Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of staurosporine, a potent but nonselective inhibitor of protein kinase C, on rat mast cell histamine release, was compared with that of two derivatives, CGP 41,251 with a high degree of selectivity for protein kinase C and the related CGP 42,700 which is without activity. Staurosporine was a more potent inhibitor of mast cell responses than CGP 41,251, in accordance with their reported potencies. CGP 42,700 was investigated in the same concentration range as CGP 41,251 and served as a control for unspecific effects. Antigen induced histamine release was more effectively inhibited by staurosporine than by CGP 41,251, and responses to compound 48/80 were only modestly affected by both drugs. Responses to the ionophore A23187 were unaffected by staurosporine whereas CGP 41,251 was an effective inhibitor at suboptimal ionophore concentrations. In contrast, responses to combinations of the phorbol ester TPA and subthreshold concentrations of the ionophore could be potently inhibited by staurosporine but were under certain conditions moderately enhanced by lower concentrations of the drug, whereas CGP 41,251 was only inhibitory. Except for a slight inhibition of ionophore responses CGP 42,700 was without effect. The results demonstrate that the actions of staurosporine cannot be ascribed solely to inhibition of protein kinase C, whereas the influence of CGP 41,251 appears to be consistent with an inhibition of this kinase.
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PMID:Influence of staurosporine, a more selective derivative CGP 41,251 and an inactive analogue CGP 42,700 on histamine release from isolated rat mast cells. 128 Jun 32

We have previously shown that protoporphyrin (PP) plus long-wave ultraviolet light (UVA) has an inhibitory effect on the release of histamine from rat peritoneal mast cells in response to various stimuli, without compromising cell viability. In the present study, we observed that protoporphyrin at a noncytolytic dose (3 ng/ml) plus UVA irradiation (0.038 J/cm2) is also able to suppress prostaglandin D2 generation by rat peritoneal mast cells in response to calcium ionophore A23187, compound 48/80, or anti-IgE antibody by 64%, 92%, and 100%, respectively. Because of the participation of protein kinase C in stimulus-secretion coupling in mast cells, we also investigated the effect of PP plus UVA on the release of histamine induced by the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA). PP plus UVA inhibited histamine release induced by PMA. The release of histamine induced by the synergistic combination of PMA (50 nM) and a low dose of calcium ionophore A23187 (0.1 microM) was also inhibited. PP plus UVA inhibited the release of histamine induced by the non-fluorescent calcium ionophore, 4-Br-A23187, by 47.8%, but had essentially no effect on changes in intracellular calcium induced by this stimulus. In contrast, both the release of histamine and changes in intracellular calcium stimulated by compound 48/80 were inhibited. We conclude from these results that PP plus UVA may affect both early and late biochemical events involved in mast cell mediator release.
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PMID:Protoporphyrin and long-wave ultraviolet light modulate metabolic events in rat peritoneal mast cells. 137 41

Our previous studies have suggested that phosphatidylcholine-specific phospholipase D (PtdCho-PLD) plays a role in IgE-dependent diacylglycerol production, protein kinase C activation and mediator release in the RBL 2H3 mast cell line. We have extended these studies to examine the mechanisms by which PtdCho-PLD may be regulated in these cells. RBL 2H3 cellular lipids were labeled with [14C]arachidonic acid or [3H]myristic acid, then PtdCho-PLD activity was monitored by the formation of radiolabeled phosphatidylethanol when ethanol was included in the incubation medium. Trinitrophenol-ovalbumin conjugate (10 ng/ml), when added to cells previously sensitized with anti-(trinitrophenelated mouse IgE) (0.5 microgram/ml), ionomycin (1 microM) and thapsigargin (0.1 microM), stimulated PtdCho-PLD activation and mediator release in cells incubated in buffer containing 1.8 mM calcium, but not in cells incubated in calcium-free, buffer. Phorbol 12-myristate 13-acetate (0.1 microM) activated PtdCho-PLD in both buffers, but on its own did not trigger mediator release. When intracellular calcium was chelated with 5,5'-dimethyl-1,2-bis(2- aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, trinitrophenol-ovalbumin conjugate failed to activate PtdCho-PLD and histamine release. Similarly, down-regulation of protein kinase C activity by long-term exposure to the phorbol ester (0.1 microM) and preincubation of the cells with protein kinase inhibitors resulted in the loss of the trinitrophenol-ovalbumin response on PtdCho-PLD activity and histamine release. Taken together, the above results suggest that IgE-dependent PtdCho-PLD activation is dependent on both activation of protein kinase C and a rise in the intracellular free calcium concentration.
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PMID:The role of calcium and protein kinase C in the IgE-dependent activation of phosphatidylcholine-specific phospholipase D in a rat mast (RBL 2H3) cell line. 137 1

Investigations of calmodulin involvement in cell responses has been complicated by the lack of selective calmodulin antagonists. A novel inhibitor, CGS 9343B, reportedly without influence on protein kinase C, is used in the present study of mast cell responses. The histamine release induced by antigen and compound 48/80 in the presence of calcium was enhanced by 10-20 microM CGS 9343B and inhibited by higher concentrations. Only inhibitory effects on the response to compound 48/80 in the absence of calcium and to the ionophore A23187 were observed, the latter being inhibited by 20 microM CGS 9343B. The influence on responses to combinations of the phorbol ester TPA and the ionophore A23187 was more complex, giving rise to enhancement at lower and inhibition at higher concentrations of CGS 9343B in a manner which depended on the experimental conditions. Unlike previously used calmodulin antagonists, CGS 9343B is devoid of detergent effects and without serious metabolic interference. The inhibitor seems useful to reveal differences in the mechanisms involved in responses to various histamine liberators. Our results conform with an inhibition of calmodulin by CGS 9343B but are at present inconclusive.
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PMID:Influence of CGS 9343B, an inhibitor of calmodulin activity, on histamine release from isolated rat mast cells. 138 72

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17 beta-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifen's inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.
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PMID:Estradiol augments while tamoxifen inhibits rat mast cell secretion. 138 69

We have used a digitonin-permeabilized cell system to study the signal transduction pathways responsible for stimulus-secretion coupling in the rat peritoneal mast cell. Conditions were established for permeabilizing the mast cell plasma membrane without disrupting secretory vesicles. Exocytotic release of histamine from digitonin-permeabilized cells required a combination of micromolar concentrations of Ca2+ and the stable guanine nucleotide analogue guanosine 5'-[gamma-thio]triphosphate (GTP[S]), but was independent of exogenous ATP. In the presence of 40 microM-GTP[S], exocytosis was half-maximal at 1.3 microM-Ca2+ and maximal at 10 microM-Ca2+; GTP[S] alone (100 microM) had no effect on histamine release in the absence of added Ca2+. In the presence of 10 microM free Ca2+, 5 microM-GTP[S] was required for half-maximal exocytosis. To examine the possible role of protein kinase C (PKC) in exocytosis, we utilized 12-O-tetradecanoylphorbol 13-acetate (TPA) to activate PKC and studied its effect on histamine release from permeabilized mast cells. Cells that had been incubated with TPA (25 nM for 5 min) exhibited increased sensitivity to both GTP[S] and Ca2+. The PKC inhibitor staurosporine blocked the effect of TPA without inhibiting normal exocytosis in response to the combination of GTP[S] and Ca2+. In addition, down-regulation of mast-cell PKC by long-term TPA treatment (25 nM for 20 h) blocked the ability of the cells to respond to TPA and inhibited exocytosis in response to Ca2+ and GTP[S] by 40-50%. These results suggest that the sensitivity of the exocytotic machinery of the mast cell can be altered by PKC-catalysed phosphorylation events, but that activation of PKC is not required for exocytosis to occur.
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PMID:Calcium- and guanine-nucleotide-dependent exocytosis in permeabilized rat mast cells. Modulation by protein kinase C. 168 46

The effects of TMB-8 and calmidazolium were investigated on mast cell responses believed to be mediated by protein kinase C, i.e. histamine release induced by TPA (tetradecanoyl-phorbol-acetate) in combination with sub-threshold concentrations of the ionophore A23187 and with antigen. Inhibition with both drugs was found in the same concentration range as observed earlier and could be counteracted by glucose, indicating an impaired oxidative energy production. Hence, the test drugs do not reveal protein kinase C selectivity.
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PMID:Influence of TMB-8 and calmidazolium on phorbol ester promoted histamine release from isolated rat mast cells. 169 33

RBL 2H3 cells, a model for mast cell function, sensitized with rat IgE, released histamine and peptidoleukotrienes (LT) in response to rabbit anti-rat IgE in a concentration-dependent manner. The calcium ionophore, A23187 also stimulated the release of both mediators but to a greater extent. The protein kinase C activator, 12-O-tetradecanoyl phorbol-13-acetate (TPA) failed to influence mediator release when added alone, but when added with either A23187 or anti-IgE, TPA significantly enhanced the release of both histamine and LT. The effects of anti-IgE, TPA and A23187 were completely inhibited by prior addition of the protein kinase C inhibitors staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7) but not by N-(2-guanidinoethyl)-5-isoquinoline-sulfonamide dihydrochloride (HA1004), a compound which has similar potency to H7 as an inhibitor of some protein kinases but is less potent as a protein kinase C inhibitor. Although other explanations are possible, these results support the hypothesis that the release of histamine and leukotrienes from RBL 2H3 cells resulting from the cross bridging of the IgE receptors, is dependent on activation of protein kinase C.
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PMID:The effects of the protein kinase C inhibitors staurosporine and H7 on the IgE dependent mediator release from RBL 2H3 cells. 169 78

We have previously shown that the ether lipid AMG (1-O-hexadecyl-2-O-methyl-sn-glycerol) has both synergistic and inhibitory effects on mast cell responses to the ionophore A23187. The present investigation showed only inhibitory effects of AMG in antigen- and compound 48/80-induced histamine release. Both enhancement and inhibition were noted in responses to the combination of A23187 and the phorbol ester TPA, at 2-5 microM and 10-20 microM and 10-20 microM AMG, respectively, as found earlier with A23187 alone. The synergistic response to AMG in combination with A23187 resembles that with TPA but required higher concentrations of A23187. The flavonoid phloretin was a potent inhibitor of the response to combinations of AMG and A23187. A pronounced synergistic interaction between AMG and TPA was found at very low concentrations of A23187. Our results do not provide much information about mechanisms involved in the inhibitory effect of AMG although some competition relating to protein kinase C activity might participate. The synergistic interactions indicate that AMG can activate protein kinase C but in a manner different from the phorbol ester.
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PMID:The influence of ether lipid (AMG) on histamine release from isolated rat mast cells: synergistic interaction with TPA indicates protein kinase C activation. 170 11

Interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate the proliferation of several kinds of cultured hematopoietic cell lines. Growth signals from IL-3 and GM-CSF cause accumulation of active Ras.GTP complexes in PT18 mouse mast cell line (Satoh, T., Nakafuku, M., Miyajima, A., and Kaziro, Y. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 3314-3318). In this paper we describe the effect of herbimycin A, a tyrosine kinase-specific inhibitor, on the activation of Ras. The increase of Ras.GTP induced by IL-3 and GM-CSF diminished in cells treated with 0.5 approximately 1 micrograms/ml of herbimycin A for 24 h prior to the addition of the growth factors. Under this condition, the extent of phosphorylation on tyrosine residues of proteins decreased. However, the activity of cAMP-dependent protein kinase and protein kinase C did not change. Growth of cells in the presence of IL-3 or GM-CSF was also completely inhibited. These observations suggest that tyrosine kinases are involved in the pathways between IL-3 and GM-CSF receptors and Ras and that they are essential for the growth stimulated by these growth factors.
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PMID:Inhibition of interleukin 3 and granulocyte-macrophage colony-stimulating factor stimulated increase of active ras.GTP by herbimycin A, a specific inhibitor of tyrosine kinases. 173 50


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