol was alkalinized by removing the weak acid acetate. 6. Ammonium chloride caused a modest increase in inositol phosphate production, suggesting that NH4Cl may have released stored Ca2+ via an increase in the intracellular inositol 1,4,5-trisphosphate concentration. 7. The increase in [Ca2+]i evoked by NH4Cl was not sustained even in the presence of extracellular Ca2+. In contrast, when a low dose of ACh was used to evoke intracellular Ca2+ release of similar magnitude, sustained Ca2+ entry was observed. 8. Alkalinizing the cytosol appeared to partially inhibit Ca2+ entry triggered by thapsigargin or by ACh. 9. We suggest that alkalinizing the cytoplasm in unstimulated lacrimal acinar cells can release Ca2+ from the intracellular agonist-sensitive Ca2+ pool. However, releasing stored Ca2+ via alkalinization does not appear to trigger significant Ca2+ entry, perhaps because intracellular alkalinization inhibits either the Ca2+ entry pathway or the mechanism which couples the entry pathway to store depletion.
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PMID:Intracellular alkalinization mobilizes calcium from agonist-sensitive pools in rat lacrimal acinar cells. 913 Jan 57


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