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)

Incubation of either C3a, C3ades Arg, or synthetic analogues of the C-terminal sequence of C3a with purified rat peritoneal mast cells resulted in a rapid and dose-dependent histamine release. The natural factors C3a and C3ades Arg were the most active of the factors tested exhibiting EC50 values of 3.3 and 2.2 microM, respectively. The corresponding 21- and 22-residue C-terminal analogues of C3a (Y21R and Y21) were less potent than intact factor exhibiting EC50 values of 10.9 and 25.1 microM, respectively. Histamine was released in a nonlytic manner and the mast cell stimulation by both natural and synthetic factors was sensitive to pertussis toxin, neuraminidase, benzalkonium chloride, and to an excess of calcium. C3a stimulated the generation of inositol polyphosphates that was inhibited by either pertussis toxin or benzalkonium chloride. The C3a anaphylatoxin also directly stimulates purified G proteins (i.e., GTPase activity) in a dose-dependent manner. The evident correlation between efficiency of C3a and C3a analogues to stimulate purified G proteins and their capacity to induce cellular histamine release led us to conclude that C3a fails to activate mast cells via a mechanism involving specific receptors on the cell. Instead, we propose that C3a either causes direct activation of G proteins of the Gi subtype, with a subsequent activation of phospholipase C, or interacts with a binding site of the cell surface specific for cationic molecules that is coupled to the G protein cascade.
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PMID:A mechanism of action for anaphylatoxin C3a stimulation of mast cells. 137 70

The neuropeptide substance P and the polyamine compound 48/80, both known to activate mast cell secretory processes, increased the rate of GTP S binding to G-proteins purified from calf brain (Go/Gi mixture). The GTPase activity of G-proteins was also increased by substance P and compound 48/80 in a dose-dependent and Mg2+-dependent way. These effects were similar to those of the wasp venom peptide mastoparan, another histamine releaser of rat peritoneal and human skin mast cells. This suggests that the secretory property of compound 48/80 and substance P is not due to a receptor-mediated process but, like mastoparan, results from a direct activation of G-proteins.
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PMID:Direct activation of GTP-binding regulatory proteins (G-proteins) by substance P and compound 48/80. 168 15

Pretreatment of purified calf brain G proteins with activated pertussis toxin or antibodies raised against the C-terminus of their alpha subunits prevented the increase in GTPase activity induced by substance P, compound 48/80 and mastoparan. These results suggest that these mast cell secretagogues activate G proteins directly via an interaction with the C-terminus of alpha subunits of G proteins by mimicking the agonist-liganded receptors.
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PMID:Interaction of substance P, compound 48/80 and mastoparan with the alpha-subunit C-terminus of G protein. 170 Nov 62

The peptide hormones bradykinin and kallidin (Lys-bradykinin), as well as their analogues [des-Arg9]-bradykinin, a selective B1 agonist, [des-Arg9,Leu8]-bradykinin, a selective B1 antagonist, and [Thi5,8,D-Phe7]-bradykinin and D-Arg0-[Hyp3,D-Phe7]-bradykinin, two selective B2 antagonists, induced rapid histamine release from purified rat peritoneal mast cells. In contrast, the N-terminal fragment bradykinin-(1-5) was inactive. These peptides also activate the GTPase activity of GTP-binding proteins (G proteins) (Go/Gi) purified from calf brain, with an order of potency identical to that observed on mast cells, [Thi5,8,D-Phe7]-bradykinin much greater than kallidin greater than bradykinin greater than D-Arg0-[Hyp3,D-Phe7]-bradykinin greater than [des-Arg9]-bradykinin greater than [des-Arg9,Leu8]-bradykinin greater than bradykinin-(1-5). This correlation suggested that G proteins are the targets of kinins in mast cells. Accordingly, the concomitant increase in inositol trisphosphates and release of histamine elicited by kinins were inhibited by pertussis toxin pretreatment of mast cells. The inhibitory effect of benzalkonium chloride showed that the G proteins involved belong to the Gi type. GTPase activity was measured in the supernatant of homogenized mast cells but not in the membranous fraction. This activity was stimulated by kinins and by the venom peptide mastoparan. The potency of peptides was similar to that observed with purified bovine G proteins. Sodium dodecyl sulfate-gel electrophoresis of mast cell supernatant revealed pertussis toxin-induced ADP-ribosylation of two proteins, in the Mr 41,000 and 40,000 range, i.e., similar to purified alpha-subunits of Gi1 and Gi2 or Gi3 subtypes. The data support the proposal that bradykinin and analogues act like mastoparan, substance P, and compound 48/80, interacting first with sialic acid residues of the cell surface and then with Gi-like proteins, inducing phospholipase C activation and intracellular calcium mobilization.
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PMID:Activation of Gi-like proteins, a receptor-independent effect of kinins in mast cells. 170 Dec 14

K(+)-channel blocker properties have been reported for mast cell-degranulating peptide (MCD) in the central nervous system, but its action mechanism in mast cells remains unknown. We studied the effect of MCD on the membrane potential of rat peritoneal mast cells using the fluorescent probe bis-oxonol. Unexpectedly, MCD induced a decrease in bis-oxonol fluorescence, in a rapid and then a slower phase, suggesting hyperpolarization of mast cells. Other K(+)-channel blockers, tetraethylammonium and 4-aminopyridine, did not significantly modify the bis-oxonol fluorescence and did not alter the effect of MCD. The late phase of bis-oxonol fluorescence decrease was inhibited by ouabain and by potassium deprivation, whereas histamine release was not affected. The first phase of putative hyperpolarization induced by MCD coincided with histamine release and with the generation of inositol polyphosphates. Prior treatment of the cells with pertussis toxin inhibited these effects of MCD. MCD stimulated the GTPase activity of purified G proteins (G0/Gi) in a concentration-dependent manner. These results indicate that the effect of MCD on mast cells is unrelated to K+ channels but that it is relevant to the activation of pertussis toxin-sensitive G proteins leading to the activation of phospholipase C. A direct interaction of MCD with G proteins is proposed, which, unlike mastoparan, does not require positive cooperativity.
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PMID:Evidence for the interaction of mast cell-degranulating peptide with pertussis toxin-sensitive G proteins in mast cells. 171 80

The guanine nucleotide-binding proteins (G proteins), which transduce hormonal and light signals across the plasma membrane, are heterotrimers composed of alpha, beta, and gamma subunits. Activation of G proteins by guanine nucleotides is accompanied by dissociation of the heterotrimer: G + alpha.beta.gamma in equilibrium alpha G + beta.gamma. Brain contains several G proteins of which the most abundant are alpha 39.beta.gamma and alpha 41.beta.gamma. We have used proteolysis by trypsin to study the functional domains of the alpha subunits. In the presence of guanosine 5'-(3-O-thio)triphosphate, trypsin removes a 2-kDa peptide from the amino terminus of these proteins (Hurley, J. B., Simon, M. I., Teplow, D. B., Robishaw, J. D., and Gilman, A. G. (1984) Science 226, 860-862; Winslow, J. W., Van Amsterdam, J. R., and Neer, E. J. (1986) J. Biol. Chem. 261, 7571-7579). Tryptic cleavage does not affect the GTPase activity of the truncated molecule nor the apparent Km for GTP. However, removal of the 2-kDa amino-terminal peptide prevents association of the alpha subunits with beta.gamma. Since the apparent substrate for pertussis toxin-catalyzed ADP-ribosylation is the alpha.beta.gamma heterotrimer, the trypsin-cleaved alpha subunit is not a substrate for the toxin. Digestion of the carboxyl terminus of alpha 39 with carboxypeptidase A prevents ADP-ribosylation by pertussis toxin but does not interfere with the formation of alpha 39.beta.gamma heterotrimers. We do not yet know whether the amino-terminal region of alpha 39 interacts with beta gamma directly or whether it is necessary to maintain a conformation of alpha 39 which is required for heterotrimer formation. Further studies are needed to define the nature of the contracts between alpha and beta gamma subunits since understanding the structural basis for their reversible interaction is fundamental to understanding their function.
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PMID:The amino terminus of G protein alpha subunits is required for interaction with beta gamma. 313 54

Phospholipase C activity, GTPase activity and cytosolic-free calcium concentration in mast cells were stimulated by compound 48/80. Accumulation of inositol phosphates in rat mast cells was stimulated by guanosine 5'-[gamma-thio]-triphosphate. Guanosine 5'-[gamma-thio]triphosphate, however, exhibited no effect upon the purified phospholipase C activity and upon phospholipase C in the mast cell homogenate. The stimulatory effect of compound 48/80 upon phospholipase C activity of intact mast cells was observed to have been well correlated with that on GTPase activity of mast cell homogenate. Compound 48/80 exhibited no effect upon the binding of radioactive guanosine 5'-[gamma-thio]triphosphate to mast cell homogenate. Phospholipase C activity was verified by the above results to become affected by compound 48/80 through guanine nucleotide-binding regulatory protein.
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PMID:Stimulation of inositol phosphate production and GTPase activity by compound 48/80 in rat peritoneal mast cells. 768 7

As part of our studies aimed at exploring the potential role(s) of protein phosphatases in mast cell signaling, we analyzed the phosphorylation status of tyrosine-containing proteins in a rat mast (RBL) cell line that expresses both native rat high affinity IgE receptors (FcepsilonRI) and functional human FcepsilonRIalpha. After FcepsilonRI aggregation, there was a rapid increase in the tyrosine phosphorylation of a number of proteins, including those of m.w. 72 and 110 kDa. Concurrent with these events, however, there was a rapid dephosphorylation of a 100-kDa protein that was constitutively phosphorylated in the unstimulated cells. Using a specific mAb, this 100-kDa protein was identified as the GTPase dynamin. Dynamin was shown to associate with the SH3 domain of the src-related tyrosine kinase p56lyn in RBL 2H3 cells both in vitro and in vivo. FcepsilonRI aggregation causes rapid internalization of the aggregated receptors via clathrin-coated pits and dynamin is known to play a role in clathrin-mediated endocytosis, so the dephosphorylation of dynamin may provide the signal for targeting the aggregated receptors to the endocytic pathway.
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PMID:Rapid dephosphorylation of the GTPase dynamin after FcepsilonRI aggregation in a rat mast cell line. 875 30

Transcription factors of the nuclear factor of activated T cells (NFAT) family play a key role in antigen receptor-mediated responses in lymphocytes by controlling induction of a wide variety of cytokine genes. The GTPases Ras and Rac-1 have essential functions in regulation of NFAT transcriptional activity in the mast cell system, where Fcepsilon receptor type 1 (FcepsilonR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcepsilonR1 activation of NFAT in mast cells. We are able to place Rac-1 in two positions in the signaling network that regulates the assembly and activation of NFAT transcriptional complexes in lymphocytes. First, we show that activity of Rac-1 is required for FcepsilonR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcepsilonR1 is a Rac-dependent but Ras-independent process. This novel signaling role for Rac-1 is distinct from its established regulation of the actin cytoskeleton. Our data also reveal a second GTPase signaling pathway regulating NFAT transcriptional activity, in which Rac-1 mediates a Ras signal. These data illustrate that the GTPase Rac-1 should now be considered as a component of the therapeutically important pathways controlling NFATC1 subcellular localization. They also reveal that GTPases may serve multiple functions in cellular responses to antigen receptor ligation.
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PMID:Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcepsilon receptor type 1 stimulation of mast cells. 968 30

Defensins are endogenous antimicrobial peptides stored in neutrophil granules. Here we report that a panel of defensins from human, rat, guinea pig, and rabbit neutrophils all have histamine-releasing activity, degranulating rat peritoneal mast cells with EC50 ranging from 70 to 2500 nM, and between 45 and 60% of the total histamine released. The EC50 for defensin-induced histamine secretion correlates with their net basic charge at neutral pH. There is no correlation between histamine release and antimicrobial potency. Degranulation induced by defensins has characteristics similar to those of activation by substance P. The maximum percent histamine release is achieved in <10 s, and it can be markedly inhibited by pertussis toxin (100 ng/ml) and by pretreatment of mast cells with neuraminidase. These properties differ from those for degranulation induced by IgE-dependent Ag stimulation and by the calcium ionophore A23187. GTPase activity, a measure of G protein activation, was induced in a membrane fraction from mast cells following treatment with defensin. Thus, neutrophil defensins are potent mast cell secretagogues that act in a manner similar to substance P and 48/80, through a rapid G protein-dependent response that is mechanistically distinct from Ag/IgE-dependent mast cell activation. Defensins may provide important pathways for communication between neutrophils and mast cells in defenses against microbial agents and in acute inflammatory responses.
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PMID:Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. 1039 91


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