Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of our work, the status of PKC-mediated signal transduction in hepatocytes in chronic endotoxemia can be summarized as follows: 1. Vasopressin (10(-8) M)-induced DAG accumulation is delayed and reduced by 50%, as compared with the response of cells of saline-infused rats. 2. Under basal conditions, total PKC activity (cytosol + pellet) is elevated due to a tendency for higher cytosolic fractional activity. 3. Both TPA- and hormonally-induced (in response to VP and PE) translocation are impaired. 4. Quantitative receptor autoradiography reveals a selective decrease in [3H-PDBu] binding sites in hepatic membranes. We conclude that modulation in endotoxemia of the DAG signal elicited by VP stimulation in hepatocytes could lead to altered transmembrane control of PKC-mediated protein phosphorylation, thereby contributing to the mechanism of impairments in the regulation of cellular metabolism.
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PMID:Modification of protein kinase C (PKC) activity and diacylglycerol (DAG) accumulation in hepatocytes in continuous endotoxemia. 278 Jul 15

Vasopressin and oxytocin both stimulated inositol phosphate accumulation in isolated uterine decidua cells. Pretreatment of cells with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) prevented this agonist-induced phosphoinositide hydrolysis. TPA (0.1 microM) alone had no effect on basal inositol phosphate accumulation, but stimulated phosphoinositide deacylation, as indicated by a 2-fold increase in lysophosphatidylinositol and glycerophosphoinositol. TPA also stimulated a dose-related release of arachidonic acid from decidua-cell phospholipid [phosphatidylcholine (PC) much greater than phosphatidylinositol (PI) greater than phosphatidylethanolamine]. The phorbol ester 4 beta-phorbol 12,13-diacetate (PDA) at 0.1 microM had no effect on arachidonic acid mobilization. The TPA-stimulated increase in arachidonic acid release was apparent by 2 1/2 min (116% of control), maximal after 20 min (283% of control), and remained around this value (306% of control) after 120 min incubation. TPA also stimulated significant increases in 1,2-diacylglycerol and monoacylglycerol production at 20 and 120 min. Although the temporal increases in arachidonic acid and monoacylglycerol accumulation in the presence of TPA continued up to 120 min, that of 1,2-diacylglycerol declined after 20 min. In decidua cells prelabelled with [3H]choline, TPA also stimulated a significant decrease in radiolabelled PC after 20 min, which was accompanied by an increased release of water-soluble metabolites into the medium. Most of the radioactivity in the extracellular pool was associated with choline, whereas the main cellular water-soluble metabolite was phosphorylcholine. TPA stimulated extracellular choline accumulation to 183% and 351% of basal release after 5 and 20 min respectively and cellular phosphorylcholine production to 136% of basal values after 20 min. These results are consistent with a model in which protein kinase C activation by TPA leads to arachidonic acid mobilization from decidua-cell phospholipid by a mechanism involving phospholipase A-mediated PI hydrolysis and phospholipase C-mediated PC hydrolysis, coupled with further hydrolysis of the 1,2-diacylglycerol product.
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PMID:Stimulation of phospholipid hydrolysis and arachidonic acid mobilization in human uterine decidua cells by phorbol ester. 282 48

REF52, a rat embryo cell line, and several transformed derivatives were used to examine the lipid-related events associated with agonist treatment (phorbol diesters, vasopressin, fetal bovine serum). Exposure of cells, prelabeled with [3H]glycerol, to TPA (12-O-tetradecanoylphorbol 13-acetate) resulted in 3-4-fold increase in the amount of intracellular diacyl[3H]glycerols as early as 10 min after treatment. Continued incubation (up to 60 min) revealed that the diacyl[3H]glycerol formed was under dynamic metabolic regulation as shown by the production of triacyl[3H]glycerols and free [3H]glycerol. Serum and vasopressin likewise induced the generation of intracellular diacyl[3H]glycerol, thereby illustrating that physiological agents provoke a similar reaction. In the three SV-40-transformed variants examined, the diacylglycerol generative-response to TPA, serum and vasopressin, was greatly diminished or totally absent. Experiments employing REF52 cells prelabeled with [3H]choline demonstrated that both TPA and vasopressin induce the hydrolysis of cellular choline-containing glycerophospholipids; this was measured by both a decrease in cell-associated phosphatidylcholine radioactivity and an increase in the production of water-soluble [3H]choline-containing metabolites in the culture medium. 92-97% of the tritium released to the medium was identified as [3H]choline. Vasopressin treatment of REF52 cells prelabeled with [3H]arachidonic acid elicited an increase of more than 11-fold in the amount of cellular diacyl[3H]glycerol and a concomitant release of arachidonic acid to the culture medium that was 12-fold higher than controls. These data demonstrate that tumor-promoting phorbol esters (agonists of protein kinase C), serum and vasopressin, increase the levels of cellular diacylglycerol by stimulating the hydrolysis of choline-containing glycerophospholipids. This agonist-directed mechanism is inoperable in transformed cells. Further, collateral with vasopressin-induced phosphatidylcholine hydrolysis, the cellular release of arachidonic acid occurs. The participation of these lipid-related responses in the signaling of agonist-directed events and their relation to cellular homeostasis is currently being explored.
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PMID:Vasopressin, phorbol diesters and serum elicit choline glycerophospholipid hydrolysis and diacylglycerol formation in nontransformed cells: transformed derivatives do not respond. 283 Sep 3

Vasopressin is actively involved in the regulation of blood pressure to the same degree as catecholamines and the renin angiotensin aldosterone system are, especially in stressful situations. Vasopressin induces and increase in blood pressure when mechanisms buffering its potent vasoconstrictor effect are altered. Vasopressin binds to specific membrane receptors classified into two main types. The V1 receptors found in blood vessels, platelets and hepatocytes are linked to two intra-cellular messengers, namely 1,2 diacylglycerol and 1,4,5 inositol triphosphate which stimulate protein kinase C and calcium-calmodulin kinase in the presence of calcium. V2-renal receptors stimulate the production of cyclic AMP which activates protein kinase A. Subsequently, the actin network is altered and particles containing pores agregate at the cell surface to produce water molecules reabsorption. Vasopressin modifies human hemostasis via platelet aggregation, stimulation of the three fractions of factor VIII, of factor XII and of fibrinopeptide A. These properties were used to treat hemostasis abnormalities seen in Von Willebrand's disease and hemophilia. There is a feed-back loop between vasopressin and the atrial natriuretic factor: vasopressin stimulates atrial natriuretic factor release via a V1 action whereas the atrial natriuretic factor reduces vasopressin release and inhibits vasopressin antidiuretic action.
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PMID:[Vasopressin, the antidiuretic hormone]. 295 73

Vasopressin and angiotensin II inhibited in a dose-dependent fashion the stimulation of ureagenesis induced by alpha 1-adrenergic activation in hepatocytes incubated in medium without calcium and containing 25 microM EGTA. Vasopressin was more potent than angiotensin II. The effect of different inhibitors of protein kinase C on the alpha 1-adrenergic blockade induced by the vasopressor peptides was tested. It was observed that N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), 4-aminoethyl-1-[2,3-bis(n-decloxyl)-n-propyl]-4-phenylpiperadin e dihydrochloride (CP-46,665-1); 8-(N,N-diethylamino)octyl-3,4, 5-trimethoxybenzoate (TMB-8), polymyxin B and 1-(5-isoquinolynsulfonyl)-2-methylpiperazine (H-7) block this effect of the vasopressor peptides in a dose-dependent fashion. The active phorbol ester, phorbol 12-myristate 13-acetate (PMA), also inhibited the alpha 1-adrenergic stimulation of ureagenesis in these cells. The inhibitors of protein kinase also blocked the effect of phorbol esters but a preincubation with the inhibitors before the addition of PMA was required. alpha 1-Adrenergic activation of phosphatidylinositol labeling was also abolished by PMA; the inhibitors of protein kinase partially blocked this effect of PMA. In summary, our data indicate that inhibitors of protein kinase C can block the alpha 1-adrenergic refractoriness induced by active phorbol esters, vasopressin and angiotensin II. The data are consistent with an important role of protein kinase C in modulating the alpha 1-adrenergic responsiveness of hepatocytes.
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PMID:Inhibitors of protein kinase C block the alpha 1-adrenergic refractoriness induced by phorbol 12-myristate 13-acetate, vasopressin and angiotensin II. 302 3

Addition of phorbol 12,13-dibutyrate (PBt2) in the presence of forskolin or cholera toxin caused marked (6- to 8-fold) and rapid accumulation of cAMP in Swiss 3T3 cells. The effect of PBt2 is mediated by protein kinase C because the synthetic diacylglycerol 1-oleoyl-2 acetylglycerol substitutes for PBt2 in enhancing cAMP accumulation and because the enhancing effect of either PBt2 or 1-oleoyl-2-acetylglycerol was prevented by down-regulation of protein kinase C. Vasopressin, which activates protein kinase C but does not directly affect adenylate cyclase in 3T3 cells, also enhanced cAMP accumulation in cells treated with cholera toxin or forskolin. This effect was abolished by down-regulation of protein kinase C. Treatment with pertussis toxin blocked the enhancing effect of PBt2 in a concentration- and time-dependent manner. Pertussis toxin neither prevented protein kinase C activation by PBt2 nor other biologic responses elicited by PBt2. The results presented here suggest an unusual function for a pertussis toxin substrate--namely, coupling protein kinase C activation to cAMP production.
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PMID:Protein kinase C activation enhances cAMP accumulation in Swiss 3T3 cells: inhibition by pertussis toxin. 303 76

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

Vasopressin was found to be an effective inhibitor of protein labelling in isolated liver cells. Its effect shows the following distinct characteristics: (1) in contrast with alpha-adrenergic agonists, its effect is observable under a wide range of cellular Ca2+-loading conditions; (2) it is not influenced by the nutritional state of the animal. The lack of vasopressin effect on valine production, and its ability to decrease protein labelling from near-saturation concentrations of [3H]valine, indicate that the observed variations in protein labelling reflect actual changes in the rate of protein synthesis. The action of vasopressin is primarily exerted on the initiation step of protein synthesis and this effect is accompanied by a decreased activity of eukaryotic initiation factor 2. Activators of protein kinase C showed similar but not additive effects on protein synthesis, as did vasopressin. It seems plausible to conclude that protein kinase C activation may play an important regulatory role in hepatic protein synthesis as a transducer of hormonal and perhaps other type of signals.
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PMID:Effect of vasopressin on the regulation of protein synthesis initiation in liver cells. 319 91

Vasopressin stimulates phosphatidylcholine hydrolysis in REF52 cells, and this phosphatidylcholine hydrolysis results in increases in choline containing metabolites in the culture medium (2.3 x control levels) and accumulation of cellular diacylglycerol (6.5 x control levels). Vasopressin is the only component of a 6-component mixture of the serum-free medium for REF52 cells that induces the phosphatidylcholine hydrolysis response. The effect of vasopressin is both time- and concentration-dependent. Maximal levels of both phosphatidyl-choline hydrolysis and accumulation of diacylglycerol are observed between 10 and 20 min after treatment with vasopressin. Effects are maximal at vasopressin concentrations of 100 ng/ml; the ED50 for vasopressin-stimulated phosphatidyl-choline hydrolysis is approximately 0.7 ng/ml. The evolution of diacylglycerol occurs in a time frame that is consistent with the diacylglycerol activating protein kinase C in a "second phase" agonist response.
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PMID:Vasopressin is the only component of serum-free medium that stimulates phosphatidylcholine hydrolysis and accumulation of diacylglycerol in cultured REF52 cells. 336 41

Vasopressin, angiotensin II, epinephrine (alpha 1-adrenergic action) and phorbol 12-myristate 13-acetate (PMA) induce increases in membrane-associated protein kinase C activity concomitant with decreases in the cytosolic activity. The data indicate that the calcium-mobilizing hormones and the active phorbol ester induce translocation from the cytosol to the plasma membrane of this protein kinase. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked the translocation to the membrane of this protein kinase induced by PMA and vasopressin.
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PMID:Phorbol esters and calcium-mobilizing hormones increase membrane-associated protein kinase C activity in rat hepatocytes. 337 82


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