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)

In this study, we report that sphingosine is a potent inhibitor of sarcoplasmic reticulum (SR) calcium release. Evidence is presented demonstrating a direct effect of sphingosine on the SR ryanodine receptor. Calcium release from "skinned" rabbit skeletal muscle fibers and isolated junctional SR derived from the terminal cisternae (TC) was measured in response to caffeine, doxorubicin, 5'-adenylyl-beta,gamma-imidodiphosphate or calcium. Sphingosine inhibited caffeine-induced release in a dose-dependent manner with an IC50 of 0.1 microM for the single muscle fibers and 0.5 microM for the isolated TC vesicles. Near complete blockage of TC calcium release rate was observed with 3 microM sphingosine. Neither sphingomyelin nor sphingosylphosphorylcholine had any effect at the 3 microM level, suggesting that the sphingosine effect was specific. Doxorubicin-induced calcium release and spontaneous calcium release were also blocked by sphingosine. Sphingosine was also capable of stimulating calcium transport in the isolated TC vesicles without an effect on Ca-ATPase activity. Ruthenium red was not capable of substantial additional stimulation of calcium transport nor inhibition of calcium release beyond the action of sphingosine. Sphingosine's blockage of calcium release was not reversed by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2- methylpiperazine dihydrochloride, suggesting that the action of sphingosine on calcium release was not dependent on ryanodine receptor phosphorylation. Sphingosine significantly increased (8-fold) the Kd for specific [3H]ryanodine binding to TC membranes and decreased the Bmax with a dose dependence similar to the inhibition of calcium release, but sphingosine did not affect the pCa tension relationship of skinned skeletal muscle fibers. These data are consistent with a direct effect of submicromolar sphingosine on the ryanodine receptor. Substantially higher concentrations of sphingosine (30-50 microM) or sphingosylphosphorylcholine (10-20 microM) were capable of inducing calcium release by themselves. Preliminary data indicate that the transverse tubule and not the SR contain substantial sphingomyelinase activity consistent with a transverse tubule source of sphingosine production. Considering that sphingosine is found in micromolar concentrations in some cells, our data indicate that sphingosine generated by the transverse tubule membranes may be a physiologically relevant mechanism for modulating SR calcium release.
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PMID:The effects of sphingosine on sarcoplasmic reticulum membrane calcium release. 138 59

In this study, we investigated the effect of the anticancer drug doxorubicin on Ca2+ fluxes of isolated highly purified sarcoplasmic reticulum fractions (longitudinal tubules and terminal cisternae (Saito, A., Seiler, S., Chu, A., and Fleischer, S. (1984) J. Cell Biol. 99, 875-885] and of chemically skinned skeletal muscle fibers of the rabbit. In terminal cisternae, doxorubicin inhibits Ca2+ uptake (IC50 at 0.5 microM) and increases 2.6-fold Ca2+-dependent ATPase rate (half-maximal activation at 3 microM) and unidirectional Ca2+ efflux (8-fold stimulation at 25 microM). On the contrary, doxorubicin is without effect on longitudinal tubules. In skinned muscle fibers, doxorubicin induces rapid and transient Ca2+ release, as measured by tension development (half-maximal stimulation at 6 microM), which is completely and reversibly inhibited by ruthenium red, a known inhibitor of Ca2+ release from isolated terminal cisternae. Doxorubicin has no effect on the sarcoplasmic reticulum Ca2+ pump and on the contractile apparatus of skinned muscle fibers. It is concluded that doxorubicin activates Ca2+ release from sarcoplasmic reticulum and opens a Ca2+ efflux pathway (Ca2+ channel) selectively localized in terminal cisternae. Doxorubicin might interact with Ca2+ channels involved in physiological Ca2+ release.
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PMID:Doxorubicin induces calcium release from terminal cisternae of skeletal muscle. A study on isolated sarcoplasmic reticulum and chemically skinned fibers. 258 66

Doxorubicin (adriamycin) is a highly effective cancer chemotherapeutic drug but its clinical utility is limited by its cardiotoxicity. Doxorubicinol, the major metabolite of doxorubicin, is up to 10 times more potent than doxorubicin at inhibiting isometric contraction of the papillary muscle isolated from the right ventricle of rabbit heart. Doxorubicinol also increases resting tension of isolated cardiac muscle indicative of incomplete relaxation between contractions, a characteristic of doxorubicinol but not of doxorubicin. This study assesses the effect(s) of doxorubicinol on a variety of ion pumps which may explain, in part, the action of the metabolite in the intact muscle. We find the doxorubicinol is a potent inhibitor (IC50 less than 5 micrograms/ml) of calcium-stimulated ATPase activity of sarcoplasmic reticulum from canine heart and rabbit skeletal muscle. At comparable levels, doxorubicinol is also a potent inhibitor of (Na + K)-ATPase of cardiac sarcolemma and the Mg-dependent ATPase activity referable to the F0F1 proton pump of mitochondria. For each of these ion pumps, doxorubicinol is at least 80 times more potent an inhibitor than doxorubicin. Doxorubicinol, between 10 and 50 micrograms/ml, increases resting tension up to 4-fold in isolated papillary muscles cyclically contracting at 30 times/min. Resting stress is relatively insensitive to doxorubicin. Thus, doxorubicinol is a potent inhibitor of several key cationic pumps that directly or indirectly regulate cell calcium and inhibits relaxation in the isolated fiber preparation. These observations add a new dimension to understanding the cardiotoxicity of doxorubicin.
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PMID:The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions. 289 Jun 36

Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.
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PMID:Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. 289 22

Doxorubicin (Adriamycin), a potent antineoplastic drug, produces progressive cardiotoxicity which may lead to ultimate cardiac failure. The effects of chronic doxorubicin treatment on cardiac actomyosin ATPase were the principal focus of the present studies. This approach was based on the established correlation between cardiac contractility and contractile protein ATPase activity. Rabbits were injected intravenously with doxorubicin (4 mg/kg) at weekly intervals for 1-7 weeks. Body weight increase was attenuated in the treated animals; heart weight/body weight ratio was unchanged. Actomyosin and water contents of ventricular muscle were not different in doxorubicin-treated as compared with vehicle control animals. Cellular damage was detected histologically after one dose of doxorubicin (equivalent to a single clinical dose), and was extensive after 4-5 weeks of treatment. Animals which received 1-2 injections of doxorubicin demonstrated a 29% average increase in actomyosin ATPase activity as compared to vehicle controls; this difference was highly significant (p less than 0.001). Further treatment with doxorubicin tended to progressively decrease ATPase activity. It is suggested that the increased actomyosin ATPase activity seen with low total doses of doxorubicin may represent a compensatory mechanism for maintenance of contractility; this interpretation is supported by the clinical observation that the morphologic evidence of progressive doxorubicin toxicity is not associated with a parallel decrease in contractility, until severe cumulative toxicity has been induced.
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PMID:Cardiac actomyosin ATPase activity after chronic doxorubicin treatment. 315 43

Histochemical properties, muscle fiber cross-sectional area, muscle fiber length, and the oxidative capacity of masticatory muscles of female rhesus monkeys were assessed following alteration in functional length by an intraoral appliance or by detachment of the muscle. Experimental groups received the appliance only (A); the appliance and subsequent detachment of the masseter (AD); the appliance and detached masseter, but with surgical reattachment of the masseter to the pterygomasseteric sling (ADR); no appliance, but detachment and reattachment of masseter (DR); or an appliance which was removed after 24 weeks to study posttreatment responses (PT). Animals were sacrificed and the muscles were studied at intervals from 4 to 48 weeks after initiation of the experimental period. The results of these studies led to the following conclusions: (1) Stretching the masseter and temporalis muscles within physiological limits did not significantly alter the proportion of fiber types, although oxidative capacity of the fibers was reduced. (2) Fibers with "intermediate" myofibrillar ATPase activity were no more prevalent in experimental than control muscles. (3) The cross-sectional area of Type I fibers of masseter muscles decreased following some experimental procedures, indicating that recruitment of these fibers is the most sensitive to altered jaw function. (4) Minimal alteration of muscle capillarity was induced by any of the experimental procedures. (5) The lengths of masseter muscle fibers in Group PT and of temporalis muscle fibers in groups AD and ADR were greater than in control animals.
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PMID:Adaptation of the masseter and temporalis muscles following alteration in length, with or without surgical detachment. 645 41

In myotonic ADR mice that are homozygous for a defect in the muscular chloride channel gene adr/Clc-1, the hyperexcitability of fast muscles is associated with secondary changes in gene expression and fibre type composition. cDNA clones derived from a set of genes down regulated in fast muscles of the myotonic ADR mouse were isolated by a subtractive cloning procedure. A total of 1200 clones were analysed for high expression in fast muscle of wild type and low expression in mutant mouse. Differential transcript levels were verified by northern blot hybridizations. The identities of the corresponding transcripts were determined by sequencing as myosin heavy chain IIB, alpha-tropomyosin, troponin C, a Ca2+ ATPase and parvalbumin mRNAs. Of these, mRNAs for parvalbumin and myosin heavy chain IIB were drastically downregulated in myotonic muscle (to < 10% of control). A full length cDNA clone for skeletal muscle alpha-tropomyosin was homologous to the mouse fibroblast tropomyosin isoform 2, except for the portion encoding the alpha-tropomyosin specific amino acids 258-284. A cDNA derived from the 1100 nucleotide parvalbumin transcript was cloned and the sequence for the as yet unknown 3' extended trailer, generated by alternative polyadenylation, was determined.
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PMID:Subtractive cDNA cloning as a tool to analyse secondary effects of a muscle disease. Characterization of affected genes in the myotonic ADR mouse. 752 80

Previous studies have demonstrated that a human glutathione conjugate transporter, designated as dinitrophenyl-S-glutathione ATPase (DNP-SG ATPase), catalyzed ATP hydrolysis in the presence of several amphiphilic compounds other than glutathione conjugates (Singhal, S. S., R. Sharma, S. Gupta, H. Ahmad, P. Zimniak, A. Radominska, R. Lester, and Y. C. Awasthi. 1991. FEBS [Fed. Eur. Biochem. Soc.] Lett. 281:255-257). We now demonstrate that DNP-SG ATPase purified from human lung and erythrocyte membranes catalyzed the hydrolysis of ATP in the presence of doxorubicin and its metabolites. Doxorubicin-stimulated ATP hydrolysis by DNP-SG ATPase was saturable with respect to doxorubicin (Km 1.2 and 2.8 microM for the lung and erythrocyte enzymes, respectively). Antibodies against DNP-SG ATPase immunoprecipitated the ATP hydrolyzing activity stimulated by doxorubicin, its metabolites, and glutathione conjugates. Inside our vesicles prepared from erythrocyte membranes took up doxorubicin, daunomycin, and vinblastine in an ATP-dependent manner. The uptake was linear with respect to time and vesicle protein, was dependent on ATP and magnesium, was inhibited by heavy metal salts or by heating the vesicles, and was sensitive to both osmolarity and orientation of the vesicles. The transport had an activation energy of 13 kcal/mol, was saturable with respect to both doxorubicin and ATP (Km values of 1.8 microM and 1.9 mM, respectively), and was competitively inhibited by glutathione conjugates as well as by a number of amphiphiles such as daunomycin or vinblastine. Transport was diminished upon coating the vesicles with antibodies against DNP-SG ATPase. Incorporation of increasing amounts of purified DNP-SG ATPase into the vesicles resulted in a linear increase in transport of doxorubicin. These studies demonstrated for the first time that a membrane protein that catalyzed the transport of anionic amphiphilic molecules such as glutathione conjugates could also mediate the transport of weakly cationic antitumor antibiotic, doxorubicin. Notably, the Km of transport was in the range of doxorubicin concentration achievable in human serum after intravenous dosing of doxorubicin.
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PMID:Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein. 790 6

Cytochalasins are a family of structurally related natural product cytotoxins that selectively depolymerize microfilaments. In this study, the interaction between several cytochalasins and the drug transporter P-glycoprotein was investigated. Dihydrocytochalasin B and cytochalasin E consistently sensitized P-glycoprotein-overexpressing human breast carcinoma cells (MCF-7/ADR) to daunomycin, vinblastine, and actinomycin D without affecting the cytotoxicity of cisplatin. These compounds did not affect the sensitivities of the parental MCF-7 cells to anticancer drugs, indicating that their effects are due to P-glycoprotein inhibition. Effects of dihydrocytochalasin B and cytochalasin E were observed at concentrations as low as 2.5 and 5 microM, respectively. In contrast, cytochalasins A, B, C, D, H, and J did not sensitize MCF-7/ADR cells to any of the drugs. The accumulation of [3H]-vinblastine by MCF-7/ADR cells and by drug-resistant human ovarian carcinoma cells (SKVLB1) was increased to the greatest extent by verapamil, followed by dihydrocytochalasin B > cytochalasin E > cytochalasin B, whereas cytochalasins A, C, D, H, and J did not alter intracellular accumulation of the drug. Similarly to verapamil, dihydrocytochalasin B significantly stimulated the ATPase activity of P-glycoprotein, while other cytochalasins were ineffective. These results demonstrate that very closely related compounds can differentially interact with P-glycoprotein. For example, the only difference between cytochalasin B and dihydrocytochalasin B is the saturation of a carbon-carbon double bond in dihydrocytochalasin B. These structural differences may provide important insight into chemical determinants for drug interaction with P-glycoprotein.
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PMID:Differential interactions of cytochalasins with P-glycoprotein. 883 87

The multidrug resistance protein (MRP) is an ATP-dependent transport protein for organic anions, as well as neutral or positively charged anticancer agents. In this study we report that dinitrophenyl-S-glutathione increases ATPase activity in plasma membrane vesicles prepared from the MRP-overexpressing cell line GLC4/ADR. This ATPase stimulation parallels the uptake of DNP-SG in these vesicles. We also show that the (iso)flavonoids genistein, kaempferol and flavopiridol stimulate the ATPase activity of GLC4/ADR membranes, whereas genistin has no effect. The present data are consistent with the hypothesis that certain (iso)flavonoids affect MRP-mediated transport of anticancer drugs by a direct interaction with MRP.
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PMID:Modulation by (iso)flavonoids of the ATPase activity of the multidrug resistance protein. 928 Mar 10


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