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)

Stimulated adherence of human neutrophils to plastic and changes in cytosolic free Ca2+ concn. [( Ca2+]i) were measured in the same cell preparations. [Ca2+]i-activation curves were constructed to compare the relation between [Ca2+]i and adhesion in response to ionomycin and formylmethionyl-leucyl-phenylalanine (FMLP). This showed that FMLP-stimulated adhesion required less increase in [Ca2+]i than did ionomycin's effect, a result suggesting that an additional stimulatory component might be involved in the response to FMLP. Protein kinase C activation was a possibility, and activation of protein kinase C with a phorbol ester (PMA) was found to stimulate adhesion with no change in [Ca2+]i. A low concentration of PMA was found to synergize with ionomycin to stimulate a greater adhesion response than with each alone, and the [Ca2+]i-activation curve for ionomycin in the presence of PMA was shifted towards that for FMLP. Thus, synergy between [Ca2+]i and protein kinase C (each of which is sufficient alone) probably explains the stimulatory effects of FMLP on adhesion of neutrophils.
 ...
PMID:A role for calcium and protein kinase C in agonist-stimulated adhesion of human neutrophils. 210 1

Various pharmacological effectors were used to investigate the mechanism of arachidonic acid release by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in guinea pig alveolar macrophages. The fMLP- and PAF-stimulated arachidonic acid release (i) was mimicked by sodium fluoride and inhibited by Bordetella pertussis toxin, suggesting the participation of a guanine nucleotide-binding protein; ii) was mimicked by A23187 but was insensitive to the calmodulin inhibitor R24571, making the involvement of a calmodulin-dependent pathway unlikely; and (iii) was mimicked by 12-O-tetra-decanoyl phorbol 13 acetate (TPA) and was, like the TPA-stimulated release, markedly decreased when protein kinase C (PKC) had been down-regulated by TPA (65% decrease) or inhibited by sphingosine, a diacylglycerol-competitive PKC inhibitor shown to completely abolish the enzyme activity from alveolar macrophages at 40 microM. Moreover, PAF and fMLP, under conditions where they stimulated arachidonic acid release, promoted an appreciable, albeit transient, translocation of PKC, suggesting a possible involvement of the enzyme in the agonist-stimulated process. However, staurosporine, another PKC inhibitor decreasing PKC activity from alveolar macrophages by 60% at 20 nM, failed to alter fMLP- and PAF-stimulated release. These data lead us to suggest that fMLP- and PAF-stimulated arachidonic acid release is mediated by mechanisms involving either a staurosporine-insensitive PKC isoform or a sphingosine-sensitive coupling between a pertussis toxin-sensitive guanine nucleotide-binding protein and phospholipase A2. Finally, the fMLP- and PAF-stimulated arachidonic acid release was inhibited by cholera toxin and was, like A23187-stimulated release, potentiated by N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H8), an exclusive protein kinase A inhibitor in alveolar macrophages, suggesting a negative regulation by protein kinase A.
 ...
PMID:Mechanism of N-formyl-methionyl-leucyl-phenylalanine- and platelet-activating factor-induced arachidonic acid release in guinea pig alveolar macrophages: involvement of a GTP-binding protein and role of protein kinase A and protein kinase C. 211 77

The effect of the lipophilic gold compound, auranofin (AUR) on the calcium homeostasis of human neutrophils treated with or without n-formyl-methionyl-leucyl-phenylalanine (FMLP) was investigated. In agreement with previous reports, FMLP induced a rapid release of intracellular Ca2+ stores followed by a smaller influx of extracellular Ca2+. AUR and staurosporine enhanced while phorbol 12-myristate 13-acetate suppressed the secondary influx of Ca2+. Mn2(+)-quenching-of-fluorescence studies indicate that phorbol 12-myristate 13-acetate incubation blocked cation entry. AUR or staurosporine potentiation of FMLP effects on cytoplasmic free Ca2+ [( Ca2+]i) was attributed to suppression of negative feedback effects of protein kinase C. AUR (5-45 microM) per se induced a slow release of internal Ca2+ stores followed by a delayed influx of extracellular Ca2+. Control studies showed that AUR did not induce the formation of inositol 1,4,5-trisphosphate, lyse cells, or promote dye leakage. Dithiothreitol suppressed the AUR effect. AUR triggered biphasic but smaller increases in [Ca2+]i of neutrophil cytoplasts. Studies with permeabilized neutrophils showed that AUR directly released Ca2+ from internal stores. By comparison, gold sodium thiomalate, which had no effect on intact cells, also released Ca2+ from permeabilized cells. Present results indicate that AUR modulated [Ca2+]i directly by mobilized Ca2+ from multiple storage sites and indirectly by inhibiting protein kinase C.
 ...
PMID:Auranofin modulated cytoplasmic free calcium in neutrophils by mobilizing intracellular calcium and inhibiting protein kinase. 214 82

In the Triton X-100-treated polymorphonuclear leukocytes (PMN), which were stimulated with formyl-Met-Leu-Phe (FMLP) for 1 min, a 64,000 molecular weight protein (p64) was preferentially phosphorylated by the incubation with [gamma-32P]ATP in the presence of Mg2+, but not in the presence of Ca2+. Phosphoamino acid analysis of pp64 revealed that the p64-kinase was a serine-specific protein kinase. The p64 was maximally phosphorylated in the first minute, suggesting that the rapid phosphorylation was related to the initial reaction for activation of the FMLP-stimulated PMN functions. The FMLP-stimulated phosphorylation of p64 was slightly inhibited by the addition of cGMP in the reaction mixture. However, addition of cAMP, the cyclic nucleotide-dependent kinase inhibitor (H-8), protein kinase C-inhibitor (H-7) or Ca/calmodulin-dependent kinase inhibitor (W-7), showed no effect on the phosphorylation. These data suggest that phosphorylation of p64 seems to be a novel protein kinase specific to p64.
 ...
PMID:Formyl-Met-Leu-Phe-dependent serine kinase for a 64,000 molecular weight protein of polymorphonuclear leukocytes in a cell-lysate system. 214 31

Chemotactic factors and phorbol esters may act synergistically to evoke neutrophil responses, but the mechanism of such interaction is not entirely clear. We investigated the combined effects of the chemotactic peptide n-formyl-methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) on protein kinase C (PKC) activity in human neutrophils. FMLP had little effect on the sharp decrease in cytosolic PKC activity induced by PMA. However, cells exposed to FMLP and PMA exhibited a synergistic increase in particulate PKC activity (1 +/- 1 pmol 32P/10(7) PMNs/min in unstimulated cells, 53 +/- 12 pmol 32P with 20 ng/ml PMA, 6 +/- 3 pmol 32P with 10(-7) M FMLP, and 191 +/- 17 pmol 32P with FMLP and PMA). FMLP also markedly increased calcium/phospholipid-independent protein kinase activity in particulate fractions of control and PMA-treated cells. Enhancement of PKC activity required the presence of cytochalasin B during cell stimulation. Cellular calcium was crucial to the FMLP effect since enhancement was decreased in cells incubated with EGTA or Quin2. These results suggest that chemotactic factors and phorbol esters may mediate synergistic effects on neutrophil responses through enhancement of particulate PKC activity. The enhancing effect is probably mediated through chemoattractant-mediated increases in intracellular calcium.
 ...
PMID:Chemotactic peptide enhancement of phorbol ester-induced protein kinase C activity in human neutrophils. 215 40

The effect of pertussis toxin on N-formyl-methionyl-leucyl-phenylalanine (FMLP), phorbol 12-myristate 13-acetate (PMA), ionomycin, and A23187-induced translocation of protein kinase C and superoxide generation was studied in human neutrophils. Pertussis toxin was shown to inhibit FMLP-induced superoxide generation in parallel with an inhibition of protein kinase C translocation. In contrast, no effect of pertussis toxin was demonstrated upon superoxide generation or protein kinase C translocation in PMA-, A23187-, or ionomycin-stimulated cells. In that superoxide generation and protein kinase C translocation were inhibited in parallel, it is concluded that a G-protein-dependent cascade is involved in the FMLP-induced activation of protein kinase C, and this cascade may be equivalent to the pathway inducing superoxide generation.
 ...
PMID:Pertussis toxin inhibits the FMLP-induced membrane association of protein kinase C in human neutrophils. 215 41

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

Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) exerts stimulatory effects on hematopoietic cells through binding to specific, high-affinity receptors (Kd = 30-100 pM). By using radiolabeled GM-CSF with high specific activity, we have investigated the factors and mechanisms that regulate GM-CSF receptor expression in normal human neutrophils, monocytes, and partially purified bone marrow myeloid progenitor cells. The neutrophil GM-CSF receptor was found to rapidly internalize in the presence of ligand through a mechanism that required endocytosis. Out of a large panel of naturally occurring humoral factors tested, only GM-CSF itself, tumor necrosis factor, and formyl-Met-Leu-Phe were found to down-regulate neutrophil GM-CSF receptor expression after a 2-hr exposure at biologically active concentrations (95% +/- 1%, 34% +/- 5%, 48% +/- 8% receptor down-regulation, respectively). GM-CSF also down-regulated its own receptor on monocytes and myeloid progenitor cells. Since formyl-Met-Leu-Phe is known to stimulate neutrophil protein kinase C activity, we also tested the ability of protein kinase C agonists to modulate GM-CSF receptor expression. Phorbol 12-myristate 13-acetate, bryostatin-1, and 1,2-dioctanoylglycerol were found to induce rapid down-regulation of the GM-CSF receptor in neutrophils, monocytes, and partially purified myeloid progenitor cells, suggesting that this effect may be at least partially mediated by protein kinase C. These data suggest that certain activators of neutrophil function may negatively regulate their biological effects by inducing down-regulation of the GM-CSF receptor.
 ...
PMID:Regulation of surface expression of the granulocyte/macrophage colony-stimulating factor receptor in normal human myeloid cells. 215 4

Human recombinant cachectin/tumor necrosis factor (TNF) was shown to prime neutrophils (PMNs), in a dose-dependent fashion, for subsequent oxidative responsiveness toward n-formyl-methionyl-leucyl-phenylalanine (FMLP). One basis for this phenomenon appeared to be TNF-mediated FMLP receptor mobilization. The maximal observed priming response was associated with a nearly twofold increase in the expression of PMN FMLP surface receptors, without changes in receptor affinity. Priming was not seen following stimulation with phorbol myristate acetate, possibly eliminating a role for the protein kinase C-dependent transductional components of FMLP-induced oxidative activity in the priming process. FMLP receptor mobilization occurred without significant degranulation as evident by an absence of increased granular enzyme release. These data support a potential role of macrophage-derived TNF in the augmentation of PMN host-defense during infectious and inflammatory challenge. TNF-mediated PMN oxidative priming may also promote oxidant tissue injury as seen in septic shock, adult respiratory distress syndrome, and multiple system organ failure.
 ...
PMID:Activation of neutrophils by cachectin/tumor necrosis factor: priming of N-formyl-methionyl-leucyl-phenylalanine-induced oxidative responsiveness via receptor mobilization without degranulation. 215 74

We studied the effect of a potent inhibitor of protein kinase C, polymyxin B (PMXB), on superoxide anion (O2-) release by human polymorphonuclear leukocytes (PMNL). PMXB was compared with another inhibitor of protein kinase C, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7). Both PMXB and H-7 inhibited phorbol myristate acetate (PMA)-stimulated O2- release. Formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated O2- release by cytochalasin B-treated PMNL was not inhibited significantly by either PMXB or H-7. 1-Oleoyl-2-acetyl-glycerol (OAG,25-100 microM) stimulated PMNL to release O2- with a long lag-time (8-10 min). Although H-7 inhibited OAG-stimulated O2- release, PMXB augmented the OAG-stimulated response by increasing rate and reducing lag time. The augmenting effect of PMXB was evident only when added after stimulation by OAG, with maximum effect observed at 3 min after addition of OAG. The augmenting effect was also seen with PMXB immobilized on agarose beads. PMXB did not affect the respiratory burst response to 1,2-dioctanoylglycerol. PMXB-augmented, OAG-stimulated O2- release was inhibited by the addition of H-7 before OAG. In contrast to the effect on O2- release, OAG-stimulated protein phosphorylation was inhibited similarly by either PMXB or H-7, when these agents were added 3 min after stimulation by OAG. These results suggested that initial activation of protein kinase C by OAG is essential for O2- release, but that PMXB acts in a manner independent from protein kinase C to augment OAG-stimulated O2- release. When priming by OAG for enhanced O2- release (as opposed to direct stimulation of O2- release) in FMLP-stimulated PMNL was examined, PMXB inhibited O2- release in OAG-primed PMNL, suggesting that protein kinase C is involved in priming of PMNL by OAG.
 ...
PMID:Effects of polymyxin B on superoxide anion release and priming in human polymorphonuclear leukocytes. 215 77


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