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)

The present studies indicate that 50 nM-10 microM-staurosporine increased cytosolic free Ca2+ concentrations ([Ca2+]i) of fura-2-loaded neutrophils in a non-linear manner. The rise in [Ca2+]i was rapid, reaching a plateau (e.g. to 0.4 microM with 1 microM-staurosporine) within 30 s, and was maintained for more than 20 min. Pretreating cells with pertussis toxin had no effect on this reaction. The elevation of [Ca2+]i was insensitive to extracellular Ca2+ concentrations and was due entirely to mobilization of intracellular Ca2+ stores. Mn(2+)-quench studies confirmed the absence of Ca2+ influx. No Ca2+ efflux occurred in staurosporine-treated cells. In combination studies, staurosporine potentiated Ca2+ influx induced by N-formylmethionyl-leucyl-phenylalanine (FMLP) and did not block Ca2+ efflux associated with peptide stimulation of neutrophils. Studies with permeabilized cells showed that staurosporine did not directly release intracellular Ca2+ stores, nor did it affect the sequestration of Ca2+ by a Ca2+/ATPase pump. A radioligand-binding assay failed to detect changes in the level of inositol 1,4,5-trisphosphate in neutrophils incubated with less than or equal to 1 microM-staurosporine, but in cells treated with 10 microM-staurosporine the assay recorded a transient increase in this second messenger similar to that induced by FMLP. Finally, lysozyme, but not beta-glucuronidase, was released from staurosporine-treated cells. The present results suggest that staurosporine increased [Ca2+]i by indirectly mobilizing internal Ca2+ stores. Staurosporine suppression of Ca2+ efflux and generation of a persistent signal may account for the maintained elevation of [Ca2+]i.
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PMID:Staurosporine clamps cytosolic free Ca2+ concentrations of human neutrophils. 157 94

Lysophosphatidylcholine (lyso-PC), a natural product of phospholipase A2 activity, induced the secretion of both granule-associated beta-hexosaminidase and newly generated leukotriene C4 from mouse bone marrow-derived mast cells. Micromolar concentrations of lyso-PC potentiated the release of beta-hexosaminidase induced by specific antigen but not the calcium ionophore, A23187. Exogenous adenosine was relatively ineffective in enhancing beta-hexosaminidase release from cells challenged with lyso PC. Lyso-PC caused a marked increase in intracellular free-calcium levels and induced the activation of protein kinase C (PKC). These effects could not be abrogated by a prolonged preincubation with pertussis toxin. Staurosporine, an inhibitor of PKC, partially inhibited the abilities of antigen and A23187 to induce beta-hexosaminidase release but was ineffective when lyso-PC was the secretagogue. Lyso-PC appears to activate mast cell PKC, but its ability to stimulate mast cell mediator release appears to be related to its ability to elevate intracellular free calcium concentrations.
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PMID:Lysophosphatidylcholine induces mast cell secretion and protein kinase C activation. 183 66

Recombinant monocyte-chemotactic and activating factor (rMCAF; alternative acronyms MCP-1, TDCF, human JE) induced migration of human monocytes across polycarbonate or nitrocellulose filters. Maximal induction of migration was observed at a concentration of 10 ng/ml (10(-9) M). Checkerboard analysis revealed that rMCAF elicited true gradient-dependent chemotactic migration, although a gradient independent chemokinetic effect was observed at low concentrations (1-5 ng/ml). rMCAF caused a rapid (less than 5 s) and transient (approximately 1.5 min) increase of free cytosolic Ca2+ ions, as assessed by the fura-2 probe. No Ca2+ increase was detected in neutrophils or lymphocytes stimulated by rMCAF. Studies conducted in the absence of extracellular Ca2+ or in the presence of Ni2+ (an inhibitor of Ca2+ influx) suggested that the increase of intracellular Ca2+ induced by rMCAF is dependent on the influx of extracellular Ca2+ through plasma membrane channels. Bordetella pertussis toxin inhibited the intracellular Ca2+ elevation and chemotaxis caused by rMCAF. The possible involvement of Ca(2+)-dependent protein kinases in rMCAF signaling pathway(s) was explored using inhibitors. Inhibitors of GMP-dependent kinase and myosin L chain kinase had no effect on rMCAF-induced monocyte migration. In contrast, protein kinase C/cAMP-dependent kinase inhibitors (such as, C-I, H-7, HA-1004, KT5720, and Staurosporine) markedly decreased rMCAF induced chemotaxis suggesting the involvement of a serine/threonine protein kinase, possibly protein kinase C, in rMCAF signaling pathway.
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PMID:The signal transduction pathway involved in the migration induced by a monocyte chemotactic cytokine. 191 57

We have previously reported that serum amyloid A (SAA) induces adhesion and chemotaxis of human monocytes and polymorphonuclear neutrophils, in vitro as well as in vivo. Since the mechanism of SAA signaling is unknown, we have investigated the possibility that SAA, like other chemoattractants such as the chemotactic peptide FMLP and chemokines, might induce migration of monocytes by G protein activation. We report here that preincubation of monocytes with pertussis toxin (PTx) inhibited SAA chemotaxis, while incubation with cholera toxin (CTx) did not. Staurosporine and H-7, both inhibitors of protein kinase C (PKC), significantly decreased rSAA-induced chemotaxis of monocytes, suggesting that PKC may be involved in the rSAA signaling pathway. Moreover, rSAA, at concentrations that were effective in chemoattracting monocytes, resulted in transient elevation of cytoplasmic calcium concentration ([Ca2+]i), and incubation of cells with PTx markedly inhibited the mobilization of Ca2+ in response to rSAA. This suggests that both chemotaxis and the rise in [Ca2+]i, are mediated by G proteins of the Gi class. The increase in [Ca2+]i, induced in monocytes by rSAA, was comparable to that elicited by FMLP, and was severalfold greater than that induced by optimal concentrations of chemokine beta-family members such as RANTES, MCAF/MCP-1, and MIP-1 alpha. The chemoattractants FMLP, RANTES, MIP-1 alpha, and MCAF/MCP-1, all failed to desensitize rSAA-induced Ca2+ influx and chemotaxis in monocytes. This suggests that SAA uses a distinct receptor that is coupled to PTx-sensitive G proteins.
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PMID:Serum amyloid A induces calcium mobilization and chemotaxis of human monocytes by activating a pertussis toxin-sensitive signaling pathway. 756 Nov 9

In the present study, we examined the effect of vasopressin (AVP) on phosphatidylcholine-hydrolyzing phospholipase D activity in primary cultured rat aortic smooth muscle cells. AVP stimulation of choline formation was dose dependent. The time-course was quite different from those of inositol phosphates. The effect of AVP on the formation of inositol phosphates (EC50 was 3 nM) was more potent than that on the formation of choline (EC50 was 30 nM). 12-O-Tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C (PKC), stimulated the formation of choline. However, 4 alpha-phorbol 12,13-didecanoate, which is inactive for PKC, had little effect. Staurosporine, an inhibitor of protein kinases, which inhibited the TPA-induced formation of choline, had little effect on the AVP-induced formation of choline. Neither calphostin C, a highly specific PKC inhibitor, nor PKC down-regulation with TPA affected AVP-induced formation of choline. A combination of AVP and TPA additively stimulated the formation of choline. The depletion of extracellular Ca2+ by (ethylenebis(oxyethylenenitrilo)tetraacetic acid significantly reduced the AVP-induced formation of choline. W-7, an antagonist of calmodulin, inhibited the AVP-induced formation of choline in a dose-dependent manner. NaF, an activator for GTP-binding protein (G-protein), stimulated the formation of choline. However, the formation of choline by a combination of AVP and NaF was not additive. Pertussis toxin had little effect on the AVP-induced formation of choline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasopressin activates phospholipase D through pertussis toxin-insensitive GTP-binding protein in aortic smooth muscle cells: function of Ca2+/calmodulin. 757 93

The human type A interleukin-8 receptor (IL-8RA) was modified to express an amino-terminal epitope tag and stably overexpressed in a rat basophilic leukemia cell line (RBL-2H3). This receptor (ET-IL-8RA) displayed functional properties similar to those of the native receptor in neutrophils in that exposure to IL-8 stimulated GTPase activity, phosphoinositide (PI) hydrolysis, intracellular calcium mobilization, and degranulation in a pertussis toxin (PTx) susceptible fashion. IL-8 induced dose- and time-dependent phosphorylation of ET-IL-8RA. Phorbol 12-myristate 13-acetate (PMA) treatment also resulted in phosphorylation of the receptor although to a lesser extent. Staurosporine totally blocked PMA-induced phosphorylation but only partially inhibited IL-8-mediated phosphorylation. Phosphorylation of ET-IL-8RA correlated with its desensitization as measured by GTPase activation and calcium mobilization. To determine the role of phosphorylation in IL-8RA signal transduction, three mutants lacking specific serine and threonine residues located at the C-terminal of this receptor were constructed by site-directed mutagenesis (M1, M2, and M3). The mutated receptors expressed in RBL-2H3 cells displayed pharmacological properties (Kd approximately 2-2.8 nM and Bmax approximately 3-3.5 pmol/mg of protein) similar to those of the wild-type ET-IL-8RA. M2 and M3, but not M1, showed a marked decrease in IL-8-induced phosphorylation compared to the wild-type receptor. M2 and M3 but not M1 were resistant to PMA-mediated phosphorylation and desensitization and were also more resistant to homologous desensitization than M1 or ET-IL-8RA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of human interleukin-8 receptor A: identification of a phosphorylation site involved in modulating receptor functions. 757 17

We previously found that 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced invasion of Matrigel was associated with augmentation of cell motility but not with metalloproteinase activity in a highly metastatic variant (L-10) of human rectal adenocarcinoma cell line RCM-1. In the present study, with a two-dimensional cell motility assay, we investigated morphology of TPA-induced motility and biochemical pathways that may be involved in the induction of such a motile response to TPA. TPA induced active cell locomotion in L-10 cells with characteristic morphology: the cells moved outwards from the cell islands mainly as a localized coherent sheet of cells with few single moved out cells, but not cell proliferation. The front cells showed locomotor morphologies with front-tail polarity and well-spread leading lamella. Thus, this TPA-induced L-10 cell spreading and motility system seems to be a good model to investigate how well-differentiated adenocarcinoma cells move as cohesive cell nests. Agents which selectively modulate the adenylate cyclase or G protein-related pathways, e.g., 2',5'-dideoxyadenosine and pertussis toxin, had negligible effect upon motility. In contrast, the membrane-permeable synthetic diacylglycerol 1-oleoyl-2-acetyl-glycerol, which has been reported to activate protein kinase C (PKC) directly, could induce cell spreading and motility. Unexpectedly, PKC inhibitors staurosporine and H-7 enhanced TPA-induced cell spreading and motility. Staurosporine itself could induce cell spreading and motility. Taken together, these observations suggested possible involvement of PKC in TPA-induced L-10 cell spreading and motility and that staurosporine might have PKC agonist effect on induction of the spreading and motility.
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PMID:A two-dimensional model of cell movement. Well differentiated human rectal adenocarcinoma cells move as coherent sheets upon TPA stimulation. 765 36

Tyrosine phosphorylation of the cellular proteins of IL-2-stimulated NK cells was determined by anti-phosphotyrosine immunoblotting. IL-2 induced tyrosine phosphorylation of a 105-110 kDa protein in a dose-dependent manner. The tyrosine phosphorylation took place within 5 min after the addition of IL-2 to NK cells, and reached a maximal level in 15 min. The degree of the tyrosine phosphorylation correlated with IL-2-induced LAK activity. Staurosporine and pertussis toxin, which slightly suppressed LAK induction, did not inhibit tyrosine phosphorylation of the 105-110 kDa protein. Genistein, TMB-8 and EGTA completely inhibited LAK induction; however, the calcium channel blocker and chelator did not prevent the protein tyrosine phosphorylation. Anti-IL-2R beta mAb almost completely suppressed tyrosine phosphorylation of the 105-110 kDa protein, but anti-IL-2R alpha mAb only slightly suppressed it; this result correlated with that of the suppression of LAK activity. No further suppression of the tyrosine phosphorylation was induced even when both mAbs were added. Western blotting of the immunoprecipitates revealed no association of PLC-gamma 1 or IL-2R beta with the 105-110 kDa protein. These results suggest that both tyrosine phosphorylation of the 105-110 kDa protein and translocation of [Ca++]i are essential for NK-LAK induction, and the tyrosine phosphorylation plays a critical role in the early stage of IL-2 signalling from the IL-2R beta chain.
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PMID:NK-LAK induction with IL-2 is regulated by tyrosine phosphorylation of a 105-110 kDa protein. 775 Sep 84

Secretion of parathyroid hormone (PTH) is regulated by Ca2+ as well as by protein kinases A and C. In this study we report that protein kinases A and C regulate PTH messenger RNA levels in vitro in dispersed bovine parathyroid cells. Incubation of bovine parathyroid cells with cholera toxin (10(-9) M), which activates adenylate cyclase and indirectly stimulates protein kinase A, increased PTH mRNA levels about 2-fold after 3 and 7 h incubation, but not at 24 h. Incubation with pertussis toxin (5 x 10(-9) M), which blocks the high-calcium-mediated inhibition of cyclic adenosine monophosphate accumulation in these cells, also reversed the inhibition of PTH mRNA levels at high Ca2+ (2.0 mM) with a marked increase in PTH mRNA levels. Pertussis toxin also increased PTH mRNA at a low extracellular Ca2+ concentration (0.7 mM) (4-fold increase) and a normal concentration (1.25 mM) (2-fold increase). Inhibition of protein kinase C both by staurosporine (1 x 10(-8) M) and by prolonged incubation with the phorbol ester phorbol 12-myristate 13-acetate (PMA) (1 x 10(-7) M), decreased PTH mRNA levels at 24 h, reaching approximately 40% and 5% of control, respectively. Staurosporine and PMA had no effect on PTH mRNA levels at 3 h. The inactive phorbol ester, phorbol 12-13-dibutyrate (PDBu), had no effect on PTH mRNA levels at 1 and 24 h. There were no changes in a control gene 18S RNA in these studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of parathyroid hormone messenger RNA levels by protein kinase A and C in bovine parathyroid cells. 778 66

Endothelins are potent peptide mediators that elicit glycogenolytic and vasoconstrictor actions in the liver. Endothelins were found to stimulate the synthesis and release of the lipid mediator platelet-activating factor in cultured rat Kupffer cells. Endothelin-mediated synthesis of platelet-activating factor required extracellular calcium in that the calcium chelator, EGTA and nifedipine, a calcium ion channel blocker, inhibited platelet-activating factor synthesis. The phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited endothelin-induced platelet activating factor synthesis. Endothelin-stimulated platelet activating factor synthesis was inhibited after treatment of Kupffer cells with cholera toxin, whereas pertussis toxin inhibited only this response to endothelin-1. Agents that elevate intracellular cyclic AMP levels were found to inhibit endothelin-induced platelet-activating factor synthesis in Kupffer cells. Staurosporine, a protein kinase C inhibitor minimized endothelin-induced platelet-activating factor synthesis but phorbol myristate acetate, an activator of protein kinase C, did not affect endothelin-induced platelet activating factor synthesis. Thus, the current study demonstrates that activation of an endothelin receptor in cultured rat Kupffer cells results in the synthesis and release of platelet-activating factor. The importance of endothelin-mediated platelet-activating factor synthesis relates to the mechanism of intercellular signaling occurring between endothelial cells (i.e., the site of endothelin synthesis) and Kupffer cells (i.e., the site of formation of secondary mediators such as platelet-activating factor and eicosanoids) within the rat liver exposed to various types of pathophysiological episodes.
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PMID:Endothelin stimulates platelet-activating factor synthesis by cultured rat Kupffer cells. 784 29


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