UMLS:C0043167 - FACTA Search

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

Both extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) induced corticoid production (steroidogenesis) concentration-dependently in bovine adrenocortical cells (BA cells). Pertussis toxin (PTX, approx. 2 microg/ml) partially inhibited (approx. 55% inhibition) extracellular ATP (100 microM)-induced steroidogenesis in BA cells. However, PTX did not inhibit extracellular UTP (100 microM)-induced steroidogenesis. Both ATP- and UTP-induced steroidogeneses were significantly inhibited by suramin (50-200 microM). These effects were inhibited significantly by reactive blue-2 (more than 100 microM) and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (more than 100 microM). Both nucleotides (1-100 microM) induced inositol phosphates accumulation and intracellular Ca2+ mobilization, but PTX did not inhibit them. The RT-PCR procedure identified only P2Y2-receptor mRNA in BA cells. These results suggest that extracellular ATP induces steroidogenesis via a unique P2 receptor linked to PTX-sensitive guanine nucleotide-binding protein (G-protein), while extracellular UTP induces steroidogenesis via P2 receptor linked to PTX-insensitive G-protein. Thus, it was concluded that at least two different P2Y-like receptors linking to steroidogenesis exist in BA cells.
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PMID:Two different P2Y receptors linked to steroidogenesis in bovine adrenocortical cells. 1059 77

To search for inhibitory nucleotide receptors in the sympathoadrenal cell lineage of the rat, voltage-activated Ca(2+) currents were recorded in PC12 cells after differentiation with nerve growth factor. ADP and ATP, but not uridine nucleotides, reduced Ca(2+) current amplitudes and slowed activation kinetics. This effect was mediated by GTP binding proteins, as it was abolished by intracellular GDP beta S and after treatment with pertussis toxin. Furthermore, depolarizations preceding the activation of Ca(2+) currents abolished the ADP-induced slowing of activation kinetics and attenuated its inhibitory action on current amplitudes. The modulatory effect of ADP was neither altered in the presence of adenosine receptor antagonists, nor mimicked by agonists at these receptors. In addition, the action of ADP was antagonized by reactive blue 2, but not by suramin or PPADS. Nucleotides tested for their inhibitory action on Ca(2+) currents displayed the following rank order of potency: 2-methylthio-ADP > or = 2-methylthio-ATP >> ADP beta S > ADP = ATP. When P2X receptors were blocked, the P2X agonists ATP and 2-methylthio-ATP still reduced Ca(2+) currents. The P2Y1 receptor antagonists adenosine-2'-phosphate-5'-phosphate and adenosine-3'-phosphate-5'-phosphate did not alter the inhibitory action of ADP, whereas the Sp-isomer of adenosine-5'-O-(1-thiotriphosphate) and 2'- and 3'-O-(4-benzoylbenzoyl)-ATP showed significant antagonistic activity. These results demonstrate that PC12 cells express an as yet unidentified P2Y receptor with pharmacological characteristics similar to those of P2Y1. As receptor-dependent modulation of Ca(2+) channels is a key event in presynaptic inhibition, this receptor may correspond to previously described presynaptic nucleotide receptors mediating autoinhibition of sympathetic transmitter release.
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PMID:P2Y receptor-mediated inhibition of voltage-activated Ca(2+) currents in PC12 cells. 1126 62

The Boredetella pertussis wlbD gene product is a putative uridine-5-diphosphate N-acetylglucosamine (UDP-GlcNAc) 2'-epimerase involved in Band A lipopolysaccharide biosynthesis. The wlbD gene is homologous to Escherichia coli rffE (32% identical), an established UDP-GlcNAc 2'-epimerase that is involved in enterobacterial common antigen (ECA) formation. The structure of the rffE protein reveals an unexpected role for a bound sodium ion in orientating a substrate-binding alpha-helix in the enzyme active site. Whilst key active-site residues in rffE are present in the wlbD sequence, the sodium-binding residues outside the active site are absent. This raises questions about the modulation of enzyme activity in these two enzymes. The wlbD gene from B. pertussis has been cloned and overexpressed in E. coli and the resulting protein has been purified to homogeneity. In the current study, crystals of the mutant Gln339Arg wlbD enzyme have been obtained by sitting-drop vapour diffusion. Uncomplexed Gln339Arg and UDP-GlcNAc complex data sets have been collected in-house on a rotating-anode generator to 2.1 A. Combined, the data sets identify the space group as P2(1)2(1)2(1), with unit-cell parameters a = 78, b = 91, c = 125 A, alpha = beta = gamma = 90 degrees. The asymmetric unit contains two monomers and 53% solvent.
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PMID:Overexpression, purification, crystallization and data collection on the Bordetella pertussis wlbD gene product, a putative UDP-GlcNAc 2'-epimerase. 1152 28

The effects of extracellular nucleotide triphosphates on the stimulation of mucin production by airway epithelial cells were examined. The order of potency in stimulating mucin secretion in primary cultures of human tracheobronchial epithelial cells is: uridine 5'-triphosphate (UTP) approximately equal to adenosine 5'-triphosphate (ATP) approximately equal to ATP-gamma-S > uridine 5'-diphosphate approximately equal to adenosine 5'-diphosphate > alpha,beta-methylene ATP >> adenosine. However, only UTP can increase mucin gene (MUC5AC, MUC5B) expression; ATP and other analogues have no stimulatory effect. The stimulation of MUC5AC and MUC5B expression by UTP is time- and dose-dependent. A similar effect on the elevation of mucous cell population in mouse airway epithelium can be demonstrated in vivo by an intratracheal instillation of UTP-saline solution. The stimulatory effect of UTP or ATP on mucin secretion was inhibited by pertussis toxin, U73122, and Calphostin C, but not by PD98059, suggesting a G-protein/ phospholipase (PL) C/protein kinase (PK) C-dependent and mitogen-activated protein kinase (MAPK)-independent signaling pathway. However, the stimulatory effect of UTP on mucin gene expression was sensitive to pertussis toxin and PD98059, but not to Calphostin C and U73122, suggesting a G-protein/MAPK-dependent and PLC/PKC-independent signaling pathway. These findings are the first demonstration that UTP, a pyrimidine nucleotide triphosphate, can enhance both mucin secretion and mucin gene expression through different signaling pathways.
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PMID:Differential regulation of airway mucin gene expression and mucin secretion by extracellular nucleotide triphosphates. 1169 42

1. Using a Ca(2+) imaging system and fura-2 AM (5 microM) we showed that exposure of polarised monolayers of human bronchial epithelial cells (16HBE14o- cell line) to aldosterone produced a fast intracellular [Ca(2+)] ([Ca(2+)](i)) decrease, in 70 % of cells. Exposure to aldosterone (1 nM) reduced the [Ca(2+)](i) by 39 +/- 9 nM (n = 282, P < 0.0001) within 10 min, from a basal [Ca(2+)](i) of 131 +/- 19 nM (n = 282). 2. The effect of aldosterone on [Ca(2+)](i) was not affected by inhibitors of the classical genomic pathway, cycloheximide (1 microM) or spironolactone (10 microM). The aldosterone-induced [Ca(2+)](i) decrease was inhibited by thapsigargin (1 microM), pertussis toxin (24 h at 200 ng ml(-1)), the adenylate cyclase inhibitors 2',3'-dideoxyadenosine (200 microM) and MDL-12,330A hydrochloride (500 microM), and the protein kinase A inhibitor R(P)-adenosine 3',5'-cyclic monophosphorothioate (200 microM). In addition, treatment of 16HBE14o- monolayers with aldosterone (1 nM) inhibited by approximately 30 % the large and transient [Ca(2+)](i) increase induced by apical exposure to uridine triphosphate (UTP, 0.1 mM), a known secretagogue in airway epithelia. 3. Our results demonstrate for the first time that in human bronchial epithelial cells, aldosterone decreases [Ca(2+)](i) levels via a non-genomic mechanism. The hormone-induced changes to [Ca(2+)](i) involve stimulation of thapsigargin-sensitive Ca(2+)-ATPase, via G-protein-, adenylate cyclase- and protein kinase A-coupled signalling pathways.
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PMID:Rapid and non-genomic reduction of intracellular [Ca(2+)] induced by aldosterone in human bronchial epithelium. 1171 79

Dendritic cells (DC) are essential to the initiation of an immune response due to their unique ability to take-up and process Ag, translocate to lymph nodes, and present processed Ag to naive T cells. Many chemokines, chemokine receptors and other G protein-coupled receptors (GPCRs) are implicated in these various aspects of DC biology. Through microarray analysis, we compared expression levels of chemokines, their cognate receptors, and selected GPCRs in human monocytes and in vitro monocyte-derived immature and mature DC. Hierarchical clustering of gene expression clearly distinguishes the three cell types, most notably highlighting exceptional levels of expression of the GPCR GPR105 within the immature monocyte-derived DC (MDDC) gene cluster. Little or no expression was observed within the monocyte and mature MDDC cluster. Putative functionality of the GPR105 receptor was demonstrated by an observed calcium flux in immature MDDC treated with the potent GPR105 agonist, uridine 5'-diphosphoglucose (UDP-glucose), while no response to the nucleotide sugar was seen in monocytes and mature MDDC. This UDP-glucose-induced calcium response was, at least in part, pertussis toxin-sensitive. Moreover, immature MDDC from some donors treated with UDP-glucose exhibit an increase in expression of the costimulatory molecule CD86, which correlates with the intensity of the UDP-glucose-induced calcium flux. Together, these data demonstrate differential expression of GPR105 on immature and mature MDDC and suggest a role for the receptor and its agonist ligand in DC activation.
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PMID:Human immature monocyte-derived dendritic cells express the G protein-coupled receptor GPR105 (KIAA0001, P2Y14) and increase intracellular calcium in response to its agonist, uridine diphosphoglucose. 1290 97

Cysteinyl leukotrienes (cysLTs) mediate vascular leakage and bronchoconstriction through the smooth muscle-associated CysLT type 1 receptor (CysLT1R), one of at least two loosely homologous cysLT-binding G protein-coupled receptors. We previously reported that CysLT1R is expressed by cultured human mast cells (hMCs), and that priming these cells with IL-4 enhances their sensitivity to calcium flux and cytokine generation in response to cys-LTs and the nucleotide ligand, uridine diphosphate (UDP), without increasing their surface expression of CysLT1R. We now report that hMCs express the type 2 receptor for cysLTs (CysLT2R) as well, and that the amount of surface CysLT2R protein increases in response to priming with IL-4. The selective function of CysLT2R was evident based on uninhibited IL-8 secretion by IL-4-primed hMCs stimulated with cys-LTs or UDP in the presence of the selective CysLT1R antagonist MK571. MK571 did inhibit IL-5 generation, calcium flux, and phosphorylation of extracellular signal-regulated kinase. IL-8 secretion was inhibited by pertussis toxin and a selective p38 kinase inhibitor, SB203580. The CysLT2 response may permit the cys-LTs and nucleotides generated in infection and tissue injury to elicit IL-8 generation by hMCs, potentially leading to neutrophilic infiltration, a characteristic of aerosol challenge-induced late-phase responses and of sudden death associated with asthma.
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PMID:Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R. 1367 72

Nucleotides are released during vascular injury from activated platelets and broken cells, which could stimulate human neutrophils. In this study, we characterized the P2Y receptors and investigated the functional effects of extracellular nucleotides on human neutrophils. Pharmacological characterization using selective agonists and pertussis toxin revealed that human neutrophils express only functional P2Y2 receptors. However, P2Y2 receptor agonists ATP or uridine triphosphate (UTP) caused intracellular Ca2+ increases in isolated human neutrophils with an EC50 of 1 microM but failed to cause release of primary granules from human neutrophils. ATP and UTP were equally potent in causing elastase release from human neutrophils in the presence of exogenous soluble fibrinogen, whereas ADP and UDP were without effect. We investigated whether nucleotides depend on generated arachidonic acid metabolites to cause degranulation. However, phenidone and MK-886, inhibitors of the 5-lipoxygenase pathway, failed to block nucleotide-induced intracellular calcium mobilization and elastase release. ATP and UTP caused activation of p38 MAPK and ERK1/2 in human neutrophils. In addition, the inhibitors of the MAPK pathway, SB-203580 and U-0126, inhibited nucleotide-induced elastase release. We conclude that fibrinogen is required for nucleotide-induced primary granule release from human neutrophils through the P2Y2 receptor without a role for arachidonic acid metabolites. Both ERK1/2 and p38 MAPK play an important role in nucleotide-induced primary granule release from human neutrophils.
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PMID:Molecular mechanism of nucleotide-induced primary granule release in human neutrophils: role for the P2Y2 receptor. 1461 90

Mammals express nine membranous adenylyl cyclase isoforms (ACs 1-9), a structurally related soluble guanylyl cyclase (sGC) and a soluble AC (sAC). Moreover, Bacillus anthracis and Bacillus pertussis produce the AC toxins, edema factor (EF), and adenylyl cyclase toxin (ACT), respectively. 2'(3')-O-(N-methylanthraniloyl)-guanosine 5'-[gamma-thio]triphosphate is a potent competitive inhibitor of AC in S49 lymphoma cell membranes. These data prompted us to study systematically the effects of 24 nucleotides on AC in S49 and Sf9 insect cell membranes, ACs 1, 2, 5, and 6, expressed in Sf9 membranes and purified catalytic subunits of membranous ACs (C1 of AC5 and C2 of AC2), sAC, sGC, EF, and ACT in the presence of MnCl(2). N-Methylanthraniloyl (MANT)-GTP inhibited C1.C2 with a K(i) of 4.2 nm. Phe-889 and Ile-940 of C2 mediate hydrophobic interactions with the MANT group. MANT-inosine 5'-[gamma-thio]triphosphate potently inhibited C1.C2 and ACs 1, 5, and 6 but exhibited only low affinity for sGC, EF, ACT, and G-proteins. Inosine 5'-[gamma-thio]triphosphate and uridine 5'-[gamma-thio]triphosphate were mixed G-protein activators and AC inhibitors. AC5 was up to 15-fold more sensitive to inhibitors than AC2. EF and ACT exhibited unique inhibitor profiles. At sAC, 2',5'-dideoxyadenosine 3'-triphosphate was the most potent compound (IC(50), 690 nm). Several MANT-adenine and MANT-guanine nucleotides inhibited sGC with K(i) values in the 200-400 nm range. UTP and ATP exhibited similar affinities for sGC as GTP and were mixed sGC substrates and inhibitors. The exchange of MnCl(2) against MgCl(2) reduced inhibitor potencies at ACs and sGC 1.5-250-fold, depending on the nucleotide and cyclase studied. The omission of the NTP-regenerating system from cyclase reactions strongly reduced the potencies of MANT-ADP, indicative for phosphorylation to MANT-ATP by pyruvate kinase. Collectively, AC isoforms and sGC are differentially inhibited by purine and pyrimidine nucleotides.
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PMID:Differential inhibition of adenylyl cyclase isoforms and soluble guanylyl cyclase by purine and pyrimidine nucleotides. 1498 Oct 84

Most current cell-based models for examining the regulation of mucin secretion demonstrate low signal-to-noise ratios, making experimental manipulation and data interpretation difficult. Using adenosine triphosphate (ATP) as a mucin secretagogue, we have developed a model of agonist-induced mucin secretion in differentiated human bronchial epithelial cells. Mucin secretory signals were estimated using enzyme-linked lectin assay, and typical signals of 300-400% of baseline were observed in response to a 30-min exposure to ATP (100 microM). ATP and uridine triphosphate equipotently stimulated mucin secretion consistent with mediation via P2Y2 receptor activation. Suramin and AR-C118925XX, a competitive P2Y2 receptor antagonist, inhibited adenosine 5'-o-(3-thiotriphosphate) (ATP-gammaS)-induced mucin secretion. A selective Gq G-protein antagonist (GP-ANT)-2A completely abrogated ATP-gammaS-induced mucin secretion. Pertussis toxin and the G(i/o)-specific, GP-ANT-2, had no effect. The phospholipase C inhibitor, D609, and the protein kinase C inhibitor, calphostin C, substantially inhibited ATP-gammaS-induced mucin secretion. Phorbol myristate acetate also stimulated mucin secretion in a calphostin C-sensitive manner. ATP-gammaS-induced mucin secretion was inhibited by the Ca2+ chelator, 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid tetra (acetoxymethyl) ester. Ionomycin and thapsigargin both stimulated mucin secretion. Our data are broadly consistent with known G-protein-coupling and downstream signaling events associated with the P2Y2 receptor. The exceptional signal-to-noise ratios obtained using this model have permitted clear evaluation of the involvement of these mechanisms in agonist-induced mucin secretion from differentiated human bronchial epithelial cells.
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PMID:Nucleotide-mediated mucin secretion from differentiated human bronchial epithelial cells. 1523 88

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