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)

Enhanced phospholipid methylation has been suggested to be an obligatory event in activation-secretion coupling in mast cells. However, we have consistently failed to demonstrate increased [3H]methyl incorporation into either whole-lipid extracts or separated lipids to accompany IgE-dependent induction of histamine release from rat peritoneal mast cells despite variation of the experimental protocol, animals and animal diet. Although the presence of 3-deazaadenosine and homocysteine thiolactone reduced IgE-dependent histamine release, treatment with these compounds elevated mast cell cyclic AMP levels. We conclude that IgE-dependent activation of mast cells is not associated with enhanced phospholipid methylation and that inhibition of histamine release by methylation inhibitors may be due to other effects of the drugs.
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PMID:IgE-dependent activation of mast cells is not associated with enhanced phospholipid methylation. 242 83

We have previously reported the presence of an ATPase, stimulated by calcium and magnesium, on the outer surface of the rat peritoneal mast cell. Experiments in which the enzyme activity was enhanced or inhibited showed a relationship to histamine secretion. Enhanced enzyme activity with increasing concentrations of the substrate (ATP) was associated with a potentiation of histamine release, and a pronounced inhibition of the enzyme caused an inhibition of the release. In the present work we have studied the influx and efflux of calcium in mast cells in relation to the activity of the Ca2+-Mg2+ ATPase on the mast cell membrane. The enzyme activity is shown to be related to calcium influx and has no effect on calcium efflux. Stimulation of the enzyme with ATP is associated with increased calcium influx into the mast cell, and inhibition of the enzyme with AMP causes inhibition of the calcium uptake. In both cases calcium efflux is unaffected. The function of the enzyme is thus different from the calcium efflux enzyme on the cytoplasmic surface, described in other cells. In addition, the Ca2+-Mg2+ ATPase on the mast cell surface is neither stimulated by calmodulin nor inhibited by the calmodulin antagonists, trifluoperazine and W-7. In mast cells the low cytosolic calcium concentration seems to be maintained by Na+-Ca2+ countertransport. Phosphorylation of the Ca2+-Mg2+ ATPase on the mast cell is likely to be associated with Ca2+ release at the cytoplasmic surface of the plasma membrane. It is thus possible that ATP hydrolysis in the membrane stimulates the contraction of microfilaments in the membrane and the cytoskeleton, and promotes the migration of the granules to the plasma membrane.
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PMID:Role of a Ca2+-Mg2+ ATPase on the mast cell surface in calcium transport and histamine secretion. 244 Feb 67

In order to study the characteristics of the intracellular Ca store of mast cells, organelles of rat peritoneal mast cells were fractionated. The binding of 45Ca was at its peak in the fractions where the highest activity of glucose-6-phosphatase, the marker enzyme for the endoplasmic reticulum (ER), was measured. The ER-rich fraction exhibited an ATP-dependent uptake of 45Ca and this uptake was inhibited by pretreatment with ATPase inhibitors such as LaCl3 or Na3VO4. When inositol 1,4,5-trisphosphate (IP3) was added to a medium containing the 45Ca-loaded ER fraction, it caused a dose-dependent release of 45Ca at concentrations higher than 0.5 microM, while inositol 1-monophosphate and inositol 1,4-bisphosphate were not effective even at higher concentrations. The results of a binding assay using 3H-labeled IP3 indicated that there exist two kinds of IP3 binding site in the ER: one is of high affinity but low capacity while the other is of low affinity and high capacity. IP3-induced 45Ca release was dose-dependently inhibited by pretreatment with c-AMP. The present study supports the assumption that the intracellular Ca store associated with histamine release from the mast cell is the ER.
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PMID:Ca uptake and Ca releasing properties of the endoplasmic reticulum in rat peritoneal mast cells. 246 54

The effects of synthetic polycations, which induce liposomal membrane fusion without inducing permeability changes, on histamine release from rat mast cells were investigated. Polyethylenimines and polyallylamines with various molecular weights released histamine from mast cells. Acetylated derivatives and triethylentetramine did not release histamine or serotonin from the cells. The histamine release induced by 10 micrograms/ml polyethylenimine with a molecular weight of 600 was inhibited by 1 mM dibutyryl cyclic AMP, but not by 1 MM 8-bromo cyclic GMP; 100 microM D-600, a calcium antagonist; or 30 microM W-7, a calmodulin inhibitor. In the presence of polyethylenimines with molecular weights of 600, 1,200 and 1,800, no detectable release of cytosolic lactate dehydrogenase was observed, indicating that histamine release induced by these polycations was not due to their cytotoxicity. The potencies of these polymers in inducing histamine release depended on their charges, but not on their degrees of polymerization. On the other hand, the actions of polyethylenimine with a molecular weight of 10,000 and polyallylamines with molecular weights of 3,000-4,000 and 10,000 in releasing lactate dehydrogenase were somewhat cytotoxic. These polycations did not induce serotonin release from rat platelets, suggesting that platelets have no coupling system of signal transduction by these polycations. Thus polycations seemed to interact with the mast cell membrane to induce histamine release, and the potencies of these polycations on mast cells seemed to differ from those of their effects on liposomes, which were examined previously.
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PMID:Synthetic polycations, polyethylenimines and polyallylamines release histamine from rat mast cells. 248 Apr 66

1. Stimulation of mast cells by externally applied secretagogues activated a slowly developing membrane current. With high external and low internal chloride (Cl-) concentrations, the current reversed at about -40 mV, but when external Cl- was made equal to internal Cl-, the reversal potential shifted to about 0 mV, demonstrating that the current carrier was Cl-. 2. In addition to external agonists, internally applied cyclic AMP and high concentrations of intracellular calcium [Ca2+]i could also activate the Cl- current. However, elevated [Ca2+]i produced only slow and incomplete activation. This suggests that the Cl- current is not directly Ca2+ activated. Also, activation of Cl- current by external agonists and by cyclic AMP was unimpaired when [Ca2+]i was clamped to low levels with internal ethylene glycol bis-N,N,N',N'-tetraacetic acid (EGTA), indicating that elevated [Ca2+]i is not necessary for activation of the Cl- current. Although activation by cyclic AMP was faster than that produced by elevated [Ca2+]i, it still required tens of seconds; thus the effect of cyclic AMP was also likely to be indirect. 3. Internal guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) could also activate the Cl- current, suggesting the involvement of a G protein in the control of the current. 4. The variance associated with the Cl- current was small, and noise analysis gave a lower limit of about 1-2 pS for the single-channel conductance. The Cl- current was reduced by 4,4'-diisothiocyano-2,2'-stilbenedisulphonate (DIDS), and during DIDS blockade, the variance of the current increased. This suggests that DIDS enters and blocks the open channel. 5. Activation of the Cl- current would make the membrane potential negative following stimulation of a mast cell, thus providing a driving force for entry of external calcium via the stimulation-induced influx pathways described in the preceding paper (Matthews, Neher & Penner, 1989).
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PMID:Chloride conductance activated by external agonists and internal messengers in rat peritoneal mast cells. 255 69

Rat mast cell granules were obtained by sonication of highly purified rat mast cells and isolated in a Percoll gradient. Phosphorylation of endogenous phosphatidylinositol in rat mast cell granules, which is catalyzed by phosphatidylinositol kinase in the granules, was assayed by measuring the incorporation of 32P from [gamma 32P]ATP into phosphatidylinositol 4-phosphate. Lipids were isolated with methanol/chloroform/HCl and were separated by thin-layer chromatography on oxalic acid impregnated silica gel plates. Phosphatidylinositol 4-phosphate areas were identified by staining with iodine, scraped and measured for 32P radioactivity. The phosphorylation reaction was inhibited by 50-500 microM adenosine, ADP and 500 microM AMP in a concentration-dependent manner. Among several anti-allergic drugs investigated. 100-1000 microM theophylline and 10-100 microM azelastine inhibited the phosphorylation reaction, but disodium cromoglycate and ketotifen had little effect.
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PMID:Inhibitory effect of adenine nucleotides and anti-allergic drugs on phosphorylation of phosphatidylinositol in rat mast cell granules. 257 58

Mast cell adenosine receptors are up-regulated functionally and numerically by chronic exposure to receptor antagonists, but their response to long-term treatment with receptor agonists has not been studied. To address this issue cultured mouse bone marrow-derived mast cells were exposed to N-ethylcarboxamide adenosine (NECA), an adenosine receptor agonist that augments stimulated mast cell mediator release. Cells grown for 3 days in 1 nM NECA responded normally to A23187 or antigen in releasing beta-hexosaminidase, but the ability of exogenous adenosine to potentiate this mediator release was attenuated markedly. This inhibition of adenosine responsiveness was partially present after 10 min of 1 microM NECA exposure and complete after 4 hr. The inhibitory effects could be reversed by washing NECA-exposed cells and returning them to culture for more than 4 hr. The adenosine present in the fetal calf serum coupled with deoxycoformycin attenuated mast cell adenosine responsiveness. The NECA-treated cells also exhibited a hyporesponsiveness to adenosine's augmentation of cell cyclic AMP content. This hyporesponsiveness was specific for adenosine receptors in that exogenous isoproterenol was able to increase cyclic AMP levels to a similar degree in both control and NECA-treated cells. Thus, chronic NECA exposure induces a homologous desensitization of mast cell adenosine receptors.
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PMID:Inhibition of mast cell adenosine responsiveness by chronic exposure to adenosine receptor agonists. 282 21

Adenosine potentiates mouse bone marrow-derived mast cell mediator release by a mechanism that appears to involve cell surface adenosine receptors. In an attempt to explore possible interactions between G proteins and adenosine receptors, mast cells were incubated with activated pertussis toxin, an agent that ADP-ribosylates and inactivates some G protein subtypes, prior to challenge with specific antigen or the calcium ionophore A23187. Mast cells preincubated with 10 ng/ml pertussis toxin for at least 2 hr exhibited an inhibition of antigen-induced beta-hexosaminidase and leukotriene C4 release. The ability of adenosine to potentiate beta-hexosaminidase release was attenuated to an even greater degree by pertussis toxin. A23187-stimulated mediator release was not altered by pertussis toxin, although a modest inhibition of the ability of adenosine to enhance A23187-induced beta-hexosaminidase release was observed in pertussis toxin-treated mast cells. Although up to 24-hr exposure to 100 ng/ml pertussis toxin did not alter resting mast cell cyclic AMP levels, the ability of adenosine to elevate cell cyclic AMP concentrations was diminished markedly by doses of the toxin higher than those required to affect mediator release. Neither antigen-stimulated intracellular free calcium level augmentation alone nor the additional potentiation of these levels by adenosine was changed by pertussis toxin treatment. Inositol trisphosphate was generated by mast cells stimulated by IgE-mediated mechanisms, but a preincubation with pertussis toxin did not influence its generation. In summary, adenosine appeared to produce some of its alterations in mast cell biochemical events by a mechanism that was partially inhibited by pertussis toxin. The nature of the G protein linked to the mast cell adenosine receptor is yet to be determined.
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PMID:Alteration of mast cell responsiveness to adenosine by pertussis toxin. 284 50

1. The L-type Ca2+ current was recorded in guinea-pig ventricular myocytes by the patch clamp technique in the whole-cell configuration. The modification of the current by intracellular application of proteases was studied. 2. During the first phase of action, trypsin, an endopeptidase, increased the amplitude of Ca2+ current about 3-fold. 3. Thereafter, there was a drastic slowing of the inactivation time course of the enhanced Ca2+ current. The half-time of inactivation increased from a control value of about 25 ms to values larger than 200 ms. 4. Cell dialysis with carboxypeptidase A, an exopeptidase, also enlarged the amplitude of Ca2+ current, but did not affect the kinetics of Ca2+ current. Leuaminopeptidase did not modify the Ca2+ current. 5. The hypothesis that Ca2+ channels are affected by the protease is supported by the fact that alterations of the extracellular Na+ or K+ concentration did not influence the modification of the membrane current. Another argument for the involvement of Ca2+ channels is that the modified membrane current could be blocked by inorganic and organic Ca2+ channel blockers (e.g. 10 microM-Cd2+, 100 microM-La3+ or 1 microM-D600). 6. Although the actions of trypsin and maximal concentrations of isoprenaline on the amplitude of the Ca2+ current were not additive, the slowing of inactivation by trypsin occurred independently from beta-adrenergic stimulation. 7. The effect of trypsin on the Ca2+ current could not be blocked by intracellular 5'-adenylyl-imidodiphosphate (AMP-PNP) or Rp-adenosine 3'5'-monothionophosphate (Rp-cAMPS), both of which are known to suppress the cyclic AMP-dependent phosphorylation of the Ca2+ channel. 8. It was concluded that trypsin may directly modify the membrane protein which forms the Ca2+ channel. Since the increment in peak Ca2+ current resembled the action of cyclic AMP-dependent phosphorylation, it may be related to the removal of a 'chemical' inactivation gate which is normally controlled by phosphorylation. The slowing of the time course of Ca2+ current inactivation by trypsin could be due to a modification of the voltage-dependent inactivation gate. Alternatively, the endopeptidase might remove an internal Ca2+ binding site normally responsible for Ca2+-dependent inactivation.
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PMID:Modification of L-type calcium current by intracellularly applied trypsin in guinea-pig ventricular myocytes. 285 49

Adenosine, when it is administered by inhalation to asthmatic subjects, is a potent bronchoconstrictor, although its mechanism of action is not known. Since adenosine has been demonstrated to potentiate IgE-dependent mediator release from mast cells, we have investigated the possible relationship between adenosine-induced bronchoconstriction and release of mast cell mediators in 14 asthmatic subjects. In the first study the effect of the putative mast cell-stabilizing drug cromolyn sodium (SCG) was observed on the dose-related changes in SGaw and FEV1 produced by inhaled adenosine and histamine in seven subjects. Inhaled SCG (20 mg) had no effect on the airway responses to histamine. In contrast SCG significantly protected against adenosine-induced bronchoconstriction in four of the seven subjects as reflected by a decrease in the airway response to the highest concentrations of adenosine, from 65 +/- 8% to 12 +/- 3% (mean +/- SEM) for SGaw and 31 +/- 7% to 8 +/- 3% for FEV1. Those three subjects whose adenosine response was unaffected by SCG had received regular SCG until 12 hr before the studies. In a separate study on eight subjects, a single inhalation of adenosine, causing a maximum 61 +/- 4% fall in SGaw at 10 min, had no significant effect on circulating levels of histamine, neutrophil chemotactic factor, or cyclic AMP. Together these two studies suggest that bronchoconstriction produced by adenosine is not a consequence of enhanced mast cell-mediator release and that the inhibitory effects of SCG occur by a mechanism other than through mast cell stabilization.
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PMID:Adenosine-induced bronchoconstriction in asthma: role of mast cell-mediator release. 298 12


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