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)

Bordetella pertussis is an important cause of infection in humans worldwide, with full expression of the syndrome associated with characteristic increases in lung permeability and airway edema. The exact cellular mechanisms by which pertussis toxin (PTX) exerts pulmonary toxicity remain unknown, but may involve its ability to ADP-ribosylate-specific G-proteins. We determined that PTX directly and reproducibly reduced lung endothelial and epithelial cell barrier function in vitro and in vivo assessed by decreases in transmonolayer electrical resistance (TER) and isolated perfused lung preparations. Alterations in lung permeability began approximately 30 min after PTX and were dependent on intrinsic ADP-ribosyltransferase activity, as neither the cell binding beta-oligomer subunit or a genetically engineered PTX mutant (devoid of ADP-ribosyltransferase activity) altered TER. PTX-induced barrier dysfunction was associated with mild increases in F-actin stress fiber formation and causally linked to p38 MAP kinase activities. PTX-mediated p38 MAP kinase activation did not involve either p42/p44 ERK, p60src, Rho family of GTPases, or phosphatidylinositol-3' kinase pathways. PTX-mediated decreases in TER were temporally linked to phosphorylation of the actin binding proteins Hsp27 and caldesmon, known substrates for the Ser/Thr kinase MAPKAP2, whose activity is regulated by p38 MAP kinase. In addition to defining novel signaling pathways involved in PTX-induced respiratory pathophysiology, these data suggest that the direct cell-activating effects of PTX be carefully considered as a potential limitation to its use as a tool in signal transduction analysis.
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PMID:Critical involvement of p38 MAP kinase in pertussis toxin-induced cytoskeletal reorganization and lung permeability. 1208 68

We have previously reported that beta-adrenergic receptor (beta-AR) stimulation promotes apoptosis in adult ventricular myocytes through PKCepsilon-mediated suppression of ERK. In this study, we investigated differential effects of beta-AR subtypes on this signal pathway. The apoptosis induced by the non-specific beta-AR agonist isoproterenol was largely blocked by the beta(1)-selective antagonist CGP 20712A, but not by the beta(2)-selective antagonist ICI 118551. A pro-apoptotic effect of beta(1)-AR was also blocked by the PKA inhibitor H89, while the protein kinase A (PKA) activators forskolin and dibutyryl-cAMP both induced apoptosis. These results indicate that beta(1)-AR-mediated PKA activation is largely responsible for the apoptosis induced by beta-AR in adult rat cardiac myocytes. This conclusion was also supported by the finding that PKA was preferentially activated by beta(1)-AR over beta(2)-AR. beta(2)-AR selectively induced anti-apoptotic ERK activation in the presence of PKCepsilon suppression, and this ERK activation was sensitive to pertussis toxin. PKCepsilon itself as well as Akt, the other anti-apoptotic factor were activated by both beta-AR subtypes. Thus, beta(1)-AR induces pro-apoptotic signals mainly through PKA activation. In contrast, beta(2)-AR is linked to Gi-mediated ERK activation, which is involved in the anti-apoptotic pathway, and is regulated by PKCepsilon. Therefore, our findings suggest a rather complex role for beta-AR subtypes in the regulation of apoptosis in adult ventricular myocytes.
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PMID:Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes. 1209 21

The proinsulin C-peptide has been held to be merely a by-product in insulin biosynthesis, but recent reports show that it elicits both molecular and physiological effects, suggesting that it is a hormonally active peptide. Specific binding of C-peptide to the plasma membranes of intact cells and to detergent-solubilised cells has been shown, indicating the existence of a cell surface receptor for C-peptide. C-peptide elicits a number of cellular responses, including Ca(2+) influx, activation of mitogen-activated protein (MAP) kinases, of Na(+),K(+)-ATPase, and of endothelial NO synthase. The pentapeptide EGSLQ, corresponding to the C-terminal five residues of human C-peptide, mimics several of the effects of the full-length peptide. The pentapeptide displaces cell membrane-bound C-peptide, elicits transient increase in intracellular Ca(2+) concentration and stimulates MAP kinase signalling pathways and Na(+),K(+)-ATPase. The Glu residue of the pentapeptide is essential for displacement of the full-length C-peptide, and free Glu can partly displace bound C-peptide, suggesting that charge interactions are important for receptor binding. Many C-peptide effects, such as phosphorylation of MAP-kinases ERK 1 and 2, stimulation of Na(+),K(+)-ATPase and increases in intracellular calcium concentrations are inhibited by pertussis toxin, supporting interaction of C-peptide with a G-protein-coupled receptor. However, all C-peptide effects cannot be explained in this manner, and it is possible that additional interactions are involved. Combined, the available observations show that C-peptide is biologically active and suggest a molecular model for its physiological effects.
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PMID:Molecular effects of proinsulin C-peptide. 1213 97

Hepatic myofibroblasts (hMFs) are central in the development of liver fibrosis during chronic liver diseases, and their removal by apoptosis contributes to the resolution of liver fibrosis. We previously identified Edg receptors for sphingosine 1-phosphate (S1P) in human hMFs. Here, we investigated the effects of S1P on hMF apoptosis. S1P reduced viability of serum-deprived hMFs by an apoptotic process that was unrelated to the conversion of S1P into sphingosine and ceramide. The apoptotic effects of S1P were receptor-independent because dihydro-S1P, an Edg agonist, had no effect. S1P also stimulated a receptor-dependent survival pathway, revealed by enhanced activation of caspase-3 by S1P in the presence of pertussis toxin. Cell survival relied on two pertussis toxin-sensitive events, activation of ERK and activation of phosphatidylinositol 3-kinase (PI3K)/Akt by S1P. Both pathways were also activated by dihydro-S1P. Blunting either ERK or PI3K enhanced caspase-3 stimulation by S1P, and simultaneous inhibition of both pathways resulted in additive effects on caspase-3 activation. In conclusion, S1P induces apoptosis of human hMFs via a receptor-independent mechanism and stimulates a survival pathway following activation of Edg receptors. The survival pathway arises from the sequential activation of G(i)/G(o) proteins and independent stimulations of ERK and PI3K/Akt. Therefore, blocking Edg receptors may sensitize hepatic myofibroblasts to apoptosis by S1P.
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PMID:Sphingosine 1-phosphate triggers both apoptotic and survival signals for human hepatic myofibroblasts. 1213 95

Skeletal muscle Na(+)-K(+)-2Cl(-) cotransporter (NKCC) activity provides a potential mechanism for regulated K(+) uptake. beta-Adrenergic receptor (beta-AR) activation stimulates skeletal muscle NKCC activity in a MAPK pathway-dependent manner. We examined potential G protein-coupled pathways for beta-AR-stimulated NKCC activity. Inhibition of G(s)-coupled PKA blocked isoproterenol-stimulated NKCC activity in both the slow-twitch soleus muscle and the fast-twitch plantaris muscle. However, the PKA-activating agents cholera toxin, forskolin, and 8-bromo-cAMP (8-BrcAMP) were not sufficient to activate NKCC in the plantaris and partially stimulated NKCC activity in the soleus. Isoproterenol-stimulated NKCC activity in the soleus was abolished by pretreatment with pertussis toxin (PTX), indicating a G(i)-coupled mechanism. PTX did not affect the 8-BrcAMP-stimulated NKCC activity. PTX treatment also precluded the isoproterenol-mediated ERK1/2 MAPK phosphorylation in the soleus, consistent with NKCC's MAPK dependency. Inhibition of isoproterenol-stimulated ERK activity by PTX treatment was associated with an increase in Akt activation and phosphorylation of Raf-1 on the inhibitory residue Ser(259). These results demonstrate a novel, muscle phenotype-dependent mechanism for beta-AR-mediated NKCC activation that involves both G(s) and G(i) protein-coupled mechanisms.
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PMID:Duality of G protein-coupled mechanisms for beta-adrenergic activation of NKCC activity in skeletal muscle. 1222 66

Anaplastic thyroid carcinomas (ATCs) are highly aggressive, extremely lethal human cancers with poor therapeutic response. Chemokines are a superfamily of small cytokine-like proteins that induce, through their interaction with G protein-coupled receptors, cytoskeletal rearrangement, firm adhesion to endothelial cells, and directional migration. In this study, we characterized the expression of CXC chemokine receptor 4 (CXCR4) and analyzed its functions in ARO cells, a human ATC cell. The normal primary cultured thyroid cells and ATC cell lines expressed CXCR4 and stromal cell-derived factor (SDF)-1 alpha transcripts, detected by RT-PCR. Fluorescence activated cell sorting analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA, and normal thyroid cells did not express membrane CXCR4, as determined by fluorescence activated cell sorting analysis. To identify the functional role of CXCR4 in ARO cells, we treated ARO cells with SDF-1 alpha and analyzed the signaling pathways, cellular migration, and proliferation. SDF-1alpha enhanced the migration but did not affect the proliferation of ARO cells or activate the Janus kinase/signal transducer and activator of transcription signaling pathways. However, SDF-1 alpha/CXCR4 activation resulted in phosphorylation of the p70S6 kinase and its target protein, ribosomal S6 protein, and also activation of the ERK1/ERK2 signaling pathways. Furthermore, SDF-1 alpha/CXCR4- mediated activation of the p70S6 kinase and phosphorylation of the S6 protein were inhibited by treatment with an mTOR/FRAP inhibitor. The specificity of the CXCR4-mediated migration of ARO cells was demonstrated by the dose-dependent inhibition of migration by neutralizing anti-CXCR4. The ATC cells, FRO and NPA, which do not express CXCR4, did not demonstrate significant SDF-1 alpha-mediated migration in vitro. In addition, the CXCR4-mediated migration of ARO cells was inhibited by treatment with pertussis toxin (a Gi-protein inhibitor) and PD 98059 (a mitogen-activated ERK kinase inhibitor) but not by LY294002 and wortmanin, phosphatidylinositol 3-kinase inhibitors. These findings suggest that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.
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PMID:CXC chemokine receptor 4 expression and function in human anaplastic thyroid cancer cells. 1251 84

(1) Thrombin, a mitogen for human cultured airway smooth muscle (HASM), has many actions that have been attributed to activation of protease-activated receptor (PARs). However, the role of PARs in the proliferative action has not been clearly identified. Moreover, thrombin elicits cytokine production in a number of cell types, but these effects have not been characterized in human ASM. (2) Thrombin (0.03-3 U ml(-1))-stimulated increases in the levels of the pro-inflammatory and fibrogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) were observed over the same concentration range observed for thrombin-stimulated mitogenesis. (3) Inhibition of thrombin proteolytic activity, with either D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)- or hirudin-treated thrombin (0.3 U ml(-1)) or in the presence of the thrombin serine protease-selective inhibitor, SDZ 217-766 (0.15 micro M), reduced the thrombin-stimulated GM-CSF levels by 91+/-3, 65+/-12 and 83+/-9% (n=8, P<0.05), respectively. PPACK treatment, hirudin and SDZ 217-766 inhibited thrombin-stimulated increase in cell number by 70+/-8, 63+/-11 and 69+/-8%, respectively. (4) PAR-selective peptides SFLLRN (PAR1; 10 micro M), SLIGKV (PAR2; 10 micro M), GYPGQV (PAR4; 100 micro M) or the combination of SFLLRN and GYPGQV elicited mitogenic responses of only 15% of that to thrombin and surprisingly, had no effect on GM-CSF levels (n=8). Nevertheless, inhibition of thrombin responses by pertussis toxin (50 ng ml(-1)) suggests that the PAR-independent actions also involve a G-protein-coupled receptor. (5) PAR1 receptor expression was evident by immunohistochemistry and these receptors were coupled to increases in intracellular calcium, but not to the phosphorylation of ERK or the increases in cyclin D1 protein levels that are essential for cell proliferation. Cross-desensitization of intracellular calcium increases by thrombin and the PAR1-selective peptide provides evidence that the PAR1 receptor responds to both ligands. (6) The failure of PAR-selective peptides to mimic thrombin responses together with the inhibition of thrombin responses by serine protease inhibitors suggest the involvement of novel proteolytic receptor targets for thrombin-induced mitogenesis and cytokine production.
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PMID:Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle. 1264 88

Isoproterenol stimulates H-K-ATPase activity in rat cortical collecting duct beta-intercalated cells through a PKA-dependent pathway. This study aimed at determining the signaling pathway underlying this effect. H-K-ATPase activity was determined in microdissected collecting ducts preincubated with or without specific inhibitors or antibodies against intracellular signaling proteins. Transient cell membrane permeabilization with streptolysin-O allowed intracellular access to antibodies. Isoproterenol increased phosphorylation of ERK in a PKA-dependent manner, and inhibition of the ERK phosphorylation prevented the stimulation of H-K-ATPase. Antibodies against the monomeric G protein Ras or the kinase Raf-1 curtailed the stimulation of H-K-ATPase by isoproterenol, whereas antibodies against the related proteins Rap-1 and B-Raf had no effect. Pertussis toxin and inhibition of tyrosine kinases with genistein also curtailed isoproterenol-induced stimulation of H-K-ATPase. It is proposed that activation of PKA by isoproterenol induces the phosphorylation of beta-adrenergic receptors and the switch from G(s) to G(i) coupling. In turn, betagamma-subunits released from G(i) would activate a tyrosine kinase-Ras-Raf-1 pathway, leading to the activation of ERK1/2 and of H-K-ATPase.
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PMID:Mechanism of activation of ERK and H-K-ATPase by isoproterenol in rat cortical collecting duct. 1267 35

Eotaxin-3 (CCL26) belongs to the group of CC chemokines that attract eosinophils, basophils, and Th2 lymphocytes. Like eotaxin (CCL11) and eotaxin-2 (CCL24), eotaxin-3 mediates its activity through CCR3. Here we show that eotaxin-3 also binds to CCR2 on monocytes and CCR2-transfected cells. In contrast to monocyte chemotactic protein 1 (MCP-1; CCL2), eotaxin-3 does not trigger intracellular calcium mobilization, enzyme release, or phosphorylation of the mitogen-activated protein (MAP) kinase ERK and induces a weak chemotaxis in monocytes. Instead, eotaxin-3 inhibits MCP-1-mediated responses, thus acting as a natural antagonist for CCR2. This study also demonstrates that eotaxin-3 promotes active movement of monocytes away from a gradient of eotaxin-3 in vitro. This repellent effect is amplified when an additional gradient of MCP-1 is applied, demonstrating that the 2 mechanisms are synergistic. Eotaxin-3 effects on monocytes are largely abolished when cells are pretreated with MCP-1 or CCR2 antagonists. Like MCP-1-mediated migration, repulsion is sensitive to Bordetella pertussis toxin, indicating the involvement of Gi protein-coupled receptors. However, using transfected cells expressing CCR2 we could not detect F-actin formation or an active movement away induced by eotaxin-3, suggesting that either expression of a single receptor type is not sufficient to mediate cell repulsion or that the used transfected cell lines lack additional interaction molecules that are required for reverse migration. Eotaxin-3 was expressed by vascular endothelial cells and was essential for endothelial transmigration of eosinophils. Our data provide a mechanism by which 2 chemokine gradients that are oriented in opposite directions could cooperate in efficiently driving out monocytes from blood vessels into tissue.
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PMID:Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes. 1268 46

1. We have examined possible mechanisms of cross-talk between the G(q/11)-linked M(3) muscarinic acetylcholine (mACh) receptor and the G(i/o)-linked M(2) mACh receptor by stable receptor coexpression in Chinese hamster ovary (CHO) cells. A number of second messenger (cyclic AMP, Ins(1,4,5)P(3)) and mitogen-activated protein kinase (ERK and JNK) responses stimulated by the mACh receptor agonist methacholine were examined in CHO-m2m3 cells and compared to those stimulated in CHO-m2 and CHO-m3 cell-lines, expressing comparable levels of M(2) or M(3) mACh receptors. 2. Based on comparisons between cell-lines and pertussis toxin (PTx) pretreatment to eliminate receptor-G(i/o) coupling, evidence was obtained for (i) an M(2) mACh receptor-mediated contribution to the predominantly M(3) mACh receptor-mediated Ins(1,4,5)P(3) response and (ii) a facilitation of the inhibitory effect of M(2) mACh receptor on forskolin-stimulated cyclic AMP accumulation by M(3) mACh receptor coactivation at low agonist concentrations (MCh 10(-9)-10(-6) M). 3. The most profound cross-talk effects were observed with respect to ERK activation. Thus, while MCh stimulated ERK activation in both CHO-m2 and CHO-m3 cells (pEC(50) values: 5.64+/-0.09 and 5.57+/-0.16, respectively), the concentration-effect relation was approx 50-fold left-shifted in CHO-m2m3 cells (pEC(50): 7.17+/-0.07). In addition, the ERK response was greater and more sustained in CHO-m2m3 cells. In contrast, only minor differences were seen in the time-courses and concentration-dependencies of JNK activation in CHO-m3 and CHO-m2m3 cells. 4. Costimulation of endogenous P2Y(2) purinoceptors also caused an approx 10-fold left-shift in the MCh-stimulated ERK response in CHO-m2 cells, suggesting that the G(q/11)/G(i/o) interaction to affect ERK activation is not specific to muscarinic receptors. 5. PTx pretreatment of cells had unexpected effects on ERK activation by MCh in both CHO-m2m3 and CHO-m3 cells. Thus, in CHO-m3 cells PTx pretreatment caused a marked left-shift in the MCh concentration-effect curve, while in PTx-treated CHO-m2m3 cells the maximal responsiveness was decreased, but the potency of MCh was only slightly affected. 6. The data presented here strongly suggest that cross-talk between M(2) and M(3) mACh receptors occurs at the level of both second messenger and ERK regulation. Further, these data provide novel insights into the involvement of G(i/o) proteins in both positive and negative modulation of ERK responses evoked by G protein-coupled receptors.
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PMID:Evidence for cross-talk between M2 and M3 muscarinic acetylcholine receptors in the regulation of second messenger and extracellular signal-regulated kinase signalling pathways in Chinese hamster ovary cells. 1271 35


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