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)

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

Rat serosal mast cell adenosine receptors were characterized by [3H]adenosine binding to cell membrane particulates, and functional changes in mast cell mediator release and cyclic AMP levels were assessed, utilizing various adenosine analogs. [3H]adenosine binding to sonicated mast cell membrane preparations at 0 degrees C in the presence of deoxycoformycin is linear with initial cell number, rapid and reversible. The cells display 16,400 +/- 1600 high affinity [3H]adenosine binding sites/cell, equivalent to 118 fmol bound/mg protein, with an equilibrium dissociation constant of 27.97 +/- 3.0 nM. Competition studies reveal that adenosine greater than 2-chloroadenosine greater than NECA greater than L-PIA greater than D-PIA in competing for [3H]adenosine binding sites and that aminophylline and cromolyn sodium also bind to the putative receptor. Adenosine and its analogs, NECA, and L-PIA, appear to activate adenylate cyclase in resting mast cells by raising cyclic AMP, suggesting an Ra cell surface adenosine receptor subtype; these same analogs potentiate mast cell B-hexosaminidase release stimulated by specific antigen. The identification of rat mast cell [3H]adenosine binding sites whose stimulation augments resting cell cyclic AMP levels and antigen-induced mediator release suggests that these receptors may be important in the biochemical mechanisms of allergic diseases. The ability to assess the number and affinity of mast cell adenosine receptors will enable one to monitor receptor alterations during pharmacologic manipulation and in disease states.
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PMID:[3H]Adenosine binding to rat mast cells--pharmacologic and functional characterization. 300 Jan 51

Activation of white cells, including the neutrophil, eosinophil, basophil, and mast cell, has long been known to be suppressed by high, nonphysiological levels of E-prostaglandins (PGE). In contrast, PGE at levels consistent with an interaction with the PGE receptor (5 X 10(-9) M) have recently been shown to suppress leukotriene (LT) and prostaglandin (PG) production by neutrophils and eosinophils. This occurs by cyclic AMP-dependent inhibition of release of substrate arachidonic acid (AA) from phospholipid pools. The additional observation that indomethacin (10(-9) M) enhances release of eicosanoids by suppressing endogenous PGE2 acting to increase cAMP levels in these cells. Theophylline and other phosphodiesterase inhibitors precisely duplicate the action of PGE2, and the combined effects of such phosphodiesterase inhibitors and adenylate cyclase stimulators are synergistic. The mechanism of action of theophylline in asthma is not know, although it is generally agreed that its effect is a direct one on the bronchial smooth muscle. The findings described in this report now permit the bronchial smooth muscle, but is primarily one of suppressing mediator release from relevant white cells by inhibition of cAMP phosphodiesterase, an action that is enhanced by the presence of inflammatory prostaglandins in the lung.
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PMID:Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept for explaining the efficacy of theophylline in asthma. 303 56

Insight into the pathogenesis of human allergic and inflammatory disorders has been obtained through a combination of in vitro and in vivo studies. These investigations have demonstrated that human basophils and mast cells release mediators after nonimmunologic as well as immunologic activation in vitro and in vivo: nonimmunologic triggers include changes in osmolarity. Although these cells share many properties, including the presence of high-affinity receptors for IgE on their cell surface, the presence of histamine in granules, the ability to generate and release large quantities of leukotriene C4 (LTC4) after activation, and the ability of several pharmacologic agents including phospholipase inhibitors, acetylene analogues of arachidonic acid (ETYA, ETI), methylxanthines, prostaglandin E2 (PGE2) beta-agonists, and cyclic AMP to inhibit mediator release, they also display notable differences. Human lung mast cells generate and release large quantities of prostaglandin D2 (PGD2) after activation; basophils generate no known cyclooxygenase product. Indomethacin, arachidonic acid, and 5-hydroperoxyeicosatetraenoic acid (5-HPETE) all enhance histamine and LTC4 release from human basophils; no effect is seen with human lung mast cells. Overnight incubation of basophils with glucocorticoids produces a marked inhibition of mediator release; this treatment does not affect the release of mast cell mediators. These in vitro observations are consistent with our in vivo observations and our hypotheses concerning the importance of these cells in allergic disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The pharmacologic control of mediator release from human basophils and mast cells. 349 82

Mast cell colonies were observed when mouse spleen or bone marrow cells were cultured in the presence of medium conditioned by concanavalin-A-stimulated spleen cells, indicating that the medium contains the factor(s) necessary for the formation of these colonies. This factor-dependent colony growth of mast cell progenitors was enhanced by cholera toxin and prostaglandin E, which act on cellular growth mainly by elevating the intracellular cyclic-AMP level. The effect of the toxin was neutralized by preincubation of the toxin with GM1 ganglioside, the receptor substance for cholera toxin, suggesting that cholera toxin exerts its action through GM1 gangliosides present on mast cell progenitors. The toxin B subunit, which binds to GM1 ganglioside but does not elevate intracellular cyclic AMP level, did not affect the colony growth of mast cell progenitors. From these results, it is suggested that intracellular cyclic AMP levels may be involved in colony growth of mast cell progenitors.
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PMID:Cholera toxin enhances factor-dependent colony growth of murine mast cell progenitors. 403 71

The principal pathological features of asthma, including tracheobronchial smooth muscle contraction and mast cell mediator synthesis and release, are calcium-dependent processes. Calcium plays an integral role in transmitting signals at the cell surface to the enzymatic machinery of the cell interior; its role as the agent for "excitation-contraction coupling" of airway smooth muscle and for "stimulus-secretion coupling" of mast cells is reviewed. A rise in intracellular calcium ion concentration triggers cellular activation. In smooth muscle, calcium bound to calmodulin stimulates the myosin light chain kinase which is important in the regulation of actin-myosin interaction. In mast cells, calcium may bind to calmodulin or to a calmodulinlike regulatory protein, and it also stimulates enzymes important in the synthesis of newly generated mediators including prostaglandins and leukotrienes. The regulatory role of cyclic AMP in both cell systems is discussed, especially as it pertains to calcium metabolism. By interfering with transmembrane calcium fluxes, the calcium channel blocking drugs have the potential for significantly modifying bronchoconstriction and airway inflammation in asthma and related bronchospastic disorders. Some of the in vitro studies of calcium channel blockers in these two cell systems are reviewed. Finally a speculation about the role of abnormal sensitivity to calcium in airway smooth muscle as a potential cause of airway hyperreactivity is entertained.
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PMID:Role of calcium in airway smooth muscle contraction and mast cell secretion. 608 60

Modulations of cyclic AMP (cAMP) levels and secretory capacity in both immunological and non-immunological stimulation of rat mast cells are influenced by the calmodulin inhibitor trifluoperazine. A model of a calcium-dependent joint regulation of cyclic nucleotide turnover in these two types of mast cell stimulation is presented.
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PMID:Modulation of mast cell cAMP levels. A regulatory function of calmodulin. 609 60

Passive cutaneous anaphylaxis (PCA) produced by antigen challenge to antibody-sensitized rats were interfered with by prior treatment with pertussis toxin, an islet-activating protein (IAP). The degree of interference was dependent on the dose and injection time of IAP; the effect of IAP developed slowly, with a maximal effect being observed 3 days later. Inhibition of PCA by IAP was associated with a decrease in histamine release from peritoneal mast cells, making it very likely that the process affected was mast cell secretion. Much less histamine was discharged in vitro, in response to certain membrane receptor (e.g. IgE receptor) stimulation, from mast cells that had been exposed to IAP than from the cells not exposed. Such an inhibitory effect of IAP was not observed when histamine release was provoked by a calcium ionophore without mediation of membrane receptors. IAP was a stronger inhibitor of histamine release than beta-adrenergic agonists. Further inhibition was produced when a beta-agonist was added to IAP-treated mast cells. The increase in the cellular content of cyclic AMP was associated with beta-agonist-induced, but not with IAP-induced, inhibition of histamine release. Thus, IAP inhibited histamine release by a mechanism in which metabolism of cyclic AMP was not directly involved.
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PMID:Suppression of passive cutaneous anaphylaxis by pertussis toxin, an islet-activating protein, as a result of inhibition of histamine release from mast cells. 614 11


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