UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of secretory phospholipase A2 (sPLA2) on intracellular Ca2+ signaling in human astrocytoma cells was studied. sPLA2 increased cytosolic [Ca2+] ([Ca2+]c) in both Ca2+-containing and Ca2+-free medium, thus suggesting Ca2+ release from intracellular stores. The activation by sPLA2 of arachidonate release via cytosolic PLA2 (cPLA2) was also independent of extracellular Ca2+. As sPLA2 requires Ca2+ for activity, these results indicate that both Ca2+ mobilization and cPLA2 activation induced by sPLA2 are unrelated to phospholipase activity but dependent on signaling mechanisms. The sPLA2-induced [Ca2+]c peak was sensitive to Bordetella pertussis toxin and inhibited by caffeine, suggesting its mediation by inositol 1,4,5-trisphosphate (IP3). sPLA2 induced tyrosine phosphorylation and membrane targeting of phospholipase Cgamma-1 (PLCgamma-1). Moreover, the Ca2+ peak was sensitive to protein tyrosine kinase inhibitors. sPLA2 activates two signaling pathways: one leading to the activation of the MAP kinase/cPLA2 cascade and another leading to PLCgamma activation and Ca2+ release.
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PMID:Secretory phospholipase A2 induces phospholipase Cgamma-1 activation and Ca2+ mobilization in the human astrocytoma cell line 1321N1 by a mechanism independent of its catalytic activity. 1038 50

We recently cloned and expressed a novel P2Y receptor (tp2y receptor) from a turkey cDNA library. Expression of this receptor in 1321N1 human astrocytoma cells confers nucleotide-dependent stimulation of phospholipase C activity; however, as we demonstrate here, it also confers nucleotide-dependent inhibition of adenylyl cyclase. Both the phospholipase C and adenylyl cyclase responses were promoted by receptor agonists over a similar range of concentrations. Moreover, not only did UTP and ATP activate the avian receptor but ITP, GTP, xanthosine 5'-triphosphate, and CTP were also agonists, with EC(50) values ranging between 0.1 and 1 microM. Similar potencies, rank-order, and selectivity of nucleotide agonists were also demonstrated for intracellular Ca(2+) mobilization measured during a 30-s stimulation under constant superfusion conditions. This observation indicates that receptor activation by nucleoside 5'-triphosphates is not produced by interconversion of these nucleotides into ATP or UTP. Pretreatment of cells with pertussis toxin completely abolished the inhibitory effect of nucleotide agonists on adenylyl cyclase, whereas the activation of phospholipase C was only partially inhibited. These results demonstrate that the avian P2Y receptor is a nucleoside triphosphate receptor of broad agonist selectivity that interacts with both pertussis toxin-insensitive and -sensitive G proteins to activate phospholipase C and to inhibit adenylyl cyclase. This is the first cloned P2Y receptor that is clearly Gi/adenylyl cyclase-linked.
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PMID:A molecularly identified P2Y receptor simultaneously activates phospholipase C and inhibits adenylyl cyclase and is nonselectively activated by all nucleoside triphosphates. 1072 29

Cannabinoids exert most of their effects in the central nervous system through the CB(1) cannabinoid receptor. This G-protein-coupled receptor has been shown to be functionally coupled to inhibition of adenylate cyclase, modulation of ion channels and activation of extracellular-signal-regulated kinase. Using Chinese hamster ovary cells stably transfected with the CB(1) receptor cDNA we show here that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces the activation of protein kinase B/Akt (PKB). This effect of THC was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoids CP-55940 and HU-210, and was prevented by the selective CB(1) antagonist SR141716. Pertussis toxin and wortmannin blocked the CB(1) receptor-evoked activation of PKB, pointing to the sequential involvement of a G(i)/G(o) protein and phosphoinositide 3'-kinase. The functionality of the cannabinoid-induced stimulation of PKB was proved by the increased phosphorylation of glycogen synthase kinase-3 serine 21 observed in cannabinoid-treated cells and its prevention by SR141716 and wortmannin. Cannabinoids activated PKB in the human astrocytoma cell line U373 MG, which expresses the CB(1) receptor, but not in the human promyelocytic cell line HL-60, which expresses the CB(2) receptor. Data indicate that activation of PKB may be responsible for some of the effects of cannabinoids in cells expressing the CB(1) receptor.
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PMID:The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. 1074 65

Activation of astrocytes is important in the pathogenesis of a variety of diseases in the central nervous system, such as infection and neurodegeneration. We found that the bacterial chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLF) induced potent migration and Ca(2+) mobilization in human astrocytoma cell lines. The effect of fMLF was pertussis toxin-sensitive, suggesting the involvement of seven transmembrane, G protein-coupled receptor(s) for fMLF. Scatchard analyses revealed that astrocytoma cell lines express both high- and low-affinity binding sites for [3H]fMLF. RT-PCR confirmed the expression of transcripts of fMLF receptors, the high-affinity FPR and the low-affinity FPRL1 by these cells. Both fMLF and F peptide, a synthetic peptide domain of HIV-1 envelope protein which specifically activates FPRL1, increased secretion of IL-6 by astrocytoma cells. Our study demonstrates for the first time that FPR and FPRL1 expressed by astrocytoma cell lines are functional, and suggests a molecular basis for the involvement of these receptors in host defense in the brain.
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PMID:Expression of functional formyl peptide receptors by human astrocytoma cell lines. 1106 27

Sphingosine-1-phosphate (SPP), a bioactive sphingolipid metabolite, suppresses apoptosis of many types of cells, including rat pheochromocytoma PC12 cells. Elucidating the molecular mechanism of action of SPP is complicated by many factors, including uptake and metabolism, as well as activation of specific G-protein-coupled SPP receptors, known as the endothelial differentiation gene-1 (EDG-1) family. In this study, we overexpressed type 1 sphingosine kinase (SPHK1), the enzyme that converts sphingosine to SPP, in order to examine more directly the role of intracellularly generated SPP in neuronal survival. Enforced expression of SPHK1 in PC12 cells resulted in significant increases in kinase activity, with corresponding increases in intracellular SPP levels and concomitant decreases in both sphingosine and ceramide, and marked suppression of apoptosis induced by trophic factor withdrawal or by C(2)-ceramide. NGF, which protects PC12 cells from serum withdrawal-induced apoptosis, also stimulated SPHK1 activity. Surprisingly, overexpression of SPHK1 had no effect on activation of two known NGF-stimulated survival pathways, extracellular signal regulated kinase ERK 1/2 and Akt. However, trophic withdrawal-induced activation of the stress activated protein kinase, c-Jun amino terminal kinase (SAPK/JNK), and activation of the executionary caspases 2, 3 and 7, were markedly suppressed. Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface G(i)-coupled SPP receptors. In agreement, there was no detectable release of SPP into the culture medium, even after substantially increasing cellular SPP levels by NGF or sphingosine treatment. In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells. Collectively, our results indicate that SPHK/SPP may play an important role in neuronal survival by regulating activation of SAPKs and caspases.
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PMID:Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. 1123 41

Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.
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PMID:The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. 1130 75

Mitogen-activated protein kinase (MAPK) can be phosphorylated by mitogens binding to G-protein-coupled receptors and is considered a major pathway involved in cell proliferation. In this study, we report on the activation of MAPK by muscarinic acetylcholine receptors in astroglial cells, namely the 1321N1 human astrocytoma cell line, primary rat cortical astrocytes, and fetal human astrocytes. Carbachol caused a rapid and transient phorphorylation of MAPK (ERK1/2) in all cell types, with an increase in MAPK activity, without changing the levels of MAPK proteins. Human astrocytoma cells were used to characterize the effect of carbachol on MAPK. Experiments with M2- and M3-receptor subtype-selective antagonists, and with pertussis toxin, indicated that the M3 subtype is responsible for activating MAPK in glial cells. Pretreatment of cells with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, or downregulation of PKC by 24-h treatment with the phorbol ester TPA inhibited carbachol-induced MAPK activation. Additional experiments with PKC alpha- or PKC epsilon-specific compounds indicated that the epsilon isozyme of PKC is primarily involved in MAPK activation by carbachol. Chelation of calcium also inhibited MAPK activation by carbachol. Two MEK (MAPK kinase) inhibitors inhibited carbachol-induced DNA synthesis but only at concentrations that exceeded those sufficient to block carbachol-induced MAPK activation. Ethanol (< or =200 mM) had no effect on MAPK when present alone and did not affect carbachol-induced MAPK activation under various experimental conditions, although it inhibits carbachol-induced DNA synthesis at low concentrations (10-100 mM). These results suggest that activation of MAPK by carbachol may be necessary but not sufficient for its mitogenic effect in astroglial cells, and that does not represent a target for ethanol-induced inhibition of DNA synthesis elicited by muscarinic receptors.
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PMID:Activation of mitogen-activated protein kinase by muscarinic receptors in astroglial cells: role in DNA synthesis and effect of ethanol. 1146 Feb 67

A(3) adenosine receptor activation has been previously demonstrated to result in both neuroprotective and neurodegenerative effects, depending upon specific pathophysiological conditions. This dual effect may depend on receptor regulation mechanisms that are able to change receptor availability and/or function. In the present study, we investigated desensitization, internalization, and down-regulation of native A(3) adenosine receptors in human astrocytoma cells after exposure to the agonist 2-chloro-N6-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (Cl-IBMECA). Cl-IBMECA induced a concentration-dependent inhibition of adenylyl cyclase activity with an EC(50) value of 2.9 +/- 0.1 nM. The effect was suggested to be mediated by A(3) adenosine receptor subtype by the use of selective adenosine receptor antagonists. Cell treatment with pertussis toxin abolished Cl-IBMECA-mediated inhibition of adenylyl cyclase activity, evidencing an A(3) receptor coupling to inhibitory G protein. Short-term exposure to the agonist Cl-IBMECA (100 nM) caused rapid receptor desensitization, within 15 min. Agonist-induced desensitization was accompanied by receptor internalization: A(3) adenosine receptor internalized with rapid kinetics, within 30 min, after cell exposure to 100 nM Cl-IBMECA. The localization of A(3) adenosine receptors on the plasma membrane and in intracellular compartments was directly revealed by immunogold electron microscopy. After desensitization, the removal of agonist led to the restoration of A(3) adenosine receptor functioning through receptor recycling to the cell surface within 120 min. Prolonged agonist exposure (1-24 h) resulted in a marked down-regulation of A(3) adenosine receptors that reached 21.9 +/- 2.88% of control value after 24 h. After down-regulation, the recovery of receptor functioning was slow (24 h) and associated with the restoration of receptor levels close to control values. In conclusion, our results demonstrated that A(3) receptors, in astrocytoma cells, are regulated after short- and long-term agonist exposure.
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PMID:A3 adenosine receptors in human astrocytoma cells: agonist-mediated desensitization, internalization, and down-regulation. 1243 5

G-protein-coupled receptors signal through Rho to induce actin cytoskeletal rearrangement. We previously demonstrated that thrombin stimulates Rho-dependent process retraction and rounding of 1321N1 astrocytoma cells. Surprisingly, while lysophosphatidic acid (LPA) activated RhoA in 1321N1 cells, it failed to produce cell rounding. Thrombin, unlike LPA, decreased Rac1 activity, and activated (GTPase-deficient) Rac1 inhibited thrombin-stimulated cell rounding, while expression of dominant-negative Rac1 promoted LPA-induced rounding. LPA and thrombin receptors appear to differ in coupling to Gi, as LPA but not thrombin-stimulated 1321N1 cell proliferation was pertussis toxin-sensitive. Blocking Gi with pertussis toxin enabled LPA to induce cell rounding and to decrease activated Rac1. These data support the hypothesis that Rac1 and Gi activation antagonize cell rounding. Thrombin and LPA receptors also differentially activated Gq pathways as thrombin but not LPA increased InsP3 formation and reduced phosphatidylinositol 4,5-bisphosphate (PIP2) levels. Microinjection of the plekstrin homology domain of phospholipase C (PLC)delta1, which binds PIP2, enabled LPA to elicit cell rounding, consistent with a requirement for PIP2 reduction. We suggest that Rho-mediated cytoskeletal responses are enhanced by concomitant reductions in cellular levels of PIP2 and Rac1 activation and thus effected only by G-protein-coupled receptors with appropriate subsets of G protein activation.
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PMID:Rho-mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2. 1544 83

In transfected cells, the P2Y14 receptor reportedly couples to pertussis toxin-sensitive G(i/o)-proteins. However, the functional coupling of endogenously expressed P2Y14 receptors to the inhibition of adenylyl cyclase activity has not been reported. Therefore, the primary aim of this study was to investigate the effects of uridine 5'-diphosphoglucose (UDP-glucose) on forskolin-stimulated cyclic AMP (cAMP) accumulation in two cell lines that reportedly express P2Y14 receptor mRNA, namely human neuroblastoma SH-SY5Y cells and human astrocytoma U373 MG cells. In U373 MG cells, UDP-glucose inhibited forskolin-stimulated cAMP accumulation in a concentration-dependent manner (pEC50=4.5 +/- 0.3). Furthermore, treatment with pertussis toxin abolished the inhibitory effects of UDP-glucose on forskolin-stimulated cAMP accumulation in U373 MG cells. In SH-SY5Y cells, UDP-glucose had no significant effect on forskolin-stimulated cAMP accumulation. To confirm the expression of P2Y14 receptor mRNA in U373 MG and SH-SY5Y cells, we performed reverse transcriptase polymerase chain reaction (RT-PCR) analysis. However, RT-PCR did not detect the expression of P2Y14 receptor mRNA in SH-SY5Y cells or surprisingly in U373 MG cells. In conclusion, we have shown that although UDP-glucose inhibits forskolin-stimulated cAMP accumulation in human U373 MG astrocytoma cells, we did not detect P2Y14 receptor mRNA in these cells. These results would suggest that the effects of UDP-glucose in U373 MG cells are independent of P2Y14 receptor expression. Thus, results obtained with UDP-glucose should be interpreted with caution, since they clearly may not necessarily reflect the involvement of the P2Y14 receptor.
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PMID:Pharmacological effects mediated by UDP-glucose that are independent of P2Y14 receptor expression. 1582 33

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