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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initial monophasic rise in cyclic AMP beginning 5-15 sec after bridging of rat mast cell IgE-Fc receptors precedes the secretion of granule constituents, thereby implying a causal relationship. Direct evidence for a relationship between IgE-dependent transmembrane activation of adenylate cyclase and granule secretion was provided by the capacity of purine-modified (R site active) and ribose-modified (P site active) adenosine analogs, respectively, to augment and suppress mediator release while simultaneously increasing and decreasing the activity of adenylate cyclase. R site stimulation alone does not cause granule secretion but augments the rate and magnitude of IgE-Fc receptor-induced secretion, reflecting the coupled relationship of such receptors. Inhibition of adenylate cyclase at the P site attenuates the rise in cellular cyclic AMP and suppresses IgE-dependent mediator release in a parallel and superimposable dose-response fashion. Further, the relationship between the attenuation in the rise in cyclic AMP and the diminution in immunologic mediator release is linear with the regression line passing through the origin, indicating a direct relationship between the IgE-dependent activation of adenylate cyclase and preformed mediator release. Although not the only events in coupled mast cell activation--secretion, there is a sequential relationship among perturbation of IgE-Fc receptors, transmembrane activation of adenylate cyclase, elevation of cytoplasmic levels of cyclic AMP, activation of cyclic AMP-dependent protein kinase, and secretion of mast cell granules.
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PMID:Role of adenylate cyclase in immunologic release of mediators from rat mast cells: agonist and antagonist effects of purine- and ribose-modified adenosine analogs. 625 61

Previous studies have shown that perturbation of the mast cell IgE-Fc receptor activates adenylate cyclase so as to raise cellular levels of cyclic AMP and to activate cyclic AMP-dependent protein kinase. Theophylline, an inhibitor of cytoplasmic cyclic nucleotide phosphodiesterase, raises cellular cyclic AMP levels, activates Type I and Type II cytoplasmic cyclic AMP-dependent protein kinase isoenzymes, and inhibits immunologic mediator release in a dose-dependent fashion. Since the EC50 values for each of these effects are similar (8 to 9.5 mM), it seems likely that a relationship exists between the activation of cyclic AMP-dependent protein kinase and the inhibition of mediator release. Such inhibition could be due to either to the uncovering of an inhibitory protein by phosphorylation or to the depletion of cyclic AMP-dependent protein kinase holoenzyme, which is essential for productive IgE-Fc receptor-induced activation-secretion coupling. PGD2, which also raises mast cell cyclic AMP levels in a dose-dependent fashion and interacts synergistically with theophylline in this regard, fails to suppress mediator release alone or to add to the inhibitory effect of theophylline. The finding that PGD2 also fails to activate cyclic AMP-dependent protein kinase suggests that the adenylate cyclase stimulated by this agonist is not linked to the mast cell activation-secretion response.
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PMID:Effects of prostaglandin D2 and theophylline on rat serosal mast cells: discordance between increased cellular levels of cyclic AMP and activation of cyclic AMP-dependent protein kinase. 626 8

Stereo-specific perturbation of the IgE-receptor (shown in previous studies) produces a monophasic rise in cyclic AMP that peaks at 15 s and a depletion of cyclic AMP-dependent protein kinase that plateaus at 30-60 s. The previously observed linear relationship between the attenuation in the monophasic rise in cyclic AMP and the quantity of mediator release in the presence of incremental concentrations of the adenosine analogue 2',5',-dideoxyadenosine, DDA, which is known to inhibit adenylate cyclase, indicated a direct relationship between receptor perturbation, transmembrane activation of adenylate cyclase, and granule secretion. The role of cyclic AMP as a second messenger in this sequence is now apparent from the linear relationship between net percent mediator release and net percent activation of cyclic AMP-dependent protein kinase isoenzyme when IgE-dependent activation of adenylate cyclase is suppressed by incremental quantities of DDA. There was a comparable percent activation of both types I and II mast cell cyclic AMP-dependent protein kinase isoenzymes with anti-IgE-induced activation and secretion, and there was a parallel suppression of the activation of both isoenzymes in the presence of DDA. Although these studies firmly link the activation of cytoplasmic cyclic AMP-dependent protein kinase to the IgE receptor-initiated transmembrane activation of adenylate cyclase. they do not discriminate among the functions of the two isoenzymes.
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PMID:Mast cell mediator release as a function of cyclic AMP-dependent protein kinase activation. 627 Feb 26

Bridging of IgE receptors on rat mast cell plasma membranes induces phospholipid methylation and a monophasic increase in cyclic AMP. The stimulation of phospholipid methylation in the plasma membrane appears to be intrinsic to the processes leading to Ca2+ influx and histamine release. Evidence was obtained that IgE receptors are closely associated with methyltransferases and adenylate cyclase in the plasma membranes. The activation of one enzyme is regulated by the other. An increase in the cyclic AMP level before receptor bridging suppressed phospholipid methylation. On the other hand, inhibition of phospholipid methylation may affect the initial rise in cyclic AMP. Our experiments also indicated that bridging the receptor activates a membrane-associated proteolytic enzyme. Inasmuch as the inhibition of the enzyme activation results in the suppression of both phospholipid methylation and initial rise in cyclic AMP induced by receptor bridging, the proteolytic enzyme may be involved in the activation of methyltransferases and adenylate cyclase.
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PMID:Biochemical analysis of triggering signals induced by bridging of IgE receptors. 627 31

Adenosine potentiates mast cell activation, but the receptor type and molecular mechanisms involved have not been defined. We, therefore, investigated the effects of adenosine on the human mast cell line HMC-1. Both the A2a selective agonist CGS21680 and the A2a/A2b nonselective agonist 5'-N-ethylcarboxamidoadenosine (NECA) increased cAMP, but NECA was fourfold more efficacious and had a Hill coefficient of 0.55, suggesting the presence of both A2a and A2b receptors. NECA 10 microM evoked IL-8 release from HMC-1, but CGS21680 10 microM had no effect. In separate studies we found that enprofylline, an antiasthmatic previously thought to lack adenosine antagonistic properties, is as effective as theophylline as an antagonist of A2b receptors at concentrations achieved clinically. Both theophylline and enprofylline 300 micro completely blocked the release of IL-8 by NECA. NECA, but not CGS21680, increases inositol phosphate formation and intracellular calcium mobilization through a cholera and pertussis toxin-insensitive mechanism. In conclusion, both A2a and A2b receptors are present in HMC-1 cells and are coupled to adenylate cyclase. In addition, A2b receptors are coupled to phospholipase C and evoke IL-8 release. This effect is blocked by theophylline and enprofylline, raising the possibility that this mechanism contributes to their antiasthmatic effects.
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PMID:Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma. 756 91

The antiinflammatory activity of rolipram, a selective inhibitor of the cyclic AMP-specific phosphodiesterase (PDE IV), was studied. Rolipram did not inhibit 5-lipoxygenase activity but did inhibit human monocyte production of leukotriene B4 (LTB4, IC50 3.5 microM). Likewise, murine mast cell release of leukotriene C4 and histamine was inhibited. In vivo, rolipram inhibited arachidonic acid-induced inflammation in the mouse, while the low Km-cyclic-GMP PDE inhibitor, zaprinast, did not inhibit. Rolipram had a modest effect on LTB4 production in the mouse, but markedly reduced LTB4-induced PMN infiltration. Beta-adrenergic receptor activation of adenylate cyclase was important for rolipram antiinflammatory activity since beta blockade abrogated arachidonic acid-induced inflammation. Thus, the antiinflammatory profile of rolipram is novel and may result from inhibition of PMN function and perhaps vasoactive amine release and leukotriene biosynthesis. These actions may be dependent upon endogenous beta-adrenergic activity and are likely mediated through inhibition of PDE IV.
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PMID:Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response. 768 37

Adenosine activates adenylate cyclase and phospholipase C in mast cells and potentiates stimulated mediator release. To determine whether activation of adenylate cyclase is necessary for the effects of adenosine on the mast cell secretory process, a specific inhibitor of cAMP-dependent protein kinase, KT5720, was used. Antigen and adenosine each induced a rapid increase in mast cell cAMP-dependent protein kinase activity within 30 s. Preincubation with KT5720 (100 nM-10 microM) suppressed cAMP-dependent protein kinase activity and inhibited antigen-stimulated beta-hexosaminidase and leukotriene C4 releases. Adenosine retained its ability to potentiate beta-hexosaminidase release in antigen- and A23187-stimulated cells even in the presence of complete cAMP-dependent protein kinase inhibition. Mast cells rendered unresponsive to adenosine-related signals by preincubation with adenosine analogs maintained this hyporesponsiveness after incubation with KT5720. It appears that the abilities of adenosine to augment mast cell degranulation and induce receptor hyporesponsiveness are independent of changes in cAMP.
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PMID:Inhibition of protein kinase A fails to alter mast cell adenosine responsiveness. 774 Oct 46

Adenosine potentiates the stimulated release of mast cell mediators. Pharmacologic studies suggest the presence of two adenosine receptors, one positively coupled to adenylate cyclase and the other coupled to phospholipase C activation. To identify mast cell adenosine receptor subtypes, cDNAs for the A1 and A2a adenosine receptors were obtained by screening a mouse brain cDNA library with the use of PCR-derived probes. Mouse bone marrow-derived mast cell cDNA libraries were constructed and screened with the use of A1 and A2a cDNA probes, which revealed the presence of A2a, but not A1, receptor clones. A putative A2b receptor was identified by using low stringency mast cell library screening. Northern blotting of mast cell poly(A)+ RNA with the use of receptor subtype probes labeled single mRNA bands of 2.4 kb and 1.8 kb for the A2a and A2b receptors, respectively. In situ cells. An A2a receptor-specific agonist failed to enhance mast cell mediator release, which suggests that the secretory process is modulated through the A2b and/or another receptor subtype. By using RNase protection assays, we found that mast cells that had been cultured in the presence of N-ethylcarboxamidoadenosine for 24 h exhibited a decrease in both A2a and A2b receptor RNA levels. Cells that had been cultured for 1 to 2 days in the presence of dexamethasone demonstrated increased amounts of A2a receptor mRNA, but no identifiable change in A2b receptor mRNA. Mast cells possess at least two adenosine receptor subtypes that may be differentially regulated.
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PMID:Cloning of two adenosine receptor subtypes from mouse bone marrow-derived mast cells. 815 66

Neuropeptides exert a variety of putative immunomodulatory actions. Despite the molecular cloning of multiple forms of receptors for several neuropeptides with putative immunomodulatory effects, including vasoactive intestinal peptide (VIP), the related peptide pituitary adenylate cyclase-activating peptide (PACAP), the opiate peptides, tachykinins, somatostatin and corticotropin-releasing factor, it has not been reported that any of the receptor genes are expressed at significant levels in cells of the immune system. The low level of expression of these receptors and lack of knowledge concerning receptor subtype has impeded progress in understanding how neuropeptides regulate immune function. For example, it is not understood why VIP produces immunomodulatory effects at concentrations far below its receptor-binding affinity. Receptors for VIP and PACAP have recently been cloned. We show here by Northern blot analysis that the VIP/PACAP1 receptor mRNA is present in total RNA prepared from mouse spleen B- and T-lymphocytes. The VIP/PACAP1 receptor mRNA was also present in human peripheral blood lymphocytes, and in a B-lymphocyte and a myelocytic cell line. The mRNA for a second form of the receptor, the VIP/PACAP2 receptor, was not expressed at detectable levels in normal cells, but was detected in several human T-cell lines and a murine mast cell line. The results indicate that VIP/PACAP1 and perhaps VIP/PACAP2 receptors mediate the diverse effects of VIP and PACAP on immune cells.
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PMID:High levels of vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor mRNA expression in primary and tumor lymphoid cells. 874 41

We sought to establish and immunocytochemically characterize primary cultures of human conjunctival epithelial (HCE) cells, and to determine the types of receptors coupled to adenylate cyclase (AC) and phospholipase C (PLC) present on them which may be stimulated following allergic or inflammatory provocation of the tissue. HCE cells possessed the key epithelial cell surface cytokeratins AE1, AE3 and AE5. Signal transduction studies (n > or = 3), using agonists and antagonists, revealed the presence of beta 2-adrenergic (isoproterenol EC50 = 5.2 nM), prostaglandin E2 (EC50 = 168 nM) and vasoactive intestinal peptide (EC50 = 0.69 nM) receptors positively coupled to AC in HCE cells. Bradykinin (EC50 = 0.83 nM), platelet activating factor (EC50 = 4.5 nM), leukotriene C4 (EC50 = 300 nM) and histamine1 (EC50 = 3.1 microM) receptors were coupled to PLC (n = 3 for each). These data suggest that HCE cells in vivo may represent target cells for mast cell mediators and certain neurotransmitters which are released into the tear-film upon allergic provocation of the conjunctiva.
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PMID:Pharmacological analysis of mast cell mediator and neurotransmitter receptors coupled to adenylate cyclase and phospholipase C on immunocytochemically-defined human conjunctival epithelial cells. 926 68


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