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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phospholipase A2 (PLA2) treatment has been shown previously to stimulate the sodium-dependent high-affinity choline uptake system as assessed by both the specific binding of [3H]hemicholinium-3 ([ 3H]HCh-3) and the uptake of [3H]choline. In the present study, the specificity of PLA2-induced stimulation upon [3H]HCh-3 binding has been examined. PLA2, as well as phospholipase C (PLC), treatment of synaptic membranes produced a dose-dependent increase in the specific binding of [3H]HCh-3 whereas neither phospholipase B nor phospholipase D had any effect. PLC-induced stimulation of [3H]HCh-3 binding resulted from a significant decrease in the Kd without a change in the maximum binding of [3H]HCh-3 binding. PLC treatment of synaptosomes resulted in an inhibition of [3H]choline uptake accompanied by an inhibition of Na+, K+-adenosine triphosphatase activity. In contrast to the increase of [3H]HCh-3 binding, the specific binding of both [3H]desipramine and [3H]mazindol was decreased by PLA2 treatment. After PLA2 treatment, [3H]HCh-3 binding was increased about 2.5-fold over basal levels in different regions of the brain. Electrolytic lesions of the medial septal nucleus and kainic acid-induced lesions of the striatum resulted in a marked reduction of [3H]HCh-3 binding in the hippocampus and the striatum, respectively. Residual [3H]HCh-3 binding in the denervated hippocampus and lesioned striatum was increased by PLA2 treatment but remained lower than that in PLA2-treated controls. Finally, atropine-induced up-regulation of [3H]HCh-3 binding in vivo was not additive with PLA2-induced stimulation. These results support the hypothesis that PLA2 might be involved in the regulation of the sodium-dependent high-affinity choline uptake.
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PMID:Specificity of the activation of [3H]hemicholinium-3 binding by phospholipase A2. 273 47

Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r = 0.02) or amiodarone serum levels (r = 0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A2 and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1-8 mg/assay) by all three drugs in the order: chlorpromazine greater than amiodarone greater than chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.
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PMID:Amiodarone--an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine. 282 97

We have shown previously that aspirin (ASA) ingestion by normal human volunteers inhibits peripheral blood monocyte phospholipase C (PLC) activities ex vivo. In order to explore further the mechanism of action of ASA, normal human monocytes and differentiated human U937 cells were treated with ASA and other salicylates. Cells preincubated with ASA were found to have decreased PLC activities. Phospholipase A2 activities were not affected by salicylates. Sodium salicylate and salicylic acid, nonacetylated relatives of ASA also inhibited PLC activity. This effect was dose and time dependent and addition of cycloheximide or actinomycin D to the preincubation mixture abrogated the inhibitory effect of salicylates on PLC. This PLC inhibitory protein induced by ASA appears distinct from lipocortin, a phospholipase A2 inhibitory protein inducible by corticosteroids.
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PMID:Aspirin inhibits phospholipase C. 294 50

One or more phospholipases of the C and A2 types exist in rodent islets and may play a pivotal role in the cell signaling cascade culminating in exocytotic insulin release. Phospholipase C generates myo-inositol-1,4,5-trisphosphate, which mobilizes a "pool" of calcium in the endoplasmic reticulum and which may also secondarily facilitate calcium (Ca++) influx from the extracellular space to replenish that pool. Diacylglycerol is also generated by phospholipase C action and activates protein kinase C; it may thereby potentiate the cellular response to elevations in cytosolic free Ca++ concentration. Arachidonic acid may be released during the degradation of diacylglycerol and may also contribute to islet activation. Phospholipase C is activated by glucose, cholinergic agonists, and probably by Ca++ fluxes. Phospholipase A2 action generates arachidonic acid and lysophospholipids. Certain lysophospholipids mobilize cellular Ca++, at least in part from superficial, plasmalemmal stores. Native (unoxygenated) arachidonic acid also has the capability of mobilizing cellular Ca++ from membrane-bound stores; it may, in addition, activate protein kinase C, as suggested by recent indirect studies. The further metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase appears to provide positive and negative modulation, respectively, of stimulated insulin secretion. Many pieces of the puzzle remain, however, to be supplied. For example, it has not yet been unequivocally demonstrated that phospholipase A2 is activated by physiologic stimuli in intact islets. Furthermore, the absence of truly specific pharmacologic stimulators or inhibitors of these processes currently precludes precise delineation of the respective physiologic roles of each potential mediator in stimulus-secretion coupling. When such roles are elucidated, it can be asked whether the defects in insulin secretion in diabetes mellitus may be due in part to abnormalities in the turnover of beta-cell membrane phospholipids and the generation of intracellular lipid-derived signals.
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PMID:Membrane phospholipid turnover as an intermediary step in insulin secretion. Putative roles of phospholipases in cell signaling. 305 98

The possible role of the phospholipase enzymes in the prolactin stimulation of mitogenesis in Nb2 node lymphoma cells was investigated. Two phospholipase inhibitors including quinacrine and alpha-para-dibromoacetophenone (BPB) were employed. Quinacrine at concentrations of 1-5 microM attenuated the magnitude of the PRL stimulation of cell division; at concentrations of 10 microM and above quinacrine abolished the PRL response. BPB at concentrations of 1-10 microM also inhibited the mitogenic effect of PRL in a concentration response fashion. The polyunsaturated fatty acid arachidonic acid partially reversed the inhibitory effects of these drugs. In further studies, exogenously added phospholipase C at concentrations of 5-50 ng/ml was found to potentiate the mitogenic effect of prolactin when prolactin was employed at a concentration that evoked a half-maximal response. By itself, however, phospholipase C had no effect on the rate of cell division. Phospholipase A2 either by itself or in the presence of prolactin was without effect.
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PMID:Possible involvement of the phospholipases in the mitogenic actions of prolactin (PRL) on Nb2 node lymphoma cells. 310 86

The mechanism of tumour necrosis factor-mediated cytotoxicity was investigated by using various inhibitors of arachidonic acid metabolism. Phospholipase A2 inhibitors with different modes of action interfered with the cytotoxic action of TNF, whereas phospholipase C inhibitors did not. Neither cyclooxygenase nor lipoxygenase-blockers had a significant effect on TNF action. Experiments with scavengers of toxic oxygen radicals gave ambiguous results. The data obtained suggest the involvement of phospholipase A2 and arachidonic acid in the cytotoxic mechanism of TNF, but the exact role of these molecules is, however, still to be determined.
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PMID:Reduced tumour necrosis factor-induced cytotoxicity by inhibitors of the arachidonic acid metabolism. 312 40

Calcium has been implicated as an important factor in prostaglandin production. Phospholipase A2, the enzyme believed to be rate limiting for prostaglandin synthesis, is stimulated by Ca2+; however, the levels of Ca2+ necessary to stimulate phospholipase A2 in cell-free systems are higher than levels achieved in intact cells in response to agonists that stimulate prostaglandin synthesis. We examined the calcium dependency of prostaglandin E2 (PGE2) synthesis in the glomerular mesangial cell. Vasopressin enhanced PGE2 synthesis by mechanisms independent of extracellular Ca2+ concentration. The Ca2+ concentration dependency of PGE2 production was established by rendering cells permeable with digitonin and clamping Ca2+ concentration at various levels. When cytosolic free Ca2+ concentration ([Ca2+]f) was set at levels equal to those measured after stimulation with vasopressin in the intact cell, the PGE2 production by the Ca2+-clamped permeabilized cells was approximately one-half of that obtained in nonpermeabilized cells stimulated with vasopressin. Since stimulation of mesangial cells with vasopressin increases protein kinase C activation as well as [Ca2+]f the effects on PGE2 production of protein kinase C activation with phorbol myristate acetate (PMA) were examined. When permeabilized cells were exposed to Ca2+ concentrations in the range of [Ca2+]f measured in cells treated with vasopressin the addition of PMA approximately doubled PGE2 production. No increase in PGE2 production was observed with PMA when Ca2+ concentration was fixed at basal levels of less than 100 nM. Ca2+-dependent acylhydrolase activity and PGE2 production were inhibited by calmodulin inhibitors, W-7 and compound 48/80. Thus, vasopressin-induced PGE2 production could be explained by a synergistic effect of protein kinase C activation together with an increase in [Ca2+]f. A synergistic action of Ca2+ and PMA on acylhydrolase activity could also be observed in nonpermeabilized cells where A23187 was used to increase [Ca2+]f. The effect of PMA was mimicked by another stimulant of protein kinase C, 1-oleoyl 2-acetylglycerol, albeit with lower potency. Neither PMA nor 1-oleoyl 2-acetylglycerol alone had any effect on acylhydrolase activity. Vasopressin, in the presence of GTP gamma S, stimulated phospholipase C in permeabilized cells when [Ca2+]f was fixed at less than 100 nM, without an associated increase in acylhydrolase activity. This evidence, together with inhibition of acylhydrolase activity with phospholipase A2 inhibitors, dibucaine and mepacrine, indicates that the primary acylhydrolase activity was due to phospholipase A2. The enhanced phospholipase A2 activity observed with protein kinase C activation when [Ca2+]f is increased may be related to phosphorylation of phospholipase A2 itself or phospholipase A2 modulatory proteins. These experiments demonstrate that both Ca2+ and protein kinase C play important roles in the regulation of phospholipase A2 and PGE2 synthesis.
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PMID:Calcium dependency of prostaglandin E2 production in rat glomerular mesangial cells. Evidence that protein kinase C modulates the Ca2+-dependent activation of phospholipase A2. 316 26

Arachidonic acid (AA), the precursor of prostaglandins and leukotrienes, can be directly liberated from membrane phospholipids by phospholipase A2 or indirectly by phospholipase C. One or both of these enzymes may be responsible for the increased content of AA found in psoriatic lesional epidermis. Keratome biopsies were obtained from normal and psoriatic individuals. After homogenization and sonication, a 10,000 g supernatant was used as the enzyme source. The activities of both phospholipase A2 and C were assayed in each sample using phosphatidylcholine and phosphatidylinositol, respectively, as substrates. Phospholipase A2 activity was found to be significantly higher than normal in both uninvolved and lesional psoriatic epidermis. In contrast, phospholipase C activity was significantly higher than normal in only the psoriatic plaque on the basis of wet weight (p less than 0.001), protein (p = 0.01), and DNA (p = 0.004) content. Phospholipase C activity in pmol diacylglycerol formed/min/microgram DNA was: normal 4.96 +/- 0.80, n = 13; uninvolved 7.29 +/- 1.06, n = 18; plaque 14.44 +/- 2.50, n = 18. Analysis (pH profile, calcium requirement, substrate specificity, and saturation kinetics) of pooled epidermal extracts showed no inherent differences in phospholipase C from normal and psoriatic epidermis, suggesting either a higher concentration or the presence of an activated form of the enzyme in psoriatic plaque. Since phospholipase C activity, in contrast to phospholipase A2 activity, is elevated only in lesional epidermis, it is possible that this enzyme contributes to AA accumulation observed in this tissue.
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PMID:Partial characterization of phospholipase C activity in normal, psoriatic uninvolved, and lesional epidermis. 355 72

The results of recent studies support the concept that Ureaplasma urealyticum may be a major cause of perinatal infection in both term and preterm infants. It has been postulated that phospholipase degradation of placental phospholipids by microorganisms triggers the onset of premature labor. Since the presence of ureaplasmas in placentas is associated with pregnancy loss, prematurity, and neonatal morbidity, we assayed U. urealyticum for the presence of phospholipase A1, A2, and C activities. Phospholipase A1 activity was low in lysates of exponential-phase cells of U. urealyticum. Phospholipase A2 activity was present and was 100-fold higher than the activity of phospholipase A1 in serotypes 3,4, and 8. The total activity and specific activity of phospholipase A2 in serotype 8 were nearly threefold higher than the activities in serotypes 3 and 4. Cell lysates of all three serotypes showed the presence of phospholipase C activity during the exponential phase of growth, and no significant difference in activity was observed among the three serotypes. In stationary-phase cells the phospholipase C activity was 10-fold lower than the activity in exponential-phase cells. Our results demonstrate that phospholipase activities are present in U. urealyticum cells and that the specific activities of phospholipase A2 differed among the three serotypes tested, while the activities of phospholipases A1 and C were similar.
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PMID:Endogenous activity of phospholipases A and C in Ureaplasma urealyticum. 370 Jun 18

Phospholipase A2 induced crenation of human erythrocytes and decreased glucose transport activity (influx rate) by 40% when 51% of phosphatidylcholine (PC) in the membrane was hydrolyzed. On the other hand, phospholipase C induced invagination of the cells and negligibly affected the glucose transport in the case of 21% hydrolysis of the PC. By altering the pH of the medium for suspending cells treated with phospholipase A2 from 7.4 to 6.0, cell shape was changed from clear crenation to slight invagination, but glucose transport activity was not affected. Cells that were treated with phospholipase A2 and then washed with albumin to remove free fatty acids produced in the cell membrane showed an almost normal cell shape and slightly higher glucose transport activity than did untreated cells. The ratios of beta-D-glucose transport rate to alpha-D-glucose transport rate in untreated cells, cells treated with phospholipase A2 and cells treated with phospholipase C were 1.13, 1.04, and 1.20, respectively. These results demonstrate that the drastic morphological change (invagination or crenation) induced by the treatment with phospholipases bears no clear relationship to the activity of glucose transport and suggest that the increase in the volume of the outer half of the lipid bilayer might reduce the rate of glucose transport across the human erythrocyte membrane and change the anomeric preference of glucose transport.
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PMID:Glucose transport into human erythrocytes treated with phospholipase A2 or C. 373 Apr 28


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