Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In membranes of myeloid differentiated HL 60 cells, the chemotactic peptide FMLP stimulates phospholipase C via a pertussis toxin-sensitive G protein. FMLP markedly stimulates the cholera toxin-dependent ADP-ribosylation of a 40 kDa protein in these membranes. This effect of FMLP is inhibited by GTP and GTP[S], and is almost completely abolished in membranes of pertussis toxin-pretreated HL 60 cells. Treatment of HL 60 membranes with cholera toxin and NAD markedly inhibits FMLP-stimulated high affinity GTPase. These results suggest that a 40 kDa G protein sensitive to both pertussis and cholera toxin functionally interacts with the formyl peptide receptor of HL 60 cells and, thus, very likely is the G protein that stimulates phospholipase C in this system.
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PMID:Receptor-mediated ADP-ribosylation of a phospholipase C-stimulating G protein. 311 66

Diacylglycerol has gained wide acceptance as an important second messenger in the signal transduction mechanism by which occupancy of certain membrane receptors such as the formyl peptide receptor of neutrophils leads to biological responses, but supporting evidence for this proposed role is limited. We have utilized a recently developed diacylglycerol kinase assay (Preiss, J. E., Loomis, C. R., Bishop, W. R., Stein, R., Niedel, J. E., and Bell, R. M. (1986) J. Biol. Chem. 261, 8597-8600) to characterize the diacylglycerol response of normal human neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and other formyl peptides. fMLP alone stimulated a slow, prolonged 36% rise in diacylglycerol levels above basal levels. Cytochalasin B enhances several fMLP-stimulated neutrophil responses, including aggregation, superoxide production, and degranulation. Pretreatment of neutrophils with cytochalasin B markedly increased the rate and extent of the diacylglycerol response to fMLP stimulation. Diacylglycerol peaked at 5 min at 206 +/- 21% above basal levels with a t1/2 of 45 s. The diacylglycerol response was time- and fMLP and cytochalasin B concentration-dependent, appropriate for the known biological activities of several peptide analogues, and completely inhibited by pretreatment with pertussis toxin. These data demonstrate that diacylglycerol may function as a second messenger for neutrophil activation and suggest that cytochalasin B enhancement of neutrophil biology may be the result of an enhanced diacylglycerol response.
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PMID:Cytochalasin B enhancement of the diacylglycerol response in formyl peptide-stimulated neutrophils. 378 96

Binding of FMLP to the neutrophil N-formyl peptide receptor (FPR) transmits signals through pertussis toxin-sensitive G proteins triggering Ca2+ flux, superoxide production, granule exocytosis, and neutrophil aggregation and adhesion involving the beta 2 (CD18) integrins. Expression of the FPR in mouse fibroblasts or human kidney cells has been shown to confer an N-formyl peptide-inducible Ca2+ flux in transfectants. Here we demonstrate that the transfected receptor can also support ligand-induced alterations in cellular adhesion. We established stable transfectants of mouse L1-2 pre-B cells with cDNA for human FPR (L1-2 FPR cells). The transfectants bind N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein with 1.4 x 10(5) sites per cell and a dissociation constant of 3.3 nM. Stimulation with FMLP induces a transient Ca2+ flux. FMLP also triggers adhesion of L1-2 FPR cells to TNF-alpha- or LPS-activated bEnd3 cells (mouse brain-derived endothelial cells) and to purified mouse VCAM-1. Binding is inhibited by Abs to VCAM-1 and to the alpha-chain of its lymphocyte receptor (the alpha 4 beta 1 integrin, VLA-4). Stimulation with FMLP does not induce a change in cell surface expression of alpha 4. Induced adhesion to VCAM-1 is rapid, detectable at the earliest times measurable (30 to 60 s after FMLP addition), and is inhibited by pertussis toxin. We conclude that FPR can mediate integrin activation not only in neutrophils but also in lymphocytes, and can trigger rapid adhesion via lymphocyte alpha 4 beta 1. The adhesion of lymphocytes is critical to their migration and targeting; our results suggest the possibility of manipulating adhesive responses through expression of chemoattractant receptors in lymphoid cells engineered for cellular therapy, allowing targeted adhesion and potentially migration in response to locally administered ligands.
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PMID:Ligand-induced adhesion to activated endothelium and to vascular cell adhesion molecule-1 in lymphocytes transfected with the N-formyl peptide receptor. 751 63

We have previously shown that the S-prenylated cysteine analogue N-acetyl-S-trans,trans-farnesyl-L-cysteine (L-AFC) inhibits basal and formyl peptide receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) to and hydrolysis of GTP by membranes of HL-60 granulocytes and have presented evidence suggesting that this inhibition was not caused by reduced protein carboxyl methylation [Scheer, A., & Gierschik, P. (1993) FEBS Lett. 319, 110-114]. We now report a detailed analysis of the structural properties of S-prenylated cysteine analogues required for this inhibition and demonstrate that S-prenylcysteines also suppress basal and receptor-stimulated GTP[S] binding to human peripheral neutrophil and HL-60 granulocyte membranes when stimulated by formyl peptide and complement C5a, respectively. S-Prenylcysteines did not affect pertussis toxin-mediated [32P]ADP-ribosylation of Gi proteins. The inhibitory effect of L-AFC was reversible and was not mimicked by farnesylic acid. L-AFC also interfered with GTP[S] binding to retinal transducin when stimulated by light-activated rhodopsin in a reconstituted system. This inhibitory effect was fully reversed upon increasing the concentration of either the G protein beta gamma dimer or the activated receptor. On the basis of these results, we suggest that S-prenylated cysteine analogues like L-AFC inhibit receptor-mediated G protein activation by specifically and reversibly interfering with the interaction of activated receptors with G proteins, most likely with their beta gamma dimers, rather than by inhibiting alpha.beta gamma heterotrimer formation.
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PMID:S-prenylated cysteine analogues inhibit receptor-mediated G protein activation in native human granulocyte and reconstituted bovine retinal rod outer segment membranes. 771 Oct 17

The hypothesis that disparate neutrophil functional responses to various chemoattractants are regulated by receptor-specific rates of G protein activation was examined in HL-60 granulocytes. The initial rates of G protein activation and the affinity of receptor-stimulated G proteins for GTP gamma S in HL-60 membranes stimulated by fMet-Leu-Phe, C5a, and leukotriene B4 (LTB4) differed significantly among the chemoattractants, with a rank order of fMet-Leu-Phe > C5a > LTB4. Equilibrium GTP gamma S binding showed that all three chemoattractants activated a common pool of G proteins. Stimulation of phospholipase D activation, measured as phosphatidylethanol generation, and superoxide release in intact cells also occurred with a rank order of fMet-Leu-Phe > C5a > LTB4. On the other hand, the rank order of receptor affinities for ligand and of the EC50 of chemoattractant stimulation of GTP gamma S binding was C5a > LTB4 > fMet-Leu-Phe. C5a and LTB4 receptor densities were similar but were less than formyl peptide receptor density. Graded pertussis toxin treatment proportionally reduced superoxide release and phospholipase D activation to all three chemoattractants. The results suggest that receptor-specific differences in G protein affinity for guanine nucleotides lead to different rates of guanine nucleotide exchange and, thereby, contribute to disparate effector enzyme and functional responses.
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PMID:Chemoattractant receptor-specific differences in G protein activation rates regulate effector enzyme and functional responses. 772 25

TNF-alpha enhances the response of polymorphonuclear leukocytes (PMN) to chemoattractants: however, the mechanism by which this occurs is unclear. We addressed the hypothesis that TNF-alpha enhances the PMN response to chemoattractants by increasing chemoattractant receptor transmembrane signaling, using fMLP as the model chemoattractant. fMLP-stimulated guanine nucleotide binding (G) protein activation was significantly increased in plasma membranes isolated from PMNs exposed to TNF-alpha 100 U/ml for 10 minutes (TNF-M), compared to membranes from control cells (CM). Formyl peptide receptor number and affinity were not significantly different in CM and TNF-M. Gi and Gs content were increased in TNF-M as measured by pertussis toxin and cholera toxin (CT) catalyzed ADP-ribosylation, respectively. The increased Gi was coupled to the formyl peptide receptor as shown by receptor-specific CT labeling of Gi. Immunoblot analysis showed that both G alpha i2 and G alpha 3 were increased in TNF-M. The functional activity of the increased G protein content was demonstrated by increased NaF-stimulated phospholipase D activity in TNF-alpha-treated PMNs. We conclude that TNF-alpha rapidly stimulates increased PMN plasma membrane expression of G proteins that couple formyl peptide receptors to effector enzymes. Regulation of G protein expression may be a significant mechanism by which TNF regulates PMN function.
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PMID:TNF-alpha stimulates increased plasma membrane guanine nucleotide binding protein activity in polymorphonuclear leukocytes. 788 23

The wasp venom, mastoparan (MP), activates reconstituted pertussis toxin (PTX)-sensitive G-proteins in a receptor-independent manner. We studied the effects of MP and its analogue, mastoparan 7 (MP 7), on G-protein activation in HL-60 cells and a reconstituted system and on nucleoside diphosphate kinase (NDPK)-catalysed GTP formation. MP activated high-affinity GTP hydrolysis in HL-60 membranes with an EC50 of 1-2 microM and a maximum at 10 microM. Unlike the effects of the formyl peptide receptor agonist, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), on GTPase, those of MP were only partially PTX-sensitive. MP-induced rises in cytosolic Ca2+ concentration and superoxide-anion formation in intact HL-60 cells were also only incompletely PTX-sensitive. N-Ethylmaleimide inhibited MP-stimulated GTP hydrolysis to a greater extent than that stimulated by fMet-Leu-Phe. Unlike the latter, MP did not enhance incorporation of GTP azidoanilide into, and cholera toxin-catalysed ADP-ribosylation of, Gi-protein alpha-subunits in HL-60 membranes. By contrast to fMet-Leu-Phe, MP did not or only weakly stimulated binding of guanosine 5'-[gamma-thio]triphosphate to Gi-protein alpha-subunits. MP 7 was considerably more effective than MP at activating the GTPase of reconstituted Gi/G(o)-proteins, whereas in HL-60 membranes, MP and MP 7 were similarly effective. MP and MP 7 were similarly effective at activating [3H]GTP formation from [3H]GDP and GTP in HL-60 membranes and by NDPK purified from bovine liver mitochondria. Our data suggest the following: (1) MP activates Gi-proteins in HL-60 cells, but (2) the venom does not simply mimic receptor activation. (3) MP and MP 7 may activate GTP hydrolysis in HL-60 membranes indirectly through interaction with NDPK. (4) MP 7 is a more effective direct activator of PTX-sensitive G-proteins than MP, whereas with regard to NDPK, MP and MP 7 are similarly effective.
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PMID:Mastoparan may activate GTP hydrolysis by Gi-proteins in HL-60 membranes indirectly through interaction with nucleoside diphosphate kinase. 799 71

The hypothesis that protein kinase C (PKC) participates in agonist-mediated desensitization of formyl peptide receptors in HL-60 granulocytes was tested. fMet-Leu-Phe and leukotriene B4(LTB4) produced homologous desensitization of agonist-stimulated intracellular calcium transients. Pre-treatment with the PKC activator, phorbol myristate acetate (PMA; 10 nM), abolished both fMet-Leu-Phe and LTB4-stimulated calcium transients. Membranes prepared from control HL-60 granulocytes (NM) or cells treated with 10 nM PMA (PMA-M) demonstrated increased formyl peptide receptor and G protein density, as determined by radioligand binding and pertussis toxin- and cholera toxin-catalysed ADP ribosylation. fMet-Leu-Phe stimulation of guanosine 5'-[gamma-thio]-triphosphate (GTP gamma S) binding and GTP hydrolysis and GDP inhibition of fMet-Leu-Phe binding were not different between NM and PMA-M. Pre-treatment with 10 nM PMA did not inhibit subsequent fMet-Leu-Phe-stimulated superoxide generation or phospholipase D activation. We conclude that PKC desensitizes fMet-Leu-Phe-stimulated phospholipase C, but not phospholipase D, responses and that PKC activation does not mediate agonist-induced desensitization of formyl peptide receptors.
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PMID:Desensitization by protein kinase C activation differentially uncouples formyl peptide receptors from effector enzymes in HL-60 granulocytes. 813 77

Differentiated HL60 cells respond to challenge with ligand by mobilizing intracellular second messengers, resulting in superoxide production, degranulation, and actin polymerization with subsequent chemotaxis and phagocytosis. The functional capabilities of undifferentiated HL60 cells have not been similarly characterized due to the absence of the cell surface receptors required to initiate these processes. To investigate these properties, undifferentiated HL60 cells were transfected with one of the better characterized neutrophil chemotactic receptors, the N-formyl peptide receptor (FPR). Expression of the recombinant FPR gene product in FPR-transfected HL60 cells and the absence of the endogenous FPR in vector-transfected HL60 cells was demonstrated by Northern blot and flow cytometric analyses. FPR-transfected HL60 cells retained their ability to undergo granulocytic differentiation with dibutyryl cAMP, as determined by FMLP- and PMA-stimulated superoxide production. Furthermore, incubation of FPR-transfected HL60 cells for 5 days in the presence of FMLP resulted in limited differentiation as evidenced by the expression of functional C5a receptors. Binding studies of FPR-transfected HL60 cells demonstrated the presence of two binding affinities with dissociation constants of 0.6 and 33 nM, similar to dibutyryl cAMP differentiated HL60 cells and human neutrophils but contrasting the single high affinity state of the FPR expressed in mouse L cell fibroblasts. FPR-transfected HL60 cells displayed FMLP-dependent calcium mobilization with an EC50 of 3 nM and actin polymerization with an EC50 of approximately 10 nM. Actin polymerization was not observed in FPR-transfected L cell fibroblasts or undifferentiated vector-transfected HL60 cells. Both calcium mobilization and actin polymerization were sensitive to treatment with pertussis toxin, indicating the requirement for a Gi-like protein. Stimulation of either undifferentiated or differentiated HL60 cells with ATP resulted in pertussis toxin-insensitive calcium mobilization but was ineffective in producing actin polymerization. The results described herein show for the first time that undifferentiated HL60 cells can respond to chemoattractant receptor stimulation with many of the properties of the mature neutrophil. Transfected HL60 cells will provide an excellent system to study the characteristics of chemotactic receptors as well as the functional properties of myeloid cells.
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PMID:Signal transducing properties of the N-formyl peptide receptor expressed in undifferentiated HL60 cells. 822 56

The rabbit neutrophil N-formyl peptide receptor (FPR) has been well studied for its ligand binding properties. Recent gene cloning experiments have established the existence of a subfamily of G protein-coupled receptors that share extensive sequence homology with the FPR, yet lack the capability of high affinity binding to FMLP. These findings prompted us to identify the structural requirement for formyl peptide ligand binding by delineation of the primary structure of the rabbit FPR. A rabbit neutrophil cDNA library was screened with a cloned human FPR cDNA probe and the insert of one positive isolate (B6) was sequenced. The 1268-bp cDNA insert encodes a peptide of 352 amino acids. Stably transfected L cell fibroblasts expressing the rabbit cDNA displayed specific binding of the ligand fMet-Leu-[3H]Phe with two affinities (Kd = 0.31 and 7.5 nM). Addition of the nonhydrolyzable guanosine triphosphate analogue, GTP gamma S, converted > or = 85% of the high affinity sites to the low affinity sites. FMLP induced mobilization of intracellular calcium in the transfected cells (EC50 = 0.5 nM), a response sensitive to pertussis toxin. FMLP stimulation desensitized the receptor such that subsequent stimulation with the same ligand produced a significantly reduced signal. These results indicate that the cloned rabbit receptor represents a high affinity FPR, and that FPR-mediated early signal transduction events can be fully reconstituted in transfected mammalian cells. The rabbit FPR sequence is 78% identical to that of the human FPR, and 68% identical to FPR2, a homologue of FPR with a low binding affinity (Kd > or = 400 nM) for FMLP. Analysis of the aligned sequences of these three proteins revealed that: 1) the amino termini and the second extracellular loops have the lowest sequence homology; 2) sequence in the intracellular domains that couple to G protein are highly conserved; and 3) the first and the third extracellular loops and their adjacent transmembrane domains of the FPR may contain residues essential for the high affinity binding of FMLP.
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PMID:The rabbit neutrophil N-formyl peptide receptor. cDNA cloning, expression, and structure/function implications. 843 84


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