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)

We have previously demonstrated that human bronchial smooth muscle cells possess a single class of high-affinity binding sites for endothelin 1. In this study, we further characterized the receptor for endothelin 1 and evaluated the signal transduction mechanisms of this peptide. Stimulation of cultured human bronchial smooth muscle cells with endothelin 1 induced mobilization of Ca2+ from both intracellular and extracellular pools with a biphasic increase in cytoplasmic free Ca2+ concentration. Endothelin 1 increased cellular levels of inositol phosphates and diacylglycerol, indicating activation of phospholipase C, but induced production of inositol phosphates in smooth muscle cell membranes only in the presence of guanosine 5'-O-(thiotriphosphate) (GTP gamma S). Treatment of smooth muscle cells with pertussis toxin failed to block the endothelin 1-induced increase in inositol phosphate production and Ca2+ mobilization. These results suggest that the receptor for endothelin 1 in bronchial smooth muscle is coupled to phospholipase C through a pertussis toxin-insensitive G protein. Affinity crosslinking experiments identified the endothelin 1 receptor as a single band with an apparent molecular weight of approximately 70,000 on sodium dodecyl sulfate polyacrylamide gel electrophoresis, further supporting the functional evidence that endothelin 1 receptor belongs to the G protein-linked rhodopsin type of receptor superfamily.
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PMID:Mechanisms of calcium mobilization and phosphoinositide hydrolysis in human bronchial smooth muscle cells by endothelin 1. 165 61

Endothelin-1 acts as a potent autocrine and paracrine mediator in the kidney. Glomeruli and renal arterioles also express functional thrombin receptors which mediate the cellular effects of thrombin. Using the binding on glomerular epithelial cells of 125I-labeled ATAP2, a monoclonal antibody raised against the functional thrombin receptor, we demonstrate here that endothelin-1 induces thrombin receptor internalization in a dose- and a time-dependent manner. The maximal effect is observed at 10(-7) M endothelin-1 corresponding to internalization of approximately 25% of thrombin receptors. It is maximal at 20 min and persists for at least 24 h. This effect is mediated by the endothelin receptor subtype A (ETA), and involves a pertussis toxin-sensitive G-protein and protein kinase C activation. Endothelin-1 does not induce thrombin receptor degradation nor change in thrombin receptor mRNA level after 2 h and 24 h of incubation. These results indicate that partial heterologous internalization of the functional thrombin receptor is induced by endothelin-1.
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PMID:Endothelin-1 induces rapid and long lasting internalization of the thrombin receptor in human glomerular epithelial cells. 750 20

Binding data point to the coexistence of three endothelin receptors (ET-R) in rat heart myocytes. Induction of phosphoinositide hydrolysis in this preparation by endothelins (ET-1 and ET-3) or sarafotoxins (SRTX-b and SRTX-c) was demonstrated by measurement of labeled inositol phosphate generation. Pertussis toxin (PT) enhanced the induction of phosphoinositide hydrolysis by all four peptides. The process seems to be mediated by at least two heterotrimeric G-proteins, the one sensitive and the other insensitive to PT. Measurement of GTPase activity induced in rat myocytes clearly indicates for the first time the direct functional coupling between ET-R and a G-protein. These GTPase activity experiments provide evidence that phosphoinositide hydrolysis is stimulated via functional coupling between the endothelin receptor of the ETA-R subtype and a PT-insensitive G-protein, Gq/11. The involvement of PT-sensitive G-proteins, i.e. Gi-like and/or Go-like proteins, in the signal transduction pathways of ETs and SRTXs is discussed.
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PMID:Functional coupling between endothelin receptors and multiple G-proteins in rat heart myocytes. 808 27

The signalling pathways used by the human endothelin A receptor to activate phospholipase A2 in Chinese hamster ovary cells were investigated. Pertussis toxin caused a partial but significant reduction in endothelin-1-induced arachidonic acid release although cAMP-dependent kinase inhibitors did not mimic its action. Extracellular calcium and its entry into the cell was essential for activation of phospholipase A2 as its removal from media or incubation with an intracellular calcium chelator-reduced activation. Nifedipine had no effect on endothelin-1-induced arachidonic acid release while divalent cations caused a significant reduction indicating the possible role of CRAC. Thapsigargin caused an increase in arachidonic acid release which was completely inhibited by pertussis toxin treatment. This further supports the involvement of CRAC in calcium influx and activation of phospholipase A2 by the human endothelin A receptor.
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PMID:Activation of phospholipase A2 by the human endothelin receptor in Chinese hamster ovary cells involves Gi protein-mediated calcium influx. 852 39

Astrocytes have been shown to express endothelin (ET) receptors functionally coupled, via different heterotrimeric G proteins, to several intracellular pathways. To assess the relative contribution of each subtype in the astrocytic responses to ET-1, effects of BQ123, an antagonist selective for the ET receptor subtype A (ETA-R), and IRL1620, an agonist selective for the ET receptor subtype B (ETB-R), were investigated in primary cultures of rat astrocytes. Binding experiments indicated that the ETB-R is the predominant subtype in these cells. Inhibition of forskolin-stimulated cyclic AMP production was observed under. ETB-R stimulation. Bordetella pertussis toxin (PTX) pretreatment completely abolished this effect, indicating that this pathway is coupled to the ETB-R via Gi protein. Increases of tyrosine phosphorylation of cellular proteins, stimulation of mitogen-activated protein kinase (MAPK), and DNA synthesis were also found to be mediated by the ETB-R, but through PTX-insensitive G protein. IRL1620-induced MAPK activation involved the adapter proteins Shc and Grb2 and the serine/threonine kinase Raf-1. This study reveals that the various effects of ET-1 in astrocytes are mediated by the ETB-R, which couples to multiple signaling pathways including the MAPK cascade.
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PMID:Coupling of ETB endothelin receptor to mitogen-activated protein kinase stimulation and DNA synthesis in primary cultures of rat astrocytes. 859 14

In rat spinal cord slices, endothelin-1 and endothelin-3 enhanced [3H]inositol phosphate production between 1 nM and 10 microM (endothelin-1 > endothelin-3) while sarafotoxin 6c and the endothelin ETB receptor agonist IRL-1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21)) were almost ineffective. BQ-123 (cyclo(D-Trp,D-Asp,L-Pro,D-Val,L-Leu), a selective endothelin ETA receptor antagonist, reduced the endothelin-1- and endothelin-3-induced [3H]inositol phosphate production, with similar inhibition constants (IC50: 16.7 +/- 3.4 and 8.0 +/- 1.6 microM, respectively). The inhibition of endothelin-1 was enhanced when BQ-123 was preincubated for 30 min instead of 15 min. BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxy- carbonyltryptophanyl-D-Nle), a selective ETB receptor antagonist, did not modify the endothelin-1-induced [3H]inositol phosphate production. Big endothelin-1 (1 nM to 1 microM) was slightly less potent than endothelin-1 in enhancing [3H]inositol phosphate production. This response was sensitive to phosphoramidon and [Phe22]big endothelin-1-(19-37), two inhibitors of endothelin-converting enzyme. Pretreatment of slices with pertussis toxin, indomethacin or PN 200-110 ((-)-isradipine, a dual inhibitor of L- and R-type Ca2+ channels) did not alter the response to 1 microM endothelin-1 while this response was abolished by tetrodotoxin. Finally, endothelin-1 enhanced [3H]inositol phosphate production with an identical EC50 (2.1 nM) in spinal cord slices of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) although the maximal response was reduced in SHR. These data indicate that endothelins stimulated [3H]inositol phosphate production in the rat spinal cord through the activation of an endothelin ETA receptor that trigger the release of an unidentified neurotransmitter. This effect does not appear to be associated to activation of a Gi/G(o)-type of G-protein, dihydropyridine-sensitive L-type Ca2+ channels or to the production of prostaglandins. Furthermore, the findings support the presence of a phosphoramidon-sensitive endothelin-converting enzyme in the spinal cord.
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PMID:Receptor and mechanism that mediate endothelin- and big endothelin-1-induced phosphoinositide hydrolysis in the rat spinal cord. 898 72

We have shown previously that cytosolic phospholipase A(2) (cPLA(2)) is responsible for endothelin-1-induced release of arachidonic acid for prostaglandin synthesis in cat iris sphincter smooth muscle (CISM) cells [Husain and Abdel-Latif (1998) Biochim. Biophys. Acta 1392, 127-144]. Here we show that p38 mitogen-activated protein (MAP) kinase, but not p42/p44 MAP kinases, plays an important role in the phosphorylation and activation of cPLA(2) in endothelin-1-stimulated CISM cells. This conclusion is supported by the following findings. Both p38 MAP kinase and p42/p44 MAP kinases were present in the CISM cells and both were activated by endothelin-1. SB203580, a potent specific inhibitor of p38 MAP kinase, but not the p42/p44 MAP kinases specific inhibitor, PD98059, markedly suppressed endothelin-1-enhanced cPLA(2) phosphorylation, cPLA(2) activity and arachidonic acid release. The addition of endothelin-1 resulted in the phosphorylation and activation of cPLA(2). Endothelin-1 stimulated p38 MAP kinase activity in a time- and concentration-dependent manner, and these effects were mediated through the endothelin-A receptor subtype. The protein kinase C (PKC) inhibitor, RO 31-8220, had no inhibitory effect on endothelin-1-induced p38 MAP kinase activation, suggesting that endothelin-1 activation of p38 MAP kinase is independent of PKC. Pertussis toxin inhibited both endothelin-1 and mastoparan stimulation of p38 MAP kinase activity and arachidonic acid release. The inhibitory effects of pertussis toxin are not mediated through cAMP formation. Mastoparan-stimulated [(3)H]arachidonic acid release and cPLA(2) activation was inhibited by SB203580, but not by RO 31-8220. These data suggest that endothelin-1 binds to the endothelin-A receptor to activate the Gi-protein which, through a series of kinases, leads to the activation of p38 MAP kinase and subsequently to phosphorylation and activation of cPLA(2). Activation of cPLA(2) leads to the liberation of arachidonic acid from membrane phospholipids. The ability of the activated endothelin-A receptor, which is coupled to both Gq- and Gi-proteins, to recruit and activate this complex signal transduction pathway remains to be elucidated. Further studies on the mechanism of these relationships could provide important information about the functions of p38 MAP kinase in smooth muscle.
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PMID:Endothelin-1 activates p38 mitogen-activated protein kinase and cytosolic phospholipase A2 in cat iris sphincter smooth muscle cells. 1043 4

The presence of endothelin-1 receptor proteins and the expression of their specific mRNAs were studied using 1st passage confluent monolayers of articular chondrocytes, isolated from 1-month and 18-month-old rats following 24-h incubation with several growth factors and cytokines. The ET-1- binding sites were predominantly of ETA subtype since BQ123, but not IRL1038 (ETB receptor subtype agonist), effectively blocked 125I-ET-1 binding. The 18-month-old rat cell monolayers bear approximately twice as many 125I-ET-1-binding sites as the 1-month-old rat cells. PDGF, EGF, and IGF-1 increased the number of binding sites in a concentration-dependent manner in both old and young rat cells with PDGF being the most active and EGF more active than IGF-1. IL-1beta, more potently than LPS, increased the number of binding sites in young rat cells only, whereas b-FGF, TGF-beta and GM-CSF had no effect or decreased slightly 125I-ET-1 binding in both types of cells. TNF-alpha strongly decreased the number of binding sites on both young and old rat cells, only. RT-PCR showed an increased expression of the specific ETA mRNA with the age of animals and in the presence of 50 ng/ml PDGF BB only. The incubation of the cells with ETs 1-3 for 10 min resulted in a 50% decrease of cellular cAMP but the blocking of the receptors with BQ123 prior to their exposure to ETs had no effect on cAMP production whereas IRL1038 counteracted this effect only marginally. This suggests a receptor-independent mechanism for ETs-induced inhibition of cAMP production. However, a 10-min co-incubation of cells with ET-1 and with one of the following agents: cholera toxin, pertussis toxin, indomethacin, L-NMA, U73122 and calphostin resulted in an almost complete (calphostin) or partial suppression of ET-1-induced inhibition of cAMP production. The significance of these findings is unclear but the increased density of ET-1 binding sites on old rat cells and its regulation by certain growth factors or cytokines suggest the involvement of ET-1 in aging and possibly in age-related diseases.
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PMID:Endothelin-1 receptors on cultured rat articular chondrocytes: regulation by age, growth factors, and cytokines, and effect on cAMP production. 1129 69