Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Recently, a family of G-protein-coupled receptors named endothelial differentiation gene (Edg) receptor family has been identified, which are specifically activated by the two serum lipids, sphingosine-1-phosphate and lysophosphatidic acid. Sphingosine-1-phosphate can also act intracellularly to release Ca2+ from intracellular stores. Since in several cell types, G-protein-coupled lysophosphatidic acid or sphingosine-1-phosphate receptors mobilize Ca2+ in the absence of a measurable phospholipase C stimulation, it was analysed here whether intracellular sphingosine-1-phosphate production was the signalling mechanism used by extracellular sphingosine-1-phosphate for mobilization of stored Ca2+. Sphingosine-1-phosphate and the low affinity sphingosine-1-phosphate receptor agonist, sphingosylphosphorylcholine, induced a rapid, transient and nearly complete pertussis toxin-sensitive Ca2+ mobilization in human embryonic kidney (HEK-293) cells. The G-protein-coupled sphingosine-1-phosphate receptors, Edg-1, Edg-3 and Edg-5, were found to be endogenously expressed in these cells. Most interestingly, sphingosine-1-phosphate and sphingosylphosphorylcholine did not induce a measurable production of inositol-1,4,5-trisphosphate or accumulation of inositol phosphates. Instead, sphingosine-1-phosphate and sphingosylphosphorylcholine induced a rapid and transient increase in production of intracellular sphingosine-1-phosphate with a maximum of about 1.4-fold at 30 s. Stimulation of sphingosine-1-phosphate formation by sphingosine-1-phosphate and sphingosylphosphorylcholine was fully blocked by pertussis toxin, indicating that extracellular sphingosine-1-phosphate via endogenously expressed G(i)-coupled receptors induces a stimulation of intracellular sphingosine-1-phosphate production. As sphingosine-1-phosphate- and sphingosylphosphorylcholine-induced increases in intracellular Ca2+ were blunted by sphingosine kinase inhibitors, this sphingosine-1-phosphate production appears to mediate Ca2+ signalling by extracellular sphingosine-1-phosphate and sphingosylphosphorylcholine in HEK-293 cells.
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PMID:Stimulation of intracellular sphingosine-1-phosphate production by G-protein-coupled sphingosine-1-phosphate receptors. 1123 14

A common intracellular signal activating polymorphonuclear leukocytes (PMN) in inflammation is a change in cytosolic calcium concentration. Previously, we have shown that interferon-gamma (IFN-gamma) induces transient calcium signals in PMN, but only after intracellular calcium store depletion. Using a digital imaging system, we show that adhesion of PMN is critical for IFN-gamma-induced calcium signals, and with PMN attached to the optimal coating, the calcium signals are evoked even in presence of extracellular calcium, that is, non-depleted calcium stores. Adhesion to fibronectin, pure or extracted from plasma by gelatin, improved the IFN-gamma responses compared with serum, plasma, or vitronectin coats. In accordance with previous observations, IFN-gamma-induced calcium signals in fibronectin adherent cells were totally abolished by the G-protein inhibitor pertussis toxin and were also inhibited by the sphingosine kinase inhibitors dimethylsphingosine (DMS) and N-acetylsphingosine (N-Ac-Sp). PMN contact with fibronectin alone, measured in cells sedimenting onto a fibronectin-coated surface or by addition of fibronectin to glass-adherent cells, evoked transient calcium signals. However, PMN in suspension did not respond to the addition of fibronectin or arginine-glycine-aspartate (RGD). The fibronectin-induced calcium signals were also clearly depressed by pertussis toxin and by the sphingosine kinase inhibitors DMS, dihydrosphingosine (DHS), and N-Ac-Sp. When the product of sphingosine kinase activity, sphingosine 1-phosphate (S1-P), was added to the cells, similar calcium signals were induced, which were dependent on a pertussis toxin-sensitive G-protein activity. Finally, addition of S1-P to the cells prior to stimulation with IFN-gamma partly mimicked the priming effect of fibronectin. In conclusion, fibronectin contact evokes by itself a calcium signal in PMN and further promotes calcium signaling by IFN-gamma. We suggest that fibronectin might activate sphingosine kinase, and that the sphingosine 1-phosphate thereby generated induces a calcium signal via a G-protein-dependent mechanism. Apparently, sphingosine kinase activity is also involved in IFN-gamma induced calcium signals.
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PMID:Fibronectin promotes calcium signaling by interferon-gamma in human neutrophils via G-protein and sphingosine kinase-dependent mechanisms. 1193 87

The role of sphingosine kinase (SphK) on basic fibroblast growth factor (bFGF)-induced proliferation of cerebral, aortic and coronary smooth muscle cells (SMC) was addressed using D-erythro-N,N-dimethylsphingosine (DMS), an inhibitor of SphK which blocks conversion of sphingosine to sphingosine-1-phosphate (S1P). DMS concentration-dependently reduced the bFGF-induced proliferation of rat cerebral and aortic, and human coronary SMC. This suggests that SphK is one of the key enzymes in the mitogenic response to bFGF in vascular SMC as supported by the finding that S1P stimulated proliferation of SMC. Fumonisin B1, a dihydroceramidesynthase inhibitor which blocks the conversion of dihydrosphingosine to seramide, did not affect SMC proliferation induced by bFGF. Staurosporine, an inhibitor of protein kinase C (PKC), inhibited proliferation of SMC induced by bFGF, and both bFGF- and S1P-induced proliferation of SMC was sensitive to pertussis toxin (PTX), an inhibitor of Gi-protein activity. The present study thus demonstrates that SphK, PKC and Gi-protein activities are required for bFGF-mitogenic signaling in SMC. The bFGF mitogenic effect in vascular SMC might at least in part act via the SphK pathway and a Gi-protein.
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PMID:D-erythro-N,N-dimethylsphingosine inhibits bFGF-induced proliferation of cerebral, aortic and coronary smooth muscle cells. 1220 93

Syndecan-4 participates in focal adhesion by non-G protein-dependent activation of protein kinase C. Ligation of syndecan-4 with antithrombin elicits pertussis toxin-sensitive chemotaxis of leukocytes. As activation of protein kinase C stimulates release of sphingosine-1-phosphate, a chemoattracting G protein-coupled receptor agonist, we studied directional migration of leukocytes in response to phorbol myristate acetate (PMA), a direct activator of protein kinase C. Human peripheral blood neutrophils, monocytes, and lymphocytes were purified and tested for chemotactic migration in micropore filter assays in response to PMA. Dose-dependent stimulation of migration was seen only when leukocytes were exposed to concentration gradients of PMA; in the absence of such a gradient, inhibition of random migration was induced. Dimethylsphingosine inhibited PMA-induced leukocyte chemotaxis, indicating that activation of sphingosine kinase for enhanced production of sphingosine-1-phosphate mediates the chemotactic response to PMA. Pertussis toxin abrogated the chemotactic response to PMA, suggesting involvement of G protein-coupled sphingosine-1-phosphate receptor. Dimethylsphingosine also inhibited leukocyte chemotaxis toward antithrombin, indicating that similar mechanisms may be involved upon syndecan-4 ligation. Data show that protein kinase C-dependent activation of sphingosine kinase may play a central role in leukocyte chemotaxis toward non-G protein-coupled receptor agonists.
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PMID:Sphingosine kinase-dependent directional migration of leukocytes in response to phorbol ester. 1235 24

Sphingolipid (SP) derivatives have diverse effects on the regulation of intracellular free calcium concentrations ([Ca2+]i) in a multitude of non-excitable cells. In the present investigation, the effect of C2-ceramide 1-phosphate (C1P) on [Ca2+]i was investigated in thyroid FRTL-5 cells. C1P evoked a concentration-dependent increase in [Ca2+]i, both in a calcium-containing and a calcium-free buffer. A substantial part of the C1P-evoked increase in [Ca2+]i was due to calcium entry. The effect of C1P was attenuated by overnight pretreatment of the cells with pertussis toxin. Similar results were obtained with C8-ceramide 1-phosphate, although the magnitude of the responses was smaller than with C1P. The phospholipase C inhibitor U73122 attenuated the effect of C1P. C1P invoked a small, but significant, increase in inositol 1,4,5-trisphosphate (IP3). However, the effect of C1P on [Ca2+]i was inhibited by neither Xestospongin C, 2-aminoethoxydiphenylborate nor neomycin. C1P mobilized calcium from an IP3-sensitive calcium store, as C1P did not increase [Ca2+]i in cells pretreated with thapsigargin. The effect of C1P on [Ca2+]i was potently attenuated by dihydrosphingosine and dimethylsphingosine, two inhibitors of sphingosine kinase, but not by the inactive SP-derivative N -acetyl sphingosine. Stimulating the cells with C1P evoked an increase in the production of intracellular sphingosine 1-phosphate. C1P did not modulate DNA synthesis or the forskolin-evoked production of cAMP. The results indicate that C1P may be an important SP participating in cellular signalling.
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PMID:Ceramide 1-phosphate increases intracellular free calcium concentrations in thyroid FRTL-5 cells: evidence for an effect mediated by inositol 1,4,5-trisphosphate and intracellular sphingosine 1-phosphate. 1241 95

FTY720, a potent immunosuppressive agent, is phosphorylated in vivo into FTY720-P, a high affinity agonist for sphingosine 1-phosphate (S1P) receptors. The effects of FTY720 on vascular cells, a major target of S1P action, have not been addressed. We now report the metabolic activation of FTY720 by sphingosine kinase-2 and potent activation of vascular endothelial cell functions in vitro and in vivo by phosphorylated FTY720 (FTY720-P). Incubation of endothelial cells with FTY720 resulted in phosphorylation by sphingosine kinase activity and formation of FTY720-P. Sphingosine kinase-2 effectively phosphorylated FTY720 in the human embryonic kidney 293T heterologous expression system. FTY720-P treatment of endothelial cells stimulated extracellular signal-activated kinase and Akt phosphorylation and adherens junction assembly and promoted cell survival. The effects of FTY720-P were inhibited by pertussis toxin, suggesting the requirement for Gi-coupled S1P receptors. Indeed, transmonolayer permeability induced by vascular endothelial cell growth factor was potently reversed by FTY720-P. Furthermore, oral FTY720 administration in mice potently blocked VEGF-induced vascular permeability in vivo. These findings suggest that FTY720 or its analogs may find utility in the therapeutic regulation of vascular permeability, an important process in angiogenesis, inflammation, and pathological conditions such as sepsis, hypoxia, and solid tumor growth.
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PMID:Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. 1295 48

G-protein-coupled bombesin receptors are capable of signaling through the G(i) protein even when receptor-coupling to G(q) is blocked by [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P (SpD), a neurokinin-1 receptor antagonist and "biased" agonist to bombesin receptors. As bombesin is a monocyte and tumor cell attractant, we were interested in the effects of SpD on cell migration. Chemotaxis of monocytes was tested in micropore filter assays. SpD was a dose-dependent agonist in monocyte migration and was not inhibited by antagonists to neurokinin-1 or -2 receptors. SpD failed to inhibit chemotaxis toward bombesin, suggesting that inhibition of bombesin receptor coupling to G(q) with SpD does not impair migratory responses elicited by bombesin. As pertussis toxin inhibited migration, coupling of receptors to G(i) may signal migration. Chemotaxis toward SpD was inhibited by bombesin receptor antagonists as well as by blocking signaling enzymes downstream of G(q) (phospholipase-3 and protein kinase C with wortmannin and bisindolylmaleimide, respectively), suggesting transactivation of G(q)-mediated chemotaxis signaling by SpD via bombesin receptors. Protein kinase C that induces sphingosine kinase activation and production of sphingosine-1-phosphate, which may lead to G(q)-dependent chemoattraction, was involved in SpD-dependent migration. Inhibition of sphingosine-1-phosphate production with dimethylsphingosine inhibited monocyte migration toward SpD. Data suggest that SpD induces migration in monocytes and signaling events involving activation of sphingosine kinase in a G(i) protein- and protein kinase C-dependent fashion. "Biased" agonism of SpD at bombesin receptors may affect normal and tumor cell migration.
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PMID:Agonist function of the neurokinin receptor antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, in monocytes. 1297 27

Lysophosphatidic acid (1-acyl-2-lyso-sn-glycero-3-phosphate; LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids which respectively act as agonists for the G-protein-coupled lpA receptors (LPA1, LPA2, and LPA3) and s1p receptors (S1P1, S1P2, S1P3, S1P4, and S1P5), collectively referred to as lysophospholipid receptors (lpR). Since astrocytes are responsive to LPA and S1P, we examined mechanisms of lpR signaling in rat cortical secondary astrocytes. Rat cortical astrocyte mRNA expression by quantitative TaqMan polymerase chain reaction (PCR) analysis revealed the following order of relative expression of lpR mRNAs: s1p3>s1p1>lpa1>s1p2=lpa3>>s1p5. Activation of lpRs by LPA or S1P led to multiple pharmacological effects, including the influx of calcium, phosphoinositide (PI) hydrolysis, phosphorylation of extracellular receptor regulated kinase (ERK) and release of [3H]-arachidonic acid (AA). These signalling events downstream of lpR activation were inhibited to varying degrees by pertussis toxin (PTX) pretreatment or by the inhibition of sphingosine kinase (SK), a rate-limiting enzyme in the biosynthesis of S1P from sphingosine. These results suggest that astrocyte lpR signalling mechanisms likely involve both Gi- and Gq-coupled GPCRs and that receptor-mediated activation of SK leads to intracellular generation of S1P, which in turn amplifies the lpR signalling in a paracrine/autocrine manner.
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PMID:Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. 1456 43

We identified and cloned the mouse orthologue of human GPR6 as a new member of the lysophospholipid-receptor family. Sphingosine-1-phosphate (S1P) activated GPR6, transiently expressed in frog oocytes or in Chinese hamster ovary (CHO) cells, with high specificity and nanomolar affinity. The GPR6 gene was found to be located on chromosome 10B1 and a single exon coded for the entire open-reading frame. Signal transduction of S1P was inhibited by pertussis toxin, suggesting a coupling of GPR6 to an inhibitory G protein. In CHO cells transfected with GPR6, the sphingosine-kinase pathway mediated Ca(2+) mobilization from internal stores. Apoptotic cell death was induced by serum deprivation or H(2)O(2) treatment and was prevented by S1P in GPR6-, but not in vector-transfected CHO cells. The antiapoptotic effect of S1P required activation of sphingosine kinase and was accompanied by an increase in MAP-kinase phosphorylation.
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PMID:Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. 1459 18

Clostridium perfringens alpha-toxin induces hemolysis of rabbit erythrocytes through the activation of glycerophospholipid metabolism. Sheep erythrocytes contain large amounts of sphingomyelin (SM) but not phosphatidylcholine. We investigated the relationship between the toxin-induced hemolysis and SM metabolic system in sheep erythrocytes. Alpha-toxin simultaneously induced hemolysis and a reduction in the levels of SM and formation of ceramide and sphingosine 1-phosphate (S1P). N-Oleoylethanolamine, a ceramidase inhibitor, inhibited the toxin-induced hemolysis and caused ceramide to accumulate in the toxin-treated cells. Furthermore, dl-threo-dihydrosphingosine and B-5354c, isolated from a novel marine bacterium, both sphingosine kinase inhibitors, blocked the toxin-induced hemolysis and production of S1P and caused sphingosine to accumulate. These observations suggest that the toxin-induced activation of the SM metabolic system is closely related to hemolysis. S1P potentiated the toxin-induced hemolysis of saponin-permeabilized erythrocytes but had no effect on that of intact cells. Preincubation of lysated sheep erythrocytes with pertussis toxin blocked the alpha-toxin-induced formation of ceramide from SM. In addition, incubation of C. botulinum C3 exoenzyme-treated lysates of sheep erythrocytes with alpha-toxin caused an accumulation of sphingosine and inhibition of the formation of S1P. These observations suggest that the alpha-toxin-induced hemolysis of sheep erythrocytes is dependent on the activation of the SM metabolic system through GTP-binding proteins, especially the formation of S1P.
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PMID:Clostridium perfringens alpha-toxin activates the sphingomyelin metabolism system in sheep erythrocytes. 1470 48


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