Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of dispersed adenohypophyseal cells from intact male rats with Neuropeptide Y (NPY) or Peptide YY (YY) at 21 degrees C increased maximal 125I LHRHa binding (Bmax) by about 50%. In presence of 10(-7) M NPY, Bmax calculated from saturation isotherm curves was 15.3 +/- 1.9 fmoles x mg-1 proteins, as compared to 10 +/- 1 fmoles x mg-1 in control incubates. The increase was dose dependent with an EC50 of 6.3 +/- 1.8 10(-10) M NPY. Preincubation of the cells with pertussis toxin (PT, 15 ng/ml) for 24 h abolished the effect, suggesting coupling of NPY receptors to G alpha o or G alpha i proteins. NPY 10(-7) M inhibited basal and Forskolin 10(-5) M stimulated intracellular cyclic AMP formation by 31.9 +/- 3.4% and 30.6 +/- 2.3% respectively. Desensitization of protein kinase C by overnight preincubation of the cells with 10(-6) M phorbol ester (PMA) did not interfere with the effect of NPY. In contrast, W7, a calmodulin inhibitor, as well as H7, a protein kinase C inhibitor with a relatively wide spectrum, suppressed the effect of NPY with IC50 of 1.4 +/- 0.6 10(-6) M and 2.2 +/- 0.5 10(-5) M, respectively. Taken together, these results suggest that NPY is able to control unmasking of a cryptic LHRH receptor pool in pituitary cells by a process dependent upon both GTP binding proteins and calmodulin dependent protein kinase.
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PMID:Neuropeptide Y enhances LHRH binding to rat gonadotrophs in primary culture. 817 May 23

Human polymorphonuclear leukocytes (PMN) express receptors for complement (C) C3b and C3bi termed CR1 and CR3, respectively. The addition of PMA or fMLP to PMN enhances the capacity of these receptors to promote binding of C3b- and C3bi-coated erythrocytes. fMLP-dependent increase of the binding of these ligand-coated erythrocytes was completely abolished by prior exposure of the PMN to pertussis toxin (IAP). GTP-binding protein (Gi alpha) was ADP-ribosylated and dysfunctional by this treatment. On the other hand, PMA-dependent binding of these ligands, as well as control binding, was inhibited only slightly, if at all, by the IAP treatment. The levels of C receptor expression on cell surface were determined by flow cytometry using monoclonal antibody against CR1 and those against the alpha and beta chains of CR3 (CR3 is composed of alpha and beta chain). Upon exposure of PMN to the chemotactic factor or PMA, or upon incubation of the cells at 37 degrees C, the surface expression of CR1 and CR3 alpha was increased. IAP also blocked an fMLP-induced increase of CR1 and CR3 alpha, but did not block the temperature- or PMA-dependent increase of these receptors. Opsonized zymosan (SOZ), another ligand for CR3, also led to an increase of both CR1 and CR3 alpha. Neither PMA nor SOZ brought about an increase of the surface expression of CR3 beta, but fMLP caused a slight increase of CR3 beta in an IAP-sensitive manner. Based on the IAP-sensitivity of the receptor expression, therefore, it appears that at least two separate mechanisms are operative in the control of C receptors. In addition, the alpha and beta chains of CR3 are regulated independently. The present data offer evidence suggesting that C receptor functions are in part regulated through a GTP-binding protein via modulation of their surface expression.
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PMID:Involvement of the pertussis toxin-sensitive GTP-binding protein in regulation of expression and function of granulocyte complement receptor type 1 and type 3. 819 Jan 26

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 present study was undertaken to examine whether and what type of interaction occurs between a synthetic glucocorticoid, dexamethasone (DEX) and an opioid peptide, met-enkephalin (MENK) upon superoxide anion (O2-) release from human polymorphonuclear cells (PMN). MENK (10(-8) M) abolished suppressed O2- release from PMNs treated with 10(-7) M DEX. This was the case in unstimulated but not in PMNs stimulated with PMA. The effect of MENK was mediated through pertussis-toxin (PTX) sensitive G-protein and since it was abolished by H7 probably involves protein kinase C (PKC) as a second messenger system. Thus, MENK can abolish DEX induced suppression of O2- release from human PMNs possibly through the interaction of second messenger pathways.
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PMID:Met-enkephalin induced escape from dexamethasone immunosuppression. 824 57

Freshly isolated rat hepatocytes, loaded with the Ca2+ probe Fluo-3, responded to homologous pancreastatin with a sudden increase in free cytosolic Ca2+ ([Ca2+]i) as well as glucose release. Addition of rat pancreastatin (0.1 microM) to hepatocytes resulted in an increase in [Ca2+]i from 150 nM to 700 nM, which declined back to nearly basal values within 2-3 min. Half-maximal and maximal effects were observed at 0.3 and 100 nM pancreastatin respectively. The increase in [Ca2+]i induced by vasopressin and noradrenaline was very similar in extent (from 150 to 800 nM) to that produced by pancreastatin. Neither the alpha 1-adrenergic blocker prazosin nor the vasopressin antagonist V1 modified the increase in [Ca2+]i induced by pancreastatin. Pig pancreastatin and its 33-49 C-terminal fragment produced about 65 and 75% of the effect of homologous pancreastatin respectively. Glucose production correlated with changes in [Ca2+]i in the same order of potency: vasopressin > rat pancreastatin > pig 33-49 pancreastatin > pig 1-49 pancreastatin. The effect of pancreastatin on [Ca2+]i was decreased by 50% when Ca2+ was omitted from the medium, and totally abolished when hepatocytes were depleted of internal Ca2+ stores by preincubation without Ca2+ and with 2 mM EGTA. When hepatocytes were preincubated for 5 min with PMA, the effects of ATP and noradrenaline were prevented, and those of vasopressin and pancreastatin remained unchanged. The pretreatment of hepatocytes with pertussis toxin diminished the response to pancreastatin and vasopressin. These results suggest that pancreastatin is a new Ca(2+)-mobilizing glycogenolytic hormone acting through a specific receptor which may involve both pertussis-toxin-sensitive and -insensitive GTP-binding regulatory proteins.
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PMID:Pancreastatin increases free cytosolic Ca2+ in rat hepatocytes, involving both pertussis-toxin-sensitive and -insensitive mechanisms. 837 59

To define the intracellular activation events stimulated by leukotriene B4 (LTB4) in human monocytes, we investigated the transient increase in cytosolic free calcium levels ([Ca2+]i) elicited by this lipid mediator. Using elutriated human monocytes, LTB4 caused a dose-dependent increase in [Ca2+]i with an ED50 of 1.0 nM. The LTB4-induced [Ca2+]i response exhibited ligand selectivity, with both the diastereomer 5S-12S-diHETE and the 20-COOH LTB4 inactive at 500 nM, while 20-OH LTB4 was a partial agonist with an approximate ED50 of 10 nM. This response demonstrated stimulus-specific deactivation and was inhibited by the specific LTB4 receptor antagonist LY-223982. These results suggest that LTB4 stimulated an increase in [Ca2+]i via interaction with a defined LTB4 receptor. The inhibitory effects of pertussis toxin and PMA on the LTB4-induced [Ca2+]i suggest that a receptor-linked guanine nucleotide-binding protein and protein kinase C are involved in the regulation of the LTB4-elicited increase in [Ca2+]i. The LTB4-induced cell activation event may play a key role in the functional responses elicited by LTB4 in human monocytes.
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PMID:Human monocytes respond to leukotriene B4 with a transient increase in cytosolic calcium. 838 85

Although a weak direct stimulus of superoxide anion (O2-) production, platelet-activating factor (PAF) markedly enhances responses to chemotactic peptides (such as n-formyl-met-leu-phe, FMLP) and phorbol esters (such as phorbol myristate acetate, PMA) in human neutrophils. The mechanism of priming was explored first through inhibition of steps in the signal transduction pathway at and following PAF receptor occupation. Priming was not altered by pertussis toxin or intracellular calcium chelation, but the PAF receptor antagonist WEB 2086 and the protein kinase C (PKC) inhibitors sphinganine and staurosporine significantly inhibited the primed response. In order to study the regulation of PAF priming, the effect of PAF alone was desensitized by exposure to escalating doses of PAF prior to exposure to the secondary stimuli. The priming effect of PAF was not desensitized under these conditions. The role of PKC in desensitization was also studied. Prior exposure to PAF also desensitized the increase in membrane PKC activity evoked by a single concentration of PAF. However, when the PAF response was desensitized, PKC priming of the response to FMLP or PMA still occurred, suggesting that PKC activity may play a role in the maintenance of the primed state despite PAF desensitization. These data suggest that: (1) PAF priming is receptor- and PKC-mediated but is independent of pertussis toxin-inhibitable G-proteins or intracellular calcium, (2) during migration in vivo, neutrophils may be desensitized to the direct effects of PAF but maintain the capacity for enhanced responses to other stimuli, (3) desensitization of PAF-induced particulate PKC activity also occurs, but PAF primes PKC activity despite PAF desensitization, and (4) distinct mechanisms govern the direct and priming effects of PAF on oxidative metabolism.
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PMID:Mechanism and regulation of neutrophil priming by platelet-activating factor. 839 Oct 6

The diacylglycerol kinase inhibitor R59022 induced chemotaxis in neutrophils. The response to R59022 was primarily chemotactic and only very little chemokinetic. Pretreatment with the protein kinase C inhibitors staurosporine and AMG-C16 inhibited chemotaxis induced by R59022 indicating the involvement of protein kinase C. In contrast, chemotaxis induced by fMet-Leu-Phe was only slightly inhibited by staurosporine and AMG16. The effects of R59022 were comparable to the effects of the protein kinase C activators DiC8 and PMA and suggest an involvement of protein kinase C. Pretreatment with pertussis toxin inhibited R59022-induced migration, fMet-Leu-Phe-induced migration, and random migration. GTP gamma S, which stimulates migration of electropermeabilized neutrophils by itself, causes an additive increase of migration in electropermeabilized neutrophils stimulated with a suboptimal concentration R59022, but causes a synergistic increase of migration in cells stimulated with a suboptimal concentration fMet-Leu-Phe. The effects of GTP gamma S on migration are completely inhibited by AMG-C16. This suggests that the GTP-binding protein involved in R59022-activated migration is the G protein that is associated with random migration.
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PMID:Neutrophil chemotaxis induced by the diacylglycerol kinase inhibitor R59022. 839 81

Interferon-gamma (IFN-gamma) is a potent growth-inhibitory cytokine also endowed with differentiating activity on neural cells. Binding of IFN-gamma to its high-affinity receptor induces a rapid and transient activation of phospholipase A2 (PLA2). The mechanism coupling the IFN-gamma receptor (IFN-gamma-R) to PLA2 activation is not clearly defined, and no information is available on this mechanism in neuroblast cells. We have tested the hypothesis that GTP-binding proteins (G-proteins) may couple the IFN-gamma-R to PLA2 in the human neuroblastoma (NB) cell line LAN-5. Incubation of NB cells with IFN-gamma resulted in a rapid increase in [3H]arachidonic acid (AA) release, and this effect was blocked by pretreatment with anti-IFN-gamma antibodies. IFN-gamma-stimulated AA release was still observed in permeabilized cells that were blocked by pretreatment with anti-IFN-gamma-R antibodies. Exposure of permeabilized LAN-5 cells to guanosine 5'-[gamma-thio]triphosphate (GTP[S]), a non-hydrolysable GTP analogue, induced a dose-dependent release of [3H]AA. A non-specific nucleotide effect was excluded, since similar stimulatory effects on AA mobilization were not observed by GTP, ATP, CTP, ADP and GDP. IFN-gamma-stimulated AA release was completely blocked by the guanine nucleotide analogue that inhibits G-protein function, guanosine 5'-[beta-thio]diphosphate (GDP[S]). A role for G-proteins in IFN-gamma-R coupling to PLA2 was further supported by the inhibition of IFN-gamma-induced [3H]AA release by treatment of permeabilized cells with pertussis toxin and with the antiserum against the common alpha-subunits of G-proteins. To determine a possible contribution to AA mobilization by the phospholipase C and diacyglycerol lipase pathway or by protein kinase C activation, the effects of neomycin, a phospholipase C inhibitor, and PMA (phorbol 12-myristate 13-acetate), a direct activator of protein kinase C, were investigated. Neither neomycin nor PMA affected either basal or IFN-gamma-stimulated AA release. Ca2+ concentration, which has been shown to regulate the activity of some PLA2s, does not appear to play an important role in the regulation of the IFN-gamma-stimulated PLA2 activity, since incubating permeabilized cells in different concentrations of Ca2+ induced AA release without affecting the IFN-gamma response. Altogether, these findings suggest the existence of IFN-gamma-R, which couples a Ca(2+)-independent PLA2 activation via pertussis-toxin-sensitive G-proteins.
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PMID:Interferon-gamma-stimulated and GTP-binding-proteins-mediated phospholipase A2 activation in human neuroblasts. 839 12

The hemolytically inactive complement component complex C5b67, designated iC5b67, can signal human polymorphonuclear leukocytes (PMN) both as a pertussis toxin-inhibitable agonist for chemotaxis and as an antagonist for C5a- and FMLP-stimulated chemotaxis and superoxide production. The signaling pathways utilized by iC5b67 have been further investigated. In contrast to mastoparan, iC5b67 failed to directly activate G proteins to stimulate inositol phosphate formation in COS cells that had been transfected with G alpha 16. In COS cells co-transfected with both G alpha 16 and the C5a receptor, iC5b67 could neither activate phospholipase C nor inhibit C5a receptor-mediated activation of phospholipase C. iC5b67 stimulated GTPase activity in a membrane-enriched fraction from PMN. These data support the hypothesis that iC5b67 signals through a unique receptor, likely G protein linked, but distinct from the C5a receptor. iC5b67 was able to mobilize intracellular stores to elicit increases in intracellular Ca2+. Based on the effects of herbimycin A, wortmannin, and chelerythrine on iC5b67-induced PMN chemotaxis, iC5b67 signaling involved activation of tyrosine and phosphatidylinositol 3-kinases, but not protein kinase C. Relevant to the capacity of iC5b67 to antagonize PMN superoxide production, iC5b67 induced rapid and sustained increases in intracellular cAMP, which others have shown can inhibit superoxide formation. Although iC5b67 antagonizes C5a and FMLP receptor-mediated superoxide generation, iC5b67 had no effect on PMA-induced superoxide formation. The distinct agonist and antagonist signaling pathways activated by iC5b67 in the PMN diverge soon after initial iC5b67 receptor-mediated transduction steps.
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PMID:Signaling by hemolytically inactive C5b67, an agonist of polymorphonuclear leukocytes. 854 34


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