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

To determine the role of protein kinase C in the regulation of active electrolyte transport in rat descending colon, the effects of phorbol dibutyrate (PDB) were studied using the Ussing chamber/voltage-clamp technique. PDB added to the serosal surface increased the short-circuit current in a concentration dependent manner with a EC50 of 3 X 10(-8) M and a maximal effect at 10(-7) M PDB. The effect was not seen with the inactive alpha-phorbol analogue but was reproduced with 1-oleoyl-2-acetylglycerol, a more permeable analogue of diacylglycerol. PDB caused a decrease in mucosal-to-serosal and net fluxes of Na and Cl and an increase in serosal-to-mucosal Cl flux, indicating inhibition of Na and Cl absorption and stimulation of Cl secretion. The PDB-induced increase in Cl secretion was virtually abolished by both indomethacin and ibuprofen, indicating a dependence on arachidonic acid metabolism via the cyclooxygenase pathway. The Cl secretion was inhibited by verapamil and Ca2+-free bathing solution on the serosal surface but not by dantrolene, suggesting the importance of extracellular Ca2+ but not intracellular stored Ca2+ in the PDB-induced secretion. The Cl secretory effect was also inhibited by tetrodotoxin and atropine, suggesting involvement of cholinergic nerves. In contrast, the PDB-induced decrease in Na and Cl absorption was not dependent on metabolites of the cyclooxygenase pathway, not dependent on extracellular Ca2+, and not blocked by tetrodotoxin. It appears likely that protein kinase C is involved in the regulation of rat colonic active Na and Cl absorption and electrogenic Cl secretion but that the pathways involved are different in the two transport systems.
 ...
PMID:Effects of phorbol esters on sodium and chloride transport in rat colon. 309 82

The synthetic antioxidants butylated hydroxytoluene (BHT), nordihydroguaiaretic acid and the one-electron donor 1,1'-dimethylferrocene, inhibit cytosolic Ca++ increase, shape change, aggregation and ATP secretion in aspirinated washed human platelets stimulated by thrombin, vasopressin and platelet-activating factor. The antioxidants also inhibit cytosolic Ca++ increase originating from intracellular stores in the presence of EGTA. The effect of phorbol ester (TPA), which promotes platelet aggregation and secretion without raising the cytosolic Ca++, is also antioxidant-sensitive. Since agonist activation of aspirinated platelets does not involve cyclooxygenase or lipoxygenase metabolites, it is suggested that other yet unknown free radical-dependent pathways are involved in the mechanism of platelet activation, both in the protein kinase C-independent events leading to the cytosolic Ca++ increase, and in those, largely protein kinase C-dependent, leading to aggregation and ATP secretion.
 ...
PMID:Inhibition by antioxidants of agonist evoked cytosolic Ca++ increase, ATP secretion and aggregation of aspirinated human platelets. 309 18

Both 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) and 3,4,2',4'-tetrahydroxychalcone inhibited 12-lipoxygenase of mouse epidermis. The IC50 of AA861 and 3,4,2',4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 microM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cyclooxygenase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10 nmol/mouse) was potently inhibited by these agents in a dose-dependent manner (1-30 mumol/mouse). TPA (5 nmol/mouse)-induced skin tumor formation was also strongly suppressed by these agents (15 mumol/mouse). Both AA861 and 3,4,2',4'-tetrahydroxychalcone failed to inhibit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.
 ...
PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects. 309 75

The present experiments were designed to determine the effects of different activators of protein kinase C on the secretion of LHRH from median eminence nerve terminals incubated in vitro. The release of prostaglandin E2 (PGE2), a metabolite of arachidonic acid intimately involved in the secretion of LHRH, was also evaluated. Synthetic diacylglycerol [1,2-didecanoylglycerol (DiC10)] significantly enhanced PGE2 release in a concentration-dependent manner. Blockade of phospholipase A2 (PLA2) activity nullified this effect. LHRH release, on the other hand, was not increased by DiC10. However, in the presence of a lipoxygenase inhibitor, DiC10 produced a concentration-related increase in LHRH release, which paralleled that in PGE2. Phospholipase C (PLC) increased both PGE2 and LHRH secretion. Again, blockade of the lipoxygenase pathway enhanced the release of LHRH by PLC without affecting the stimulated secretion of PGE2. A phorbol ester, phorbol 12,13-dibutyrate (PDBu), markedly increased LHRH secretion while inducing a modest increase in PGE2 release. Both effects of PDBu were unaffected by lipoxygenase inhibition. DiC10, PDBu, and PLC significantly augmented LHRH secretion from tissues in which metabolism of arachidonic acid had been prevented by inhibition of both cyclooxygenase and lipoxygenase pathways, suggesting that activation of protein kinase C, independent of PLA2 activation, can lead to the secretion of this neural peptide. Some lipoxygenase metabolites had either no effect on [5- and 15-hydroxyeicosatetraenoic (5- and 15-HETE)] or induced a marginal stimulation of (12-HETE) LHRH release. At certain concentrations, 12-HETE enhanced the stimulatory effect of the phorbol ester on LHRH release. Our results suggest that activation of protein kinase C can stimulate LHRH secretion from nerve terminals in vitro and, further, that diacylglycerol may represent an important intracellular messenger participating in the events leading to LHRH secretion. In addition, stimulation with DiC10 and PLC uncovered inhibitory [unknown arachidonic acid metabolite(s) via lipoxygenase] and stimulatory (PGE2 via cyclooxygenase) pathways through with arachidonic acid metabolites may participate in the intracellular transduction of signals modulating neural peptide secretion.
 ...
PMID:Transmembrane signals mediating neural peptide secretion: role of protein kinase C activators and arachidonic acid metabolites in luteinizing hormone-releasing hormone secretion. 309 97

Prolactin (PRL)-stimulated ornithine decarboxylase (ODC) activity and subsequent proliferation are inhibited by the cyclopeptides cyclosporine (CsA) and didemnin B (DB) in Nb 2 node lymphoma cells. Similar concentrations of these agents also inhibit 125I-PRL binding, suggesting that their inhibitory effects on these PRL-dependent physiologic responses are mediated at least in part at the level of PRL receptor interactions. The phorbol ester TPA stimulated ODC activity and [3H]thymidine incorporation to 54% and 31% that of a near-optimal mitogenic concentration of PRL (10 ng/ml), suggesting that mitogenesis in these cells is coupled to some degree to the activation of protein kinase C (PKC). The calcium ionophore A23187 increased ODC activity only slightly and actually decreased [3H]thymidine incorporation to a value below the "cells only" controls. The addition of TPA plus A23187 did not further enhance the effects of TPA to elevate ODC activity and [3H]thymidine incorporation. However, A23187 significantly elevated PRL-stimulated ODC activity with a subsequent inhibition of [3H]thymidine incorporation, suggesting a block of entry into S phase. Both cyclopeptides decreased the elevation of ODC activity in G1 phase of cell cycle in response to PRL, suggestive of a site of action for these agents in early G1, a conclusion compatible with their ability to inhibit PRL binding to these cells. Addition of CsA or DB 2 hr after PRL had no effect on PRL-stimulated ODC activity detectable at 6 hr, but addition of either as late as 6 hr still affected the extent of mitogenesis. This is in line with the requirement for PRL to be present in the culture medium for a minimum of 3 to 6 hr to invoke a maximal effect on mitogenesis. Addition of either cyclopeptide after the cells were in S phase had no effect on the extent of [3H]thymidine incorporation. An inhibitor of the cyclooxygenase pathway (indomethacin) enhanced both PRL-stimulated ODC activity and proliferation, whereas inhibition of the lipoxygenase pathway by NDGA attenuated only proliferation, suggesting that in Nb 2 cells, products of the lipoxygenase pathway may contribute to the mechanism of PRL-stimulated mitogenesis. Because Nb 2 lymphoma cells were derived from estrogenized rats, estrogen was tested as a mitogen. By itself it was not mitogenic, but in conjunction with PRL, estradiol-17 beta elevated the ODC response and inhibited proliferation. Inhibitors of PKC known to have minimal effects on RNA synthesis, quercetin and gossypol, totally inhibited both the elevations of ODC activity and [3H]thymidine incorporation in response to PRL in Nb 2 lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Prolactin-dependent mitogenesis in Nb 2 node lymphoma cells: effects of immunosuppressive cyclopeptides. 309 47

We have investigated the role of phospholipid-sensitive calcium-dependent protein kinase (protein kinase C) in prostaglandin F2 alpha synthesis by monolayer cultures of swine granulosa cells. In this system, specific phorbol ester derivatives known to activate protein kinase C significantly augmented the production of prostaglandin F2 alpha. Phorbol ester in conjunction with the ionophore A23187 synergistically increased prostaglandin F2 alpha production. These stimulatory actions were dose- and time-dependent, and could be abolished by the cyclooxygenase inhibitor, indomethacin, or the protein synthesis inhibitor, cycloheximide. Moreover, the rank order of potency of phorbol esters in enhancing prostaglandin F2 alpha production was concordant with that demonstrated for activation of protein kinase C in the swine ovary. In addition, a nonphorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol, also significantly enhanced prostaglandin F2 alpha biosynthesis. The synthesis of immunoassayable prostaglandin F2 alpha was confirmed by high-pressure liquid chromatographic purification of this radiolabeled metabolite of [3H]arachidonic acid. Thus, the present studies indicate that the protein kinase C effector pathway in the swine granulosa cell is functionally coupled to prostaglandin F2 alpha production.
 ...
PMID:Activation of protein kinase C is coupled to prostaglandin F2 alpha synthesis in the ovary: studies in cultured swine granulosa cells. 310 13

Carrageenan induced aggregation and ATP release of washed rabbit platelets. The aggregation was resistant to indomethacin or creatine phosphate/creatine phosphokinase system but sensitive to mepacrine or p-bromophenacyl bromide. Chlorpromazine, verapamil or tetracaine inhibited carrageenan-induced aggregation, ATP release reaction and membrane-bound calcium redistribution in washed platelets. Agents elevating cyclic nucleotides selectively inhibited the release reaction without affecting the aggregation. The mechanism of carrageenan-mediated platelet responses may be due to both activation of phospholipases A2 and C. Platelet activating factor, protein kinase C and inositol triphosphate or phosphatidic acid could be mediated by carrageenan to accomplish the cyclooxygenase-independent events.
 ...
PMID:Cyclooxygenase--independent pathway of phospholipase activation in carrageenan--induced platelet aggregation. 310 12

Walker 256 carcinosarcoma cells induce the aggregation of rat platelets and concomitant production of eicosanoid metabolites (e.g., 12-hydroxyeicosatetraenoic acid, thromboxane A2). Cyclooxygenase inhibitors, but not lipoxygenase inhibitors, were able to inhibit platelet aggregation induced in vitro by low concentrations of agonists. At high agonist concentrations, neither cyclooxygenase nor lipoxygenase inhibitors affected platelet aggregation; however the combination of both inhibitors resulted in inhibition of aggregation. Also, a low concentration of agonist induced minimal eicosanoid metabolism, whereas a high concentration resulted in increased eicosanoid metabolism. These inhibitors, at the doses tested, did not inhibit protein kinase C activity.
 ...
PMID:The role of platelet cyclooxygenase and lipoxygenase pathways in tumor cell induced platelet aggregation. 310 14

Membrane assembly of the C5b-9 proteins on gel-filtered human platelets has been shown to initiate the nonlytic release of alpha-granule contents and expression of membrane prothrombinase sites, suggesting cellular activation by these ostensibly cytolytic plasma proteins (Wiedmer, T., Esmon, C. T., and Sims, P. J. (1986) J. Biol. Chem. 261, 14587-14592). We now examine the mechanism of the C5b-9-induced release reaction. The release of alpha-granule contents upon C5b-9 assembly is accompanied by expression of alpha-granule membrane glycoprotein 140 on the platelet surface, confirming that the complement-mediated release reaction occurs by secretory fusion of the alpha-granule with the plasma membrane. C5b-9 binding initiates the phosphorylation of both 40- and 20-kDa platelet proteins, indicative of activation of protein kinase C and myosin light chain kinase, respectively. Activation of cellular protein kinases under these conditions was not accompanied by the formation of inositol phosphates and was found to strictly depend upon extracellular Ca2+, suggesting that the platelet's secretory response to the C5b-9 proteins is triggered directly by the influx of Ca2+ across the plasma membrane. measurement of intracellular Ca2+ confirmed that elevation of this ion in the cytosol was strictly dependent upon increased plasma membrane permeability due to C5b-9 assembly and was not accompanied by mobilization of this ion from internal storage pools. The C5b-9-mediated secretory response was blocked by sphingosine, a potent inhibitor of protein kinase C, but was unaffected by the cyclooxygenase inhibitor indomethacin, suggesting that feedback (receptor-linked) by thromboxane is not required for platelet activation after C5b-9 insertion.
 ...
PMID:Complement C5b-9-stimulated platelet secretion is associated with a Ca2+-initiated activation of cellular protein kinases. 311 83

We have examined the role of phospholipid-sensitive calcium-dependent protein kinase (protein kinase C) in prostaglandin E2 synthesis by monolayer cultures of swine granulosa cells. Specific phorbol ester derivatives known to activate protein kinase C significantly augmented the production of prostaglandin E2. These stimulatory actions were dose and time-dependent, and could be abolished by the cyclooxygenase inhibitor, indomethacin, or the protein synthesis inhibitor, cycloheximide. Moreover, the rank order of potency of phorbol esters in enhancing prostaglandin E2 production was concordant with that demonstrated for activation of protein kinase C. Phorbol ester in conjunction with the divalent cation ionophore, A23187, increased prostaglandin E2 production synergistically. In addition, a non-phorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol, also significantly enhanced prostaglandin E2 biosynthesis. The stimulated synthesis of prostaglandin E2 was confirmed by high-pressure liquid chromatographic purification of this radiolabeled metabolite of 3H-arachidonic acid, and by capillary gas chromatography high-resolution mass spectrometry. Thus, the present studies indicate that the protein kinase C effector pathway is functionally coupled to prostaglandin E2 production in the swine granulosa cell.
 ...
PMID:Activation of protein kinase C is coupled to prostaglandin E2 synthesis in swine granulosa cells. 311 12


<< Previous 1 2 3 4 5 6 7 8 9 10