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)

Leukotriene D4 (LTD4) at concentrations greater than 1 nM induced phosphatidylinositol bisphosphate (PIP2) hydrolysis and protein kinase C (PKC) activation in primary culture of airway smooth muscle cells. Within seconds of activation, an increase in inositol 1,4,5-trisphosphate (IP3) was observed reaching a maximum at 5 min. The level of IP3 decreased after 5 min and was followed by an increase in inositol 1,4-bisphosphate (IP2) and inositol 1-monophosphate (IP1). LTD4-induced PIP2 hydrolysis was inhibited by 1 h pretreatment of cells with 10 micrograms/ml of pertussis toxin (PTX). LTD4 activated both soluble and particulate forms of PKC by 2-3-fold. The LTD4-induced PKC activation was blocked by treatment of cells with PTX, suggesting the involvement of a PTX-sensitive G-protein. To assess the involvement of G(i) in smooth muscle cell receptor activation, the modulation of adenylyl cyclase activity was investigated. LTD4 did not stimulate cAMP formation in smooth muscle cells, and did not inhibit forskolin-induced cAMP formation. These data suggest that the LTD4 receptor in airway smooth muscle cells is coupled to a PTX-sensitive G-protein, possibly G(o).
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PMID:Polyphosphoinositide hydrolysis and protein kinase C activation in guinea pig tracheal smooth muscle cells in culture by leukotriene D4 involve a pertussis toxin sensitive G-protein. 133 Jun 44

The nature of the leukotriene-D4 (LTD4) induced cell shrinkage in Ehrlich ascites tumor cells has been investigated. LTD4 treatment of Ehrlich cells induces net loss of cellular KCl and cell shrinkage independent of the initial cell volume. LTD4 also produces water loss and reduction in cell volume when all extracellular and all intracellular Cl has been replaced by NO3. On the other hand, LTD4 fails to produce any significant changes in cell volume in the presence of the K-channel blocker quinine, suggesting that LTD4 in Ehrlich cells induces Cl-independent K loss through the Ca2+-dependent K channels. However, the effect of physiological doses of LTD4 on cell volume seems not to be as potent in Cl-free, NO3 cells when compared to Cl-containing cells, indicating that LTD4 in Ehrlich cells also provokes Cl-dependent K loss. LTD4 seems not to produce K loss through an electroneutral K+/H+ exchange system. LTD4 still produces Cl-independent K loss and cell shrinkage in the presence of the anti-calmodulin drug pimozide but not in the presence of the LTD4 receptor antagonist L-649,923 or the 5-lipoxygenase inhibitor NDGA. Pretreatment of the cells with pertussis toxin, which inactivates inhibitory guanine nucleotide binding proteins (G-proteins), leads to partial inhibition of the LTD4-induced shrinkage. It is suggested that the LTD4-induced activation of K and Cl transporting systems in Ehrlich ascites tumor cells is mediated via a G-protein coupled receptor and that LTD4 might exert its effect through another lipoxygenase product. The Ca2+-calmodulin complex is not involved in the LTD4-induced activation of K and Cl transporting systems.
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PMID:Leukotriene-D4 induced cell shrinkage in Ehrlich ascites tumor cells. 247 62

The growth-promoting effect of leukotriene D4 (LTD4) has been observed in a variety of cells, including human glomerular epithelial cells. The purpose of this study was to determine the mechanisms underlying this process. LTD4 induction of [3H]thymidine uptake in human glomerular epithelial cells was blocked by the LTD4 receptor antagonist L648,051 when added in a 50-fold excess and by pertussis toxin. Neither drug affected basal DNA synthesis. These results suggest that the LTD4-mediated signal transduction implies activation of a GTP-binding protein that is coupled to a specific receptor. The possible role of protein kinase C (PKC) activation was also studied. In the presence of the PKC inhibitor H-7 or after downregulation of PKC levels by chronic treatment with phorbol ester, stimulation of [3H]thymidine uptake by LTD4 was greatly inhibited. Moreover, treatment of the cells by LTD4 resulted in a time-dependent increase of cytosolic PKC activity, whereas addition of phorbol 12-myristate 13-acetate reduced this activity. Therefore PKC-dependent mechanisms are likely to mediate the growth-promoting effect of LTD4. Finally, three approaches were used to determine the potential role of the Na+-H+ exchanger. First, progressive removal of extracellular Na+ using N-methyl-D-glucamine+ as a substitute inhibited LTD4-induced [3H]thymidine uptake with a 50% inhibitory concentration (IC50) of 85 mM. Second, addition of amiloride reduced the LTD4 growth effect with an IC50 of 6.5 microM, whereas three amiloride analogues exhibited lower IC50 values in accordance with their greater affinity for the Na+-H+ exchanger.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Leukotriene D4-induced proliferation of glomerular epithelial cells: PKC- and Na+-H+ exchanger-mediated response. 254 86

A basophilic leukemic cell line from rat (RBL-1) was used to characterize leukotriene D4 (LTD4) receptor-mediated biochemical and pharmacological effects. [3H]LTD4 binding to the plasma membrane enriched preparation was stereo-selective, specific and saturable. Sodium ions and guanine nucleotides specifically regulated [3H]LTD4 binding to the membrane receptors. Leukotriene E4 (LTE4) and high affinity specific antagonists bound to the receptor with a rank-order potency equivalent to that for the LTD4 receptors in guinea pig lung. In the [3]myoinositol labeled RBL-1 cells, LTD4 and LTE4 induced a rapid hydrolysis of [3H]phosphoinositides. The biosynthesis of the [3H]inositol-trisphosphate was rapid and was detectable at 15-sec poststimulation. The biosynthesis of [3H]inositol-monophosphate was stereo-selective and specific and was inhibited specifically by receptor antagonists. In fura-2 loaded RBL-1 cells, LTD4 and LTE4 induced a transient intracellular Ca++ mobilization. Agonist-induced Ca++ mobilization was specific and stereo-selective and was inhibited by specific receptor antagonists. The most (greater than 85%) LTD4-induced immediate response of Ca++ mobilization was from intracellular sources, whereas a small amount (less than 15%) was derived from the extracellular milieu. Both components were stimulated by receptor agonists and inhibited by the receptor antagonists, suggesting that they were regulated by the LTD4 membrane receptors. In addition, the results also suggested that a guanine nucleotide binding protein, insensitive to islet activating protein from Bordetella pertussis (not Gi or Go), was involved in the signal transduction mechanisms for LTD4 receptors in RBL-1 cells. These results suggested that the plasma membrane enriched LTD4 receptor was coupled via an islet activating protein insensitive G protein to a phosphoinositide specific phospholipase C. Agonist binding to the receptor could activate phospholipase C and resulted in phosphoinositide hydrolysis. Diacylglycerol and inositol trisphosphate could function as intracellular messengers that trigger or contribute to calcium mobilization in RBL-1 cells.
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PMID:Leukotriene D4 receptor-mediated phosphoinositol hydrolysis and calcium mobilization in rat basophilic leukemic cells. 284 29

The C6-sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) evoked increases in the cytosolic concentration of intracellular calcium ([Ca+2]i) in dimethylsulfoxide-differentiated HL-60 cells, as assessed by the fluorescence of quin-2. The increases in [Ca+2]i reached a peak within 15-90 s, attained 50% of the maximum level at 1.2 nM LTD4 and 60 nM LTC4, were greater in maximal magnitude for LTD4 than LTC4, and subsided in 5-7 min. Flow cytometric evaluation of the LTD4-induced increases in [Ca+2]i, reflected in increases in the fluorescence of intracellular indo-1, revealed that a mean of 77% of differentiated HL-60 cells responded, as contrasted with lesser increases in only 50% of undifferentiated HL-60 cells. The capacity of pretreatment of HL-60 cells with LTD4 to prevent subsequent responses of [Ca+2]i to LTC4 and LTD4, and the finding that the serine-borate inhibitor of conversion of LTC4 to LTD4 suppressed concurrently both LTC4-induced rises in [Ca+2]i and increases in adherence to Sephadex G-25 indicated that the responses of HL-60 cells to LTC4 required conversion to LTD4. That pertussis toxin and a chemical antagonist of LTD4 reduced the [Ca+2]i response suggested a dependence on LTD4 receptors. The LTD4-induced increases in [Ca+2]i were dependent on extracellular calcium and diminished by lanthanum, but not affected by nifedipine nor associated with changes in membrane potential, as measured with the fluorescent probe 3,3'-dipentyloxacarbocyanine. Thus, the increase in [Ca+2]i in HL-60 cells, which is coupled to an increase in adherence, appears to involve LTD4 receptor-specific and voltage-independent calcium channels in the plasma membrane.
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PMID:Stimulation by leukotriene D4 of increases in the cytosolic concentration of calcium in dimethylsulfoxide-differentiated HL-60 cells. 347 71

The cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory disorders, in particular asthma, for which the CysLT receptor antagonists pranlukast, zafirlukast, and montelukast, have been introduced recently as novel therapeutics. Here we report on the molecular cloning, expression, localization, and pharmacological characterization of a CysLT receptor (CysLTR), which was identified by ligand fishing of orphan seven-transmembrane-spanning, G protein-coupled receptors. This receptor, expressed in human embryonic kidney (HEK)-293 cells responded selectively to the individual CysLTs, LTC(4), LTD(4), or LTE(4), with a calcium mobilization response; the rank order potency was LTD(4) (EC(50) = 2.5 nM) > LTC(4) (EC(50) = 24 nM) > LTE(4) (EC(50) = 240 nM). Evidence was provided that LTE(4) is a partial agonist at this receptor. [(3)H]LTD(4) binding and LTD(4)-induced calcium mobilization in HEK-293 cells expressing the CysLT receptor were potently inhibited by the structurally distinct CysLTR antagonists pranlukast, montelukast, zafirlukast, and pobilukast; the rank order potency was pranlukast = zafirlukast > montelukast > pobilukast. LTD(4)-induced calcium mobilization in HEK-293 cells expressing the CysLT receptor was not affected by pertussis toxin, and the signal appears to be the result of the release from intracellular stores. Localization studies indicate the expression of this receptor in several tissues, including human lung, human bronchus, and human peripheral blood leukocytes. The discovery of this receptor, which has characteristics of the purported CysLT(1) receptor subtype, should assist in the elucidation of the pathophysiological roles of the CysLTs and in the identification of additional receptor subtypes.
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PMID:Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. 1046 54

We investigated the role of cysteinyl leukotriene (CysLT) receptors on leukotriene D(4)-induced actin reorganization and the signaling pathways of the response in human bronchial smooth muscle cells. The effects of leukotriene D(4) on actin reorganization in human bronchial smooth muscle cells were evaluated by dual-fluorescence labeling of filamentous (F) and monomeric (G) actin with fluorescein isothiocyanate (FITC)-labeled phalloidin and Texas Red-labeled DNase I, respectively. Leukotriene D(4) (100 nM) induced actin reorganization in the presence and absence of extracellular Ca(2+). The CysLT type 1 (CysLT(1)) receptor antagonist ONO 1078 (4-oxo-8(-)[p-(4-phenylbutyloxy) benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) inhibited leukotriene D(4)-induced actin reorganization. Pretreatment with pertussis toxin, C3 exoenzyme, or tyrosine kinase inhibitors significantly reduced leukotriene D(4)-induced actin reorganization. However, phosphatidylinositol-3-kinase and protein kinase C inhibitors had little effect on these responses. These results suggest that leukotriene D(4)-induced actin reorganization in human bronchial smooth muscle cells is extremely dependent on the CysLT(1) receptor coupled with pertussis toxin-sensitive G protein, Rho GTPases and tyrosine phosphorylation pathways.
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PMID:Leukotriene D(4)-induced Rho-mediated actin reorganization in human bronchial smooth muscle cells. 1122 89

We report the identification of an EST encoding a murine cysteinyl leukotriene (mCysLT) receptor. LTD4, LTC4 and LTE4 but not LTB4 or various nucleotides activated Ca2+-evoked Cl- currents in mCysLT1 expressing Xenopus laevis oocytes. The response to LTD4 was blocked by MK-571, reduced by pretreatment with pertussis toxin (PTX), and was partly dependent on extracellular Ca2+. The identified murine CysLT1 receptor differs from the hCysLT1 receptor with regard to PTX sensitivity, receptor-mediated Ca2+ influx, and antagonist sensitivity.
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PMID:Identification of a murine cysteinyl leukotriene receptor by expression in Xenopus laevis oocytes. 1134 26

Recent studies suggest that bone marrow (BM)-derived chemotactic mediators such as chemokines play key roles in hematopoietic stem cell trafficking. Lipid mediators, particularly leukotrienes, are involved in leukocyte chemotaxis during inflammation but have also been detected in the normal BM. Therefore, the effects of leukotrienes on hematopoietic progenitor cells were analyzed. Cysteinyl leukotrienes, particularly leukotriene D4 (LTD4), induced strong intracellular calcium fluxes and actin polymerization in mobilized and BM CD34(+) progenitors. Chemotaxis and in vitro transendothelial migration of CD34(+) and more primitive CD34(+)/CD38(-) cells were 2-fold increased by LTD4 at an optimum concentration of 25 to 50 nM. Accordingly, CD34(+) cells expressed the 7-transmembrane LTD4 receptor CysLT1 by reverse transcriptase-polymerase chain reaction and Western blot. Effects of LTD4 were suppressed by the CysLT1 receptor antagonist MK-571 and reduced by pertussis toxin. In contrast, LTB4 induced strong responses only in mature granulocytes. LTD4-induced calcium fluxes were also observed in granulocytes but were not reduced by MK-571, suggesting that these effects were mediated by other receptors (eg, CysLT2) rather than by CysLT1. In addition, expression of 5-lipoxygenase, the key enzyme of leukotriene biosynthesis, was detected in both hematopoietic progenitor cells and mature leukocytes. The study concludes that the functionally active LTD4 receptor CysLT1 is preferentially expressed in immature hematopoietic progenitor cells. LTD4 released in the BM might regulate progenitor cell trafficking and could also act as an autocrine mediator of hematopoiesis. This would be a first physiologic effect of cysteinyl leukotrienes apart from the many known pathophysiologic actions related to allergy and inflammation. (Blood. 2001;97:3433-3440)
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PMID:Chemotaxis and transendothelial migration of CD34(+) hematopoietic progenitor cells induced by the inflammatory mediator leukotriene D4 are mediated by the 7-transmembrane receptor CysLT1. 1136 34

We investigated whether cysteinyl leukotrienes (cysLT) are intracrine signal transducers that regulate human eosinophil degranulation mechanisms. Interleukin (IL)-16, eotaxin, and RANTES stimulate vesicular transport-mediated release of preformed, granule-derived IL-4 and RANTES from eosinophils and the synthesis at intracellular lipid bodies of LTC(4), the dominant 5-lipoxygenase-derived eicosanoid in eosinophils. 5-Lipoxygenase inhibitors blocked IL-16-, eotaxin-, and RANTES-induced IL-4 release; but neither exogenous LTC(4), LTD(4), nor LTE(4) elicited IL-4 release. Only after membrane permeabilization enabled cysLTs to enter eosinophils did LTC(4) and LTD(4) stimulate IL-4, but not RANTES, release. LTC(4)-elicited IL-4 release was pertussis toxin inhibitable, but inhibitors of the two known G protein-coupled cysLT receptors (cysLTRs) (CysLT1 and CysLT2) did not block LTC(4)-elicited IL-4 release. LTC(4) was 10-fold more potent than LTD(4) and at low concentrations (0.3-3 nM) elicited, and at higher concentrations (>3 nM) inhibited, IL-4 release from permeabilized eosinophils. Likewise with intact eosinophils, LTC(4) export inhibitors, which increased intracellular LTC(4), inhibited eotaxin-elicited IL-4 release. Thus, LTC(4) acts, via an intracellular cysLTR distinct from CysLT1 or CysLT2, as a signal transducer to selectively regulate IL-4 release. These results demonstrate that LTC(4), well recognized as a paracrine mediator, may also dynamically govern inflammatory and immune responses as an intracrine mediator of eosinophil cytokine secretion.
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PMID:Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion. 1223 16


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