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)

Essentially pure preparations of normal density eosinophils obtained from patients with hypereosinophilic syndrome (HES) were stimulated with complement factor 5a (C5a), platelet-activating factor (PAF), FMLP and neutrophil-activating peptide (NAP-1/IL-8). Three responses were studied, the transient rise in cytosolic free calcium concentration ([Ca2+]i) (derived from indo-1 fluorescence), shape changes (measured by laser turbidimetry), and exocytosis of eosinophil peroxidase (EPO) (assessed by H2O2/luminol-dependent chemiluminescence). Responses were obtained with all four agonists, but C5a and PAF were by far more potent than FMLP and NAP-1/IL-8, which induced only minor effects. Pretreatment of the cells with pertussis toxin attenuated [Ca2+]i changes, EPO release and, to a lesser extent, shape changes, indicating that GTP-binding proteins of Gi-type are involved in receptor-dependent signal transduction processes leading to these responses. A clear dissociation was observed in the control of the shape change response and EPO exocytosis. The shape change was not affected by Ca2+ depletion or treatment with the protein kinase inhibitor staurosporine, but exocytosis was prevented by Ca2+ depletion and markedly enhanced by staurosporine. The activation of the contractile system, leading to shape changes and motility, thus appears to be independent of the classical signal transduction pathway involving phospholipase C, a [Ca2+]i rise and protein kinase C activation. Exocytosis is, as expected, Ca2+ dependent and appears to be under a negative control involving protein phosphorylations.
 ...
PMID:Shape changes, exocytosis, and cytosolic free calcium changes in stimulated human eosinophils. 204 Jun 92

H2O2, in addition to producing highly reactive molecules through hydroxyl radicals or peroxidase action, can exert a number of direct effects on cells, organelles and enzymes. The stimulations include glucose transport, glucose incorporation into glycogen, HMP shunt pathway, lipid synthesis, release of calcium from mitochondria and of arachidonate from phospholipids, poly ADP ribosylation, and insulin receptor tyrosine kinase and pyruvate dehydrogenase activities. The inactivations include glycolysis, lipolysis, reacylation of lysophospholipids, ATP synthesis, superoxide dismutase and protein kinase C. Damages to DNA and proteoglycan and general cytotoxicity possibly through oxygen radicals were also observed. A whole new range of effects will be opened by the finding that H2O2 can act as a signal transducer in oxidative stress by oxidizing a dithiol protein to disulphide form which then activates transcription of the stress inducible genes. Many of these direct effects seem to be obtained by dithiol-disulphide modification of proteins and their active sites, as part of adaptive responses in oxidative stress.
 ...
PMID:H2O2 has a role in cellular regulation. 207 30

Icosanoid formation in platelets depends on the concentration of free arachidonate that is mainly liberated from membrane phospholipids by phospholipase A2. The concentration of free arachidonate is also controlled by the activities of the reacylating enzymes arachidonoyl-CoA synthetase and lysophospholipid acyltransferase. In human platelet microsomes we determined the high enzyme activities of 5.9 nmol.min-1.(10(9) platelets)-1 for the arachidonoyl-CoA synthetase and 37 nmol.min-1.(10(9) platelets)-1 for the lysophospholipid acyltransferase. The activities of these reacylating enzymes were strongly reduced by hydrogen peroxide (H2O2) and methyl mercury that are primary stimuli of arachidonate release in intact platelets. H2O2 inhibited the arachidonoyl-CoA synthetase with an IC50 of 3.3 mmol/l without affecting the lysophospholipid acyltransferase. Sulfhydryl group protection by 3-mercapto-1,2-propanediol did not overcome the inhibition but glutathione prevented the inhibition of the arachidonoyl-CoA synthetase by H2O2. This suggests that glutathione by virtue of the glutathione peroxidase reduces H2O2 rather than that it protects free sulfhydryl groups of the arachidonoyl-CoA synthetase. Methyl mercury left the arachidonoyl-CoA synthetase activity unaffected but inhibited the lysophospholipid acyltransferase activity with an IC50 of 3.4 mumol/l. The inhibition is probably evoked by the blockade of sulfhydryl groups of the lysophospholipid acyltransferase because it disappeared when 3-mercapto-1,2-propanediol was added at a concentration higher than that of methyl mercury. Thrombin as a physiological full agonist, Ca2+ less than or equal to 1 mmol/l, the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (TPA) and 1-oleoyl-2-acetylglycerol as model stimuli of protein kinase C neither influenced arachidonoyl-CoA synthetase nor lysophospholipid acyltransferase. It is concluded that the inhibitory effect of H2O2 and methyl mercury on the arachidonate-reacylating enzymes arachidonoyl-CoA synthetase or lysophospholipid acyltransferase, respectively, are responsible for their capacity to stimulate icosanoid release in intact cells. Thrombin and its intracellular messengers Ca2+ and diacylglycerol do not directly affect arachidonoyl-CoA synthetase and lysophospholipid acyltransferase.
 ...
PMID:Primary stimuli of icosanoid release inhibit arachidonoyl-CoA synthetase and lysophospholipid acyltransferase. Mechanism of action of hydrogen peroxide and methyl mercury in platelets. 210 13

The dependence on protein kinase C (PKC) of arachidonic acid (AA) metabolism stimulated by the biologically important oxidant H2O2, as compared to zymosan particles, was investigated in the rat alveolar macrophage. The PKC inhibitor staurosporine markedly reduced AA release and eicosanoid synthesis stimulated by zymosan, but only slightly inhibited AA release and metabolism induced by H2O2. Furthermore, in macrophages depleted of PKC by extended exposure to phorbol 12-myristate 13-acetate, AA release in response to zymosan was greatly inhibited, whereas that stimulated by H2O2 was attenuated to a significantly lesser degree. Thus, zymosan-stimulated AA metabolism requires active PKC, whereas H2O2-induced metabolism is largely PKC-independent. This provides direct evidence for the existence of two pathways of agonist-stimulated AA metabolism, which differ in their dependence on PKC, in the alveolar macrophage.
 ...
PMID:Differential dependence on protein kinase C of arachidonic acid metabolism stimulated by hydrogen peroxide and by zymosan in the alveolar macrophage. 212 6

Neutrophil dysfunction consequent to influenza A virus infection has been described in vivo and in vitro and may contribute to the serious bacterial sequelae which occur in influenza-infected hosts. On the premise that such dysfunction may represent a form of "deactivation," we sought to characterize neutrophil activation by the virus in comparison with other agonists. The virus induces a respiratory burst in which H2O2 (but not O2-) are formed. Preceding the respiratory burst, a rise in intracellular calcium (Ca2+i) is noted, but both responses are nearly independent of extracellular Ca2+, unlike those elicited by the other well-characterized Ca2+-dependent agonists, formyl-methyl-leucyl-phenylalanine (FMLP), or Concanavalin-A (Con-A). The Ca2+ increase is paralleled by IP3 generation, implying that it is the result of phospholipase C (PLC) activation. The virus also elicits neutrophil membrane depolarization, which is independently mediated from the Ca2+ increase and respiratory burst and may reflect protein kinase C (PK-C) activation. Virus-induced responses are insensitive to pertussis toxin (PT); cholera toxin does inhibit these responses but in a nonspecific manner. Thus, although influenza virus activates PLC in neutrophils, it does so in a PT-insensitive manner and does not elicit or require a discernible Ca2+ influx to generate a respiratory burst response. In aggregate, the data indicate that influenza A virus activates neutrophils in a manner distinct from that of other well-described neutrophil agonists. These results illustrate the diversity of neutrophil activation mechanisms and support the notion that further characterization of this pathway may facilitate understanding of neutrophil dysfunction induced by the virus.
 ...
PMID:Characterization of influenza A virus activation of the human neutrophil. 215 30

The respiratory burst of murine alveolar macrophages (AM) was compared with that of peritoneal macrophages (PM). Superoxide anion (O2-) released from resident AM was similar to that of resident PM. That is, resident AM or PM exposed to phorbol myristate acetate (PMA) released only a small amount of O2-, whereas both macrophages released a large amount of O2- when stimulated with zymosan particles. AM as well as PM obtained from mice injected with Mycobacterium bovis BCG 3 weeks previously (abbreviated to BCG-AM and BCG-PM, respectively) showed an enhanced killing activity to Candida parapsilosis. O2- release of BCG-AM stimulated with zymosan was similar to that of BCG-PM. In both BCG-AM and BCG-PM, maximal O2- response was obtained by stimulation with a lower concentration of zymosan than the concentration which required for resident macrophages to release maximal amount of O2-. There was however, a remarkable difference between the ability of BCG-AM and BCG-PM to release O2- when stimulated with PMA. Markedly enhanced O2- release of BCG-PM was observed. In contrast, O2- release of BCG-AM exposed to PMA was almost the same as that of resident AM. Hydrogen peroxide release of BCG-AM, when stimulated with PMA or zymosan, was compatible with O2- release. Isoquinolinylsulfonyl piperadine (H-7), an inhibitor of protein kinase C, inhibited O2- release of PMA-stimulated BCG-AM and BCG-PM in a dose-dependent manner and the extent of inhibition was greater in O2- release of PM than that of AM. Superoxide anion release in response to zymosan was slightly inhibited by H-7.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Oxygen radical generation of murine alveolar macrophages]. 217 Jul 30

In a "respiratory burst", fertilized sea urchin eggs consume oxygen to produce H2O2 as an extracellular oxidant to crosslink their protective surface envelopes. The egg generates H2O2 via a NADPH-specific oxidase that requires protein kinase C for activation. To further study the physiological regulation of the respiratory burst and cortical granule exocytosis, we have measured azide-insensitive oxygen uptake and fertilization envelope assembly in ionophore-stimulated eggs. Procaine, trifluoperazine, staurosporine, and H-7, which inhibit protein kinase C by different mechanisms, suppressed egg oxygen consumption without affecting fertilization envelope assembly. In contrast, both exocytosis and oxygen uptake were blocked in N-ethylmaleimide-treated eggs. When the eggs were stimulated with ionophore in Na-free artificial seawater, which prevents the increase in pHi, oxidase activity was inhibited. This effect was reversed by elevation of cytoplasmic pH with the membrane-permeant base NH4Cl. We conclude that protein kinase C was not involved in the events downstream from the ionophore-dependent elevation of Ca2+ which induced cortical granule exocytosis. However, the respiratory burst was inhibited despite the increase in Ca2+ that triggered exocytosis. The likely target for inhibition of the burst was protein kinase C. Cytoplasmic alkalinization was necessary for optimal rates of H2O2 synthesis, further implicating pHi as a regulator of the egg oxidase.
 ...
PMID:Protein kinase C activates the respiratory burst of fertilization, but not cortical granule exocytosis, in ionophore-stimulated sea urchin eggs. 222 97

Partially reduced oxygen species are toxic, yet activated sea urchin eggs produce H2O2, suggesting that the control of oxidant stress might be critical for early embryonic development. We show that the Ca2(+)-stimulated NADPH oxidase that generates H2O2 in the "respiratory burst" of fertilization is activated by a protein kinase, apparently to regulate the synthesis of this potentially lethal oxidant. The NADPH oxidase was separated into membrane and soluble fractions that were both required for H2O2 synthesis. The soluble fraction was further purified by anion exchange chromatography. The factor in the soluble fraction that activated the membrane-associated oxidase was demonstrated to be protein kinase C (PKC) by several criteria, including its Ca2+/phophatidylserine/diacyl-glycerol-stimulated histone kinase activity, its response to phorbol ester, its inhibition by a PKC pseudosubstrate peptide, and its replacement by purified mammalian PKC. Neither calmodulin-dependent kinase II, the catalytic subunit of cyclic AMP-dependent protein kinase, casein kinase II, nor myosin light chain kinase activated the oxidase. Although the PKC family has been ubiquitously implicated in cellular regulation, enzymes that require PKC for activation have not been identified; the respiratory burst oxidase is one such enzyme.
 ...
PMID:A specific requirement for protein kinase C in activation of the respiratory burst oxidase of fertilization. 233 2

The mechanism of the inhibitory action of glucocorticoids on glucose uptake is incompletely understood. Treatment with corticosteroids of cells in which glucose uptake is stimulated at insulin postbinding and postreceptor sites may clarify the site of the steroid inhibitory action. Hydrogen peroxide, which has been shown to stimulate the insulin receptor tyrosine kinase, and phorbol myristate acetate (PMA) which stimulates protein kinase C were, therefore, used as stimulators of glucose transport in this study. These studies demonstrate that dexamethasone and the sphingoid bases, sphinganine and sphingosine, inhibit glucose uptake that has been stimulated at either the receptor kinase or protein kinase C level in both 3T3-L1 and 3T3-C2 cells. These data confirm glucocorticoid inhibitory action at a post binding level and support the suggestion that some corticosteroid inhibitory effects may be mediated by an action on sphingolipid metabolism.
 ...
PMID:Inhibitory action of sphingosine, sphinganine and dexamethasone on glucose uptake: studies with hydrogen peroxide and phorbol ester. 236 44

The regulatory effect of H2O2 on both the cytotoxic activity and the specific binding of TNF-alpha was studied by using TNF-alpha-sensitized murine L929 cells. When these cells were exposed simultaneously to TNF-alpha and H2O2 (100 to 500 microM), the cytotoxic activity of TNF-alpha was inhibited by up to 66.6%. This inhibition was also effective when the cells were pretreated by H2O2, but not when TNF-alpha alone was preexposed to H2O2. These data suggest that H2O2 altered the cell sensitivity to TNF-alpha, without modifying the activity of the TNF-alpha molecule. Maximum loss of cell sensitivity to TNF-alpha occurred after 30-min preexposure to 500 microM H2O2. Complete restoration of TNF-alpha sensitivity was obtained within 12 h after H2O2 removal. It required protein synthesis as demonstrated by the suppressive effect of actinomycin D. The inhibitory effect of H2O2 was suppressed by catalase, but was unaffected by the scavengers of hydroxyl radical and hypochlorous acid, suggesting that H2O2 but not one of its metabolites was responsible for this inhibition. H2O2 inhibitory effect did not implicate any change in prostaglandin production or in PKC activity. In contrast, H2O2 effect was associated with an about 50% loss of the density of cell membrane 125I-TNF-alpha receptors (2949 vs 5620 binding sites per cell), without change in their affinity (3.9 vs 3.4 nM). Moreover H2O2 did not affect the rate of degradation of TNF-alpha, and only slightly increased the degree of internalization of 125I-TNF-alpha receptors. These findings indicate that H2O2 can down-regulate the cellular response to TNF-alpha, possibly by reducing the TNF-alpha-binding capacity.
 ...
PMID:Reduction in tumor necrosis factor binding and cytotoxicity by hydrogen peroxide. 236 95


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