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)

Several phosphoproteins are involved in stimulus-secretion coupling. The beta and gamma subunits of immunoglobulin E binding protein (FC epsilonRI) and three other protein bands get phosphorylated during stimulation of mast cell secretion. These additional proteins of 42, 59 and 68 kDa are also phosphorylated when secretion is stimulated by compound 48/80 (C48/80). A 78 kDa band, however, is phosphorylated as secretion wanes after stimulation with C48/80 and by the anti-allergic drug disodium cromoglycate (cromolyn). Phosphorylation was blocked by protein kinase C inhibitors. We investigated the isozyme involved by first showing that a cation ionophore prevented the phosphorylation of the 78 kDa protein, while a Ca2+ chelator did not affect phosphorylation even though it enhanced the inhibitory effect of cromolyn. This protein was identified as moesin by immunoprecipitation. Protein kinase C activators had no effect on 78 kDa protein phosphorylation either in the presence or absence of Ca2+ ions, but prevented its phosphorylation by cromolyn. Protein phosphatase inhibitors prolonged the duration, but not the amount of phosphate incorporated in the 78 kDa protein band while cromolyn had no effect on protein phosphatase action in vitro. The insensitivity of the 78 kDa protein phosphorylation to calcium and protein kinase C activators suggests that an atypical protein kinase C isozyme may be involved. Western blot analysis identified the presence of isozymes alpha, beta, delta and zeta, of which only the latter fits the profile suggested by the present findings.
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PMID:Ca2+ and phorbol ester effect on the mast cell phosphoprotein induced by cromolyn. 1035 62

While histamine is the crucial mediator of pruritus in type 1 allergic reactions, its role in atopic dermatitis (AD) is unclear. In this study, the role of mast cell mediators in protein extravasation and pruritus was evaluated using intradermal microdialysis. The microdialysis capillaries were used to apply the mast cell degranulating substance compound 48/80 (C48/80; 0.05%) or histamine (0.01%) and also to deliver H1-blockers (cetirizine, 200 microg mL-1) in nine AD patients and nine controls. Large pore size membranes (3000 kDa) enabled simultaneous analysis of protein extravasation. Itch sensation was measured psychophysically and weal and flare reaction were evaluated planimetrically. Protein extravasation induced by histamine and C48/80 was significantly reduced in AD patients. Blockade of H1-receptors by cetirizine significantly reduced C48/80-induced protein extravasation in AD patients and controls to an identical level. C48/80-induced pruritus was abolished by cetirizine in controls, whereas pruritus in AD patients was unchanged after H1 blockade. We conclude that mast cell mediators others than histamine are involved in C48/80-induced pruritus in AD patients. Whether the reduced capacity of AD patients to induce protein extravasation is of pathophysiological relevance for pruritus remains to be established.
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PMID:Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study. 1084 27

To clarify the effect of mast cell-derived histamine release in the brain on anxiety, histaminergics-induced anxiety-like behaviors were examined by a light/dark test in mast cell-deficient (W/Wv) and congenitally normal (+/+) mice. In +/+ mice, when cimetidine (an H2 receptor antagonist) was coadministered with thioperamide (a neuronal histamine releaser acting via inhibition of H3 autoreceptors) or Compound 48/80 (C48/80, a selective histamine releaser from mast cells), the time spent in the light zone and the number of crossings between light and dark zones in a light/dark test decreased significantly, suggesting induction of anxiety. In W/Wv mice, however, experimental anxiety was induced by coadministration of thioperamide-cimetidine, but not C48/80-cimetidine. These results suggest that both nonneuronal mast cell-derived histamine and neuronal histamine play an important role in inducing experimental anxiety.
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PMID:Experimental anxiety induced by histaminergics in mast cell-deficient and congenitally normal mice. 1190 Aug 17

The aim of this study was to investigate the feasibility of intramyocardium kinetics of histamine release by microdialysis in the isolated rat heart and ascertain if the inhibition of histamine release is implicated in the antiarrhythmic effect of preconditioning. A 30 min normothermic global ischaemia model followed by 30 min reperfusion was carried out in the control group (n= 9). In the preconditioning group (n= 8) there was a 5 min global ischaemia followed by 10 min of reperfusion. A mast cell stabilizing group received the disodium cromoglycate ( 10 micro M, n= 10). The last group received a mast cell degranulator, compound 48/80 (1micro g ml (-1), n= 10). In the control group, the histamine release during reperfusion was significantly different from the basal concentration ( 18.4 +/- 6.5 vs 1.9 +/- 0.5 nM, P< 0.05) and was associated with a maximal period of severe arrhythmias. The ischaemic preconditioning modified the histamine release kinetics with an early mast cell degranulation ( 9.7 +/- 1.5 nM) and a significant decrease in the total period of severe arrhythmias in comparison with the control group ( P< 0.05). In the disodium cromoglycate group, the histamine release during reperfusion decreased ( 3.1 +/- 0.7 nM) and was associated with a maximal period of severe arrhythmias. In the C48/80 group, the increase in the histamine released during reperfusion ( 21.2 +/- 5.0 nM) was associated with a maximal period of severe arrhythmias. These results showed firstly the feasibility of kinetic histamine release in myocardium interstitial fluid on the isolated rat heart and secondly that the inhibition of histamine release did not play a direct role in the antiarrhythmic effect of preconditioning.
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PMID:Ischaemic preconditioning and mast cell histamine release: microdialysis of isolated rat hearts. 1212 26

Mast cell activation, or neurogenic inflammation, is known to induce lowering of interstitial fluid pressure (P(if)) and plasma protein extravasation (PPE) in several tissues from both rats and mice. To examine a possible role of connective tissue mast cells (CTMCs) in these inflammatory responses, we used mice with dysfunctional CTMCs due to lack of the N-deacetylase/N-sulfotransferase-2 enzyme (NDST-2(-/-)). P(if) and PPE were measured after challenge with compound 48/80 (C48/80), and P(if) alone was measured after treatment either with capsaicin, substance P (SP), or calcitonin gene-related peptide (CGRP). Measurements of P(if) in anesthetized (fentanyl/fluanison and midazolam, 1:1) mice were performed in paw skin with glass capillaries connected to a servo-controlled counterpressure system. PPE was measured with microdialysis by using hollow plasmapheresis fibers (cutoff at 3,000 kDa) placed subcutaneously on the back. Intravenous administration of C48/80 lowered P(if) significantly (P < 0.05) in NDST-2(-/-) mice (-1.67 +/- 0.42 mmHg) compared with vehicle (-0.57 +/- 0.17 mmHg) but the lowering was significantly (P < 0.05) less compared with that of the NDST-2(+/+) mice (-2.31 +/- 0.47 mmHg). PPE was increased 300% after treatment with C48/80 in NDST-2(+/+) mice, whereas there was no increase in PPE in NDST-2(-/-) mice. Capsaicin, SP, and CGRP lowered P(if) significantly (P < 0.05) compared with vehicle and to the same extent in both NDST-2(+/+) and NDST-2(-/-) mice. We can conclude that although NDST-2(-/-) mice demonstrate an altered response in P(if) after mast cell activation, there was no similar alteration after neurogenic inflammation. Therefore, we suggest that neurogenic inflammation in mouse skin is not exclusively dependent on intact CTMCs.
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PMID:Neurogenic inflammation in mice deficient in heparin-synthesizing enzyme. 1460 57

This study sought to investigate the effects of nadroparine on an in vivo experimental model of type I hypersensitivity response in the rat conjunctiva. Following drug application onto the eye, either before or after challenge with the mast cell degranulator, basic polyamine compound 48/80, the conjunctival histamine content and the nitrite levels in the conjunctival lavage fluid were quantified fluorometrically and spectrophotometrically, respectively. Instillation into the eye of nadroparine inhibited the C48/80-induced decreases in conjunctival histamine and the delayed increases in nitrite levels, without influencing basal mediator levels. Protamine did not induce histamine release and only partially reversed the effects of nadroparine post-challenge, yet it had no effect on the protective action of the drug when administered prior to degranulation. The results showed that nadroparine was equally effective in attenuating the effects of compound 48/80 in the eye when administered topically either before or after challenge.
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PMID:Nadroparine inhibits the hypersensitivity response in the conjunctiva. 1463 83

Upregulation of CGRP-immunoreactive (IR) primary afferent nerve fibers accompanied by mastocytosis is characteristic for the Schistosoma mansoni-infected murine ileum. These mucosal mast cells (MMC) and CGRP-IR fibers, which originate from dorsal root (DRG) and nodose ganglia, are found in close apposition. We examined interactions between primary cultured MMC and CGRP-IR DRG neurons in vitro by confocal recording of intracellular Ca(2+) concentration ([Ca(2+)](i)). The degranulatory EC(50) for the mast cell secretagogue compound 48/80 (C48/80; 10 microg/ml) and the neuropeptides CGRP (2.10(-8) M) and substance P (SP; 3.10(-8) M) were determined by measurement of extracellular release of the granule chymase, mouse mast cell protease-1. Application of C48/80 (10 microg/ml) and CGRP and SP (both 10(-7) M) to Fluo-4-loaded MMC induced a transient rise in [Ca(2+)](i) after a lag time, indicative of mast cell degranulation and/or secretion. The CGRP response could be completely blocked by pertussis toxin (2 microg/ml), indicating involvement of G(i) proteins. Application of MMC juice, obtained by C48/80 degranulation of MMC, to Fluo-4-loaded DRG neurons induced in all neurons a rise in [Ca(2+)](i), indicative of activation. Degranulation of MMC by C48/80 in culture dishes containing Fluo-4-loaded DRG neurons also caused activation of the DRG neurons. In conclusion, these results demonstrate a bidirectional cross-talk between cultured MMC and CGRP-IR DRG neurons in vitro. This indicates that such a communication may be the functional relevance for the close apposition between MMC and CGRP-IR nerve fibers in vivo.
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PMID:In vitro activation of murine DRG neurons by CGRP-mediated mucosal mast cell degranulation. 1501 15

The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.
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PMID:Degranulation of mast cells located in median eminence in response to compound 48/80 evokes adrenocortical secretion via histamine and CRF in dogs. 1523 94

In allergen-induced asthma, activation of lung mast cells leads to bronchial constriction, increased mucus secretion, and an increase in the localization of inflammatory cells to the airways. The purpose of this study was to explore the role of mast cells in adenosine-mediated airway reactivity and inflammation using the mast cell degranulating agent, compound 48/80 (C48/80). Mice were sensitized and challenged with ragweed (or 0.9% saline) followed by C48/80 administration twice a day in increasing doses for 5 days. Dose-responsiveness to the nonspecific adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) was established, and lung lavage was performed 24 h later for cell differential analysis to evaluate inflammation. At a dose of 375 microg/ml (aerosolized NECA), C48/80 pretreatment resulted in a significant attenuation in airway reactivity when compared with sensitized control mice (330.07 versus 581.57%, respectively). Lung lavage from the C48/80 treated mice showed a decrease in eosinophils (17.7 versus 60.9%, respectively) and an increase in macrophages when compared with the sensitized control group (76.4 versus 30.8%, respectively). These results support the conclusion that mast cell degranulation plays an important role in adenosine receptor-mediated airway hyperresponsiveness and inflammation.
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PMID:Involvement of mast cells in adenosine-mediated bronchoconstriction and inflammation in an allergic mouse model. 1562 27

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.
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PMID:Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone. 1607 87


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