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)

Cyclic AMP responses to phorbol esters were studied in cultured bovine adrenal medullary cells. Phorbol esters that activate protein kinase C (PKC: phorbol 12,13-dibutyrate, phorbol 12,13-didecanoate) increased cellular cyclic AMP levels by up to 100% over 5 min, and this was maintained for up to 3 h. The effect was mimicked by 1,2-dioctanoyl-sn-glycerol but not by inactive phorbol esters. The effect of active phorbol esters was concentration dependent over the range 50-500 nM, and was abolished by the PKC inhibitor, Ro 31-8220 (10 microM). The response was enhanced by 3-isobutyl-1-methylxanthine (1 mM) and by forskolin (0.3 microM), was enhanced following pertussis toxin pretreatment (100 ng/ml, 7.5 h) and was unaffected by removing extracellular Ca2+. The phorbol ester cyclic AMP response was additive with that to K+ depolarisation, and synergised with those to prostaglandin E1 and dimaprit. The results indicate PKC activation increases cyclic AMP formation in bovine adrenal medullary cells, probably by a direct action on adenylate cyclase or Gs.
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PMID:Regulation of cyclic AMP levels by phorbol esters in bovine adrenal medullary cells. 767 99

Receptor-mediated calcium entry was investigated in Fura 2 loaded FRTL-5 cells. The purinergic agonist ATP activated the release of sequestered calcium and the entry of extracellular calcium. Downregulation of protein kinase C (PKC) substantially enhanced the ATP-evoked calcium entry. Pretreatment of the cells with pertussis toxin (Ptx) decreased the ATP-evoked calcium entry by 56% and the release of sequestered calcium by 34%. In PKC-downregulated cells, the effect of Ptx treatment on the ATP-evoked increase in [Ca2+]i was 73% and 44%, respectively. Phorbol myristic acetate (PMA) decreased the ATP-evoked calcium entry to the same extent as Ptx. In Ptx-treated cells, the ATP-evoked influx of 45Ca2+ was attenuated. Stimulation of the cells with P2p-purinergic agonist GTP evoked no entry of calcium, although GTP released the same amount of sequestered calcium as did ATP. PKC downregulation or pretreatment with Ptx had no effects on the GTP-evoked responses, whereas PMA decreased the GTP-evoked release of calcium. We conclude that the ATP-activated rapid calcium entry pathway is a second messenger-operated calcium channel.
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PMID:Evidence for a pertussis toxin sensitive calcium entry pathway in thyroid FRTL-5 cells. 779 Mar 85

We have isolated a 5199-nucleotide cDNA from a mouse library containing an open reading frame encoding the 1099-amino acid type VII adenylyl cyclase protein. The type VII protein is most closely related in primary structure to an unpublished human adenylyl cyclase clone (GenBank accession no. D25538) and type II adenylyl cyclase. Northern blot analysis demonstrates that the type VII mRNA is most abundant in mouse heart, spleen, and lung. cAMP content rises rapidly in HEK 293 cells overexpressing type VII adenylyl cyclase following treatment with phorbol ester, peaking by 4 min, while cells expressing the type II adenylyl cyclase reach peak accumulation only after 20 min. Increases in intracellular calcium through treatment of type VII-293 cells with either ATP or A23187 alone failed to increase intracellular cAMP content. Phorbol ester treatment acted synergistically with beta-adrenergic stimulation to increase cAMP content in type VII-transformed cells. Pretreatment of type VII-transformed cells with pertussis toxin fails to prevent phorbol ester potentiation of isoproterenol stimulation. Thus the ability of phorbol ester to increase basal and isoproterenol-stimulated type VII activity appears to be a direct effect on this adenylyl cyclase isoform and not the result of modification of the inhibitory G protein, Gi.
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PMID:Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells. 796 50

We previously reported that prostaglandin F2 alpha (PGF2 alpha) receptor is coupled to pertussis toxin (PTX)-sensitive GTP-binding protein (G protein) in osteoblast-like MC3T3-E1 cells [Miwa et al. (1990): Biochem Biophys Res Commun 171:1229-1235]. In the present study, we examined the effect of PGF2 alpha on the activation of phosphatidylcholine-hydrolyzing phospholipase D in MC3T3-E1 cells. PGF2 alpha stimulated the formation of choline in a dose-dependent manner in the range between 10 nM and 10 microM. The formation of choline was stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC)-activating phorbol ester. 4 alpha-Phorbol 12, 13-didecanoate, a PKC-nonactivating phorbol ester, had little effect on choline formation. The formation of choline stimulated by a combination of PGF2 alpha and TPA was additive. Staurosporine, an inhibitor for protein kinases, which inhibited the effect of TPA on choline formation, dose-dependently enhanced the formation of choline induced by PGF2 alpha. NaF, an activator of G protein, stimulated the formation of choline. The formation of choline stimulated by a combination of PGF2 alpha and NaF was not additive. NaF-induced formation of choline was dose-dependently enhanced by staurosporine. PTX dose-dependently inhibited the PGF2 alpha-induced formation of choline. These results strongly suggest that PGF 2 alpha activates phospholipase D independently from the activation of PKC in osteoblast-like cells and PTX-sensitive G protein is involved in the PGF2 alpha-induced phospholipase D activation.
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PMID:Prostaglandin F2 alpha activates phospholipase D independently from activation of protein kinase C in osteoblast-like cells. 796 70

Phorbol esters (PDBu) stimulate alpha-secretase cleavage and secretion of the Alzheimer amyloid precursor protein (APP). To determine whether any cytoplasmic residues or sequence motifs mediate the PDBu effect on APP processing, this region of APP was altered by point mutations or deletions. To differentiate the mutated APP from the endogenous APP, the APP751 ectodomain between amino acids 1 and 647 was replaced by a human secreted alkaline phosphatase derivative (SEAP). The resultant fusion protein (SEAP-APP751) was cleaved by alpha-secretase at the same site as full-length APP, and its secretion was stimulated by PDBu at a level similar to APP751. However, PDBu-stimulated secretion of the SEAP-APP751 fusion protein reached its maximum level after 30 min of treatment, while secretion of APP751 reached its maximum after 60 min, suggesting that the APP ectodomain affects the kinetics of APP secretion. Mutation of the cytoplasmic serines to alanines had no effect on the PDBu-stimulated secretion of the SEAP-APP, indicating that protein kinase C (PKC) phosphorylation of the cytoplasmic domain of APP is not important for stimulation of APP secretion. Similarly, deletion of the cytoplasmic domain between amino acids 719 and 751 had no effect on the PDBu-stimulated secretion. However, deletion of amino acids 707-751 resulted in a significant increase in the secretory cleavage of the SEAP-APP707 delta C construct, suggesting that the sequence 707-719 is important for the regulated secretion of APP. Cholera toxin, but not pertussis toxin, reduced the PDBu-induced secretion of APP by more than two-fold, suggesting that the PDBu response may be modulated by a cholera toxin sensitive heterotrimeric G-protein.
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PMID:Study of the phorbol ester effect on Alzheimer amyloid precursor processing: sequence requirements and involvement of a cholera toxin sensitive protein. 805 94

Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3-E1 osteoblasts if polyvalent cations differentially modulate the agonist-stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E1 (PGE)-stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)-stimulated cAMP production. In contrast, these cations had no effect on forskolin- or cholera toxin-induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12-myristate 13-acetated (PMA) mimicked the effects of cations on PGE1- and PTH-stimulated cAMP accumulation in MC3T3-E1 cells, respectively, diminishing and augmenting the responses. Moreover, down-regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd3+) from attenuating PGE1- and enhancing PTH-stimulated cAMP production, indicating involvement of PKC-dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol-specific phospholipase C (PI-PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd(3+)-mediated suppression of PGE1-stimulated cAMP, suggesting actions independent of Gm. Thus, polyvalent cations may either stimulate or inhibit hormone-mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.
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PMID:Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts. 872 76

Monocyte chemotactic protein-1 (MCP-1), a specific chemoattractant for monocytes, has been thought to play an important role in the recruitment and accumulation of monocytes within the glomerulus seen in glomerular diseases. This study examined the role of tumor necrosis factor (TNF)-alpha-mediated cellular signal transduction pathways on mesangial cell MCP-1 gene expression and monocyte migration. Incubation of mesangial cells with TNF-alpha stimulated MCP-1 mRNA expression in a dose- and time-dependent manner. Phorbol myristate acetate (PMA), a protein kinase C (PKC) activator, increased MCP-1 message by mesangial cells while depleting PKC decreased MCP-1 gene expression to control levels. Activation of PKC-depleted mesangial cells with PMA but not with TNF-alpha inhibited MCP-1 mRNA expression. Similarly, calphostin C, a PKC inhibitor, failed to inhibit TNF-alpha-induced MCP-1 expression. The incubation of mesangial cells with various protein tyrosine kinase inhibitors (PTK, e.g., herbimycin, tyrphostin, genistein) blocked TNF-alpha-induced MCP-1 mRNA message. Additional experiments examining the role of cAMP on MCP-1 expression indicated that the preincubation of mesangial cells with various cAMP generating substances (pertussis toxin, isoproterenol, dbcAMP) did not induce mesangial cell MCP-1 mRNA transcripts. However, the coincubation of mesangial cells with TNF-alpha and dbcAMP completely inhibited TNF-alpha-induced MCP-1 gene expression. Finally, TNF-alpha-activated mesangial cell media increased monocyte transmigration that could be blocked by neutralizing anti-MCP-1. These studies indicate that TNF-alpha facilitates monocyte transmigration into the glomerulus mediated by the increased expression of MCP-1 by mesangial cells. TNF-alpha-induced mesangial cell MCP-1 expression is regulated by signal transduction pathways involving PTK but not those dependent on PKC or cAMP.
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PMID:Role of tumor necrosis factor-alpha on mesangial cell MCP-1 expression and monocyte migration: mechanisms mediated by signal transduction. 879 1

The present study investigated transcellular signalling mechanism involved in thrombin-induced production of plasminogen activator inhibitor-1 (PAI-1) in cultured vascular baboon aortic smooth muscle cells (BASMC). Treatments with thrombin dose-dependently increased the steady state levels of PAI-1 mRNA and the generation of PAI-1 antigen from BASMC. Thrombin receptor-activating peptide mimicked the effect of thrombin on the generation of PAI-1. Sodium fluoride (1 mM) stimulated PAI-1 generation from BASMC. Pertussis toxin dose-dependently suppressed thrombin-induced increase of PAI-1 generation. Treatment with 5 mM neomycin, 10 microM U73122 or 1 microM calphostin C blocked thrombin-induced PAI-1 generation. Phorbol myristate acetate at 10 nM for 3 h strongly stimulated the generation of PAI-1 from BASMC. Forskolin (100 microM) or 8-bromo-cAMP (100 microM) suppressed thrombin-induced PAI-1 generation. The responses of quiescent BASMC to thrombin or the inhibitors on PAI-1 generation were comparable to that of growing cells. The results of the present study suggest that pertussis toxin-sensitive G proteins and a phospholipase C are involved in thrombin-induced generation of PAI-1 in BASMC, which may transmit signals from occupied thrombin receptor to protein kinase C and thereby increase the generation of PAI-1. Elevated levels of intracellular cAMP may negatively regulate the generation of PAI-1 from vascular SMC.
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PMID:G proteins and phospholipase C mediate thrombin-induced generation of plasminogen activator inhibitor-1 from vascular smooth muscle cells. 916 40

1. The effect of the non-steroidal anti-inflammatory drugs naproxen, mefenamic acid, phenylbutazone, piroxicam and tolmetin on the vanadate (0.3 mM)-induced tonic contraction, as well as the modifications of these effects by the G-protein inhibitor pertussis toxin, and the inhibitors of protein kinase A, Rp-cAMPS (Rp-Adenosine 3',5'-cyclic monophosphothioate triethylamine salt) and protein kinase C, H-7 [1(5-isoquinolynilsulfonyl)-2-methyl-piperazine], have been assayed to study the possible nature of intracellular mediators contributing to the inhibitory effects of NSAIDs in rat uterine smooth muscle incubated in medium lacking calcium plus EDTA. The effect of phorbol 12,13-dibutyrate on vanadate contraction and its modification with H-7 has also been examined. 2. Naproxen (6-600 microM), mefenamic acid (6-300 microM), phenylbutazone (6-300 microM), piroxicam (6-600 microM) and tolmetin (6-600 microM) produced concentration-dependent relaxation of vanadate-induced tonic contraction. The potency order, in accordance with their respective IC50 values was: phenylbutazone > or = mefenamic acid > or = naproxen > tolmetin > or = piroxicam. 3. The relaxant effects of naproxen, phenylbutazone, piroxicam and tolmetin were significantly antagonized with pertussis toxin (50 ng ml-1), Rp-cAMPS (100 microM) and H-7 (1 microM). However, the effect of mefenamic acid was unmodified by the three drugs. This suggests that the effect of mefenamic acid and other NSAIDs occur by different mechanisms. 4. Phorbol 12,13-dibutyrate relaxed the vanadate contraction but the maximal relaxation achieved (54.8 +/- 8.3%, n = 4) was lower than those induced with the NSAIDs. On the other hand, H-7 (1 microM) did not modify the relaxant effect of phorbol 12,13-dibutyrate. This suggests that H-7 behaves as a PKA, but not a PKC inhibitor, under the present experimental conditions. 5. The relaxation by naproxen, phenylbutazone, piroxicam and tolmetin is presumably produced by increasing cAMP because the effects of these are antagonized with Rp-cAMPS and H-7, and by pertussis-toxin-sensitive mechanisms.
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PMID:Contribution of cAMP to the inhibitory effect of non-steroidal anti-inflammatory drugs in rat uterine smooth muscle. 972 23

In C9 (Clone 9) liver cells, angiotensin 11 increased the intracellular Ca2+ content, inositol phosphate production and c-fos mRNA expression. Other angiotensins were also active with the order of potency being angiotensin II = angiotensin III >> angiotensin I > angiotensin IV. Losartan, but not PD 123177 (1-(4-amino-3-methyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imida zo [4,5c]pyridine-6-carboxylic acid), blocked the effects of angiotensin II. Pertussis toxin did not alter these actions of angiotensin II. These data indicate that the effects were mediated through angiotensin AT1 receptors involving pertussis toxin-insensitive G-proteins. Phorbol myristate acetate was also able to increase c-fos mRNA expression. The action of angiotensin II was consistently greater than that of the active phorbol ester. Staurosporine but not genistein inhibited this effect of angiotensin II. Angiotensin II- and phorbol myristate acetate-induced proto-oncogene mRNA expression was attenuated in cells incubated overnight with the active phorbol ester, which suggests a major role of protein kinase C.
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PMID:Angiotensin AT1 receptors in Clone 9 rat liver cells: Ca2+ signaling and c-fos expression. 987 76


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