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 coupling of two endothelin receptor subtypes (ET(A) and ETB) to several types of guanine-nucleotide-binding regulatory protein (G protein) was examined. Two subtypes of receptor cDNAs were transfected alone or together with four different G protein alpha subunit cDNAs in COS-7 cells. In ET(A) receptor-transfected cells, endothelin-1 (ET-1) activated phosphatidylinositol-specific phospholipase C as measured by the production of phosphatidylinositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. ETB-receptor-transfected cells also produced Ins(1,4,5)P3 on stimulation by ET-1. The ET-1-induced production of Ins(1,4,5)P3 was markedly higher in G alpha q-cotransfected or G alpha 11-cotransfected cells than in cells transfected with each receptor alone. ET-1 also stimulated production of cAMP in ET(A) or ETB receptor-transfected cells. The production of cAMP was synergistically amplified by G alpha s co-transfection with each receptor. In contrast, when G alpha i2 was co-transfected with the ET(A) or ETB receptor, ET-1 displayed an inhibitory action on forskolin-stimulated cAMP accumulation. Pertussis-toxin treatment of the G alpha i2-transfected cells resulted in abolition of the endothelin-induced inhibition of cAMP accumulation. These observations indicate that both ET(A) and ETB receptors are able to couple to Gq, G11, Gs and Gi2, and suggest that endothelin receptors stimulate multiple effectors via several types of G protein simultaneously. The overall effects induced by endothelin may differ in cell types depending on the level of expression of each G-protein subtype in the cell.
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PMID:Molecular identification of guanine-nucleotide-binding regulatory proteins which couple to endothelin receptors. 788 89

1. We designed a new method to determine quantitatively the intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells in situ, using front-surface fluorometry and fura-2-loaded porcine aortic valvular strips. Using this method, we investigated the characteristics of the G-protein involved in endothelin-1 (ET-1)-induced changes in [Ca2+]i of endothelial cells in situ. 2. Endothelial cells were identified by specific uptake of acetylated-low density lipoprotein labelled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-Ac-LDL). Double staining with DiI-Ac-LDL and fura-2 showed that the valvular strip was covered with a monolayer of endothelial cells and that the cellular component which contributed to the fura-2 fluorescence, [Ca2+]i signal, was exclusively endothelial cells. 3. ET-1 (10(-7) M) induced an elevation of [Ca2+]i consisting of two components: the first was a rapid and transient elevation to reach a peak, followed by a second, sustained elevation (the second phase). The first phase was composed of extracellular Ca(2+)-independent and -dependent components, while the second phase was exclusively extracellular Ca(2+)-dependent. The extracellular Ca(2+)-independent component of the first phase was due to the release of Ca2+ from intracellular storage sites. The second phase and part of the first phase of [Ca2+]i elevation were attributed to the influx of extracellular Ca2+. The Ca2+ influx component was completely inhibited by 10(-3) M Ni2+ but was not affected by 10(-5) M diltiazem. 4. Pertussis toxin (IAP) markedly inhibited the extracellular Ca2+-dependent elevation of [Ca2+]j, but had no effect on the extracellular Ca2+-independent elevation of [Ca2+], caused by ET-1 (10-7M).5. Bradykinin (10-7 M) or ATP (10- 5M) elevated [Ca2+]i and these responses also consisted of extracellular Ca2+-independent and extracellular Ca2+-dependent components. IAP had no effect on either component of the [Ca2+]i elevation induced by bradykinin or ATP.6. From these findings we conclude that, in porcine endotheliel cells in situ, ET-1 elevates [Ca2+]i as are result of a Ca2+ influx component from the extracellular space and release of intracelluarly stored Ca2+ .The Ca2+ influx is regulated by an IAP-sensitive G-protein, while the release of Ca2+ from the intracellular store is not.
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PMID:Sensitivity of G-protein involved in endothelin-1-induced Ca2+ influx to pertussis toxin in porcine endothelial cells in situ. 803 27

Endothelin-1 is a peptide hormone constitutively secreted by vascular and endocardial endothelial cells. Secretion of endothelin-1 is increased under certain pathophysiological conditions, including coronary vasospasm, cardiac ischaemia and myocardial infarction. We have examined the effect of endothelin-1 on the protein kinase A (PKA)-dependent chloride current in voltage-clamped guinea pig ventricular myocytes. This conductance, induced by catecholamines through beta-adrenergic receptors, counteracts the simultaneously increased L-type calcium current by shortening the action potential duration. We report here that endothelin-1, acting through ETA (endothelin-1-selective) receptors, inhibited the current through a pertussis toxin-sensitive mechanism, analogous to muscarinic receptors, by reducing the intracellular cyclic AMP concentration. This effect of endothelin-1 should help protect the ventricle against potentially arrhythmogenic shortening of the action potential during ischaemia when the circulating levels of catecholamines are increased.
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PMID:Inhibition of the cardiac protein kinase A-dependent chloride conductance by endothelin-1. 751 70

Voltage-sensitive ion channels play fundamental roles in the regulation of cardiac function by various neurotransmitters. Endothelins have strong positive inotropic and chronotropic effects, for which recent studies have implicated various intracellular mechanisms. However, very little is known about the underlying ion-channel regulation by the peptide. We report here that endothelin-1 consistently hyperpolarizes the membrane and shortens the duration of the action potential in mammalian atrial myocytes, leading to suppression of electrical excitability of the heart. Endothelin-1, but not endothelin-3, inhibited the L-type calcium current by decreasing cyclic AMP accumulation and activated the muscarinic potassium current by stimulating a pertussis toxin-sensitive GTP-binding protein. Consistent with these results, endothelin-1 strongly reduced the heart rate when it was increased by beta-adrenoceptor stimulation. These effects were blocked by an ETA (endothelin-1-selective) receptor-selective antagonist, BQ123 (refs 8-11). The ETA receptor-mediated regulation of cardiac ion channels gives new insight into our understanding of the physiological and pathophysiological roles of endothelins in the control of cardiac function.
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PMID:Endothelin-A receptor mediates cardiac inhibition by regulating calcium and potassium currents. 751 70

The kinetic properties of endothelin-1 (ET-1) binding sites and the production of inositol phosphates (IPs; IP1, IP2, IP3), cyclic AMP, thromboxane B2, and prostaglandin F2 alpha induced by various endothelins (ET-1, ET-2, ET-3, and sarafotoxin S6b) were examined in endothelial cells derived from human brain microvessels (HBECs). The presence of both high- and low-affinity binding sites for ET-1 with KD1 = 122 pM and KD2 = 31 nM, and Bmax1 = 124 fmol/mg of protein and Bmax2 = 909 fmol/mg of protein, respectively, was demonstrated on intact HBECs. ET-1 dose-dependently stimulated IP accumulation with EC50 (IP3) = 0.79 nM, whereas ET-3 was ineffective. The order of potency for displacing ET-1 from high-affinity binding sites (ET-1 > ET-2 > sarafotoxin S6b > ET-3) correlated exponentially with the ability of respective ligands to induce IP3 formation. ET-1-induced IP3 formation by HBEC was inhibited by the ETA receptor antagonist, BQ123. The protein kinase C activator phorbol myristate ester dose-dependently inhibited the ET-1-stimulated production of IPs, whereas pertussis toxin was ineffective. Cyclic AMP production by HBECs was enhanced by both phorbol myristate ester and ET-1, and potentiated by combined treatment with ET-1 and phorbol myristate ester. Data indicate that protein kinase C plays a role in regulating the ET-1-induced activation of phospholipase C, whereas interaction of different messenger systems may regulate ET-1-induced accumulation of cyclic AMP. ET-1 also stimulated endothelial prostaglandin F2 alpha production, suggesting that activation of phospholipase A2 is most likely secondary to IP3-mediated intracellular calcium mobilization because both ET-1-induced IP3 and prostaglandin F2 alpha were inhibited by BQ123. These findings are the first demonstration of ET-1 (ETA-type) receptors linked to phospholipase C and phospholipase A2 activation in HBECs.
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PMID:Endothelin-1 receptor binding and cellular signal transduction in cultured human brain endothelial cells. 829 22

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

1. In cultures of bovine tracheal smooth muscle cells, platelet-derived growth factor-BB (PDGF), bradykinin (BK) and endothelin-1 (ET-1) stimulated the tyrosine phosphorylation and activation of both pp42 and pp44 kDa forms of mitogen-activated protein (MAP) kinase. 2. Both ET-1 and PDGF stimulated a sustained activation of MAP kinase whilst the response to BK was transient. 3. Activation of MAP kinase occurred in a concentration-dependent manner (EC50 values: ET-1, 2.3 +/- 1.3 nM; BK, 8.7 +/- 4.1 nM, PDGF, 9.7 +/- 3.2 ng ml-1). 4. Pretreatment with the protein kinase C (PKC) inhibitor Ro-318220, significantly reduced ET-1 activation of MAP kinase at 2 and 5 min but enhanced MAP kinase activation at 60 min. 5. Following chronic phorbol ester pretreatment, BK-stimulated activation of MAP kinase was abolished whilst the responses to PDGF and ET-1 were only partly reduced (80 and 45% inhibition respectively). 6. Pretreatment with pertussis toxin reduced ET-1 stimulated activation of MAP kinase particularly at later times (60 min), but left the responses to both PDGF and BK unaffected. 7. ET-1 also stimulated a 3 fold increase in [3H]-thymidine incorporation which was abolished by pertussis toxin pretreatment. In contrast, PDGF stimulated a 131 fold increase in [3H]-thymidine incorporation which was not affected by pertussis toxin. 8. These results suggest that a pertussis toxin-sensitive activation of MAP kinase may play an important role in ET-1-stimulated DNA synthesis but that activation of MAP kinase alone is not sufficient to induce the magnitude of DNA synthesis observed in response to PDGF.
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PMID:Stimulation by endothelin-1 of mitogen-activated protein kinases and DNA synthesis in bovine tracheal smooth muscle cells. 856 58

The objective of this study was to determine whether adenosine A1 or A2 receptor was responsible for the regulation of protein kinase C (PKC) in porcine coronary artery and its coupling to G-protein. Endothelium denuded arterial rings were incubated with PDBu (200 nM) in the presence or absence of adenosine receptor agonists and antagonists for 1 day. Following incubation, the arterial rings were contracted with increasing concentrations of endothelin-1 (ET-1) (10(-10)-10(-7) M). Arteries incubated with PDBu alone failed to produce contraction in response to ET-1. On the contrary, inclusion of A1 receptor agonist ENBA at 10(-9) M in the incubation media with PDBu protected against the PDBu induced blunting of the ET-1 contractions by 50%. Incubation with ENBA alone increased ET-1 dependent contractions by about 2 fold. Inclusion of A1 receptor antagonist, N0861 at 10(-6) M along with PDBu and ENBA, completely blocked the protective effect of ENBA against the PDBu induced attenuation of ET-1 contractions. N0861 also completely blocked the increase in ET-1 contractions in the arterial rings incubated with ENBA alone. Another A1 receptor antagonist DPCPX also produced similar results as N0861. On the contrary, arterial rings incubated with relatively specific A2 receptor agonist CGS 21680 at 10(-4) M did not produce any protection against PDBu induced blunting of the ET-1 contractions. Incubation with CGS 21680 alone also did not significantly alter the ET-1 contractions. Interestingly, inclusion of A2 receptor antagonist DMPX at 10(-4) M in the incubation media along with CGS 21680 mimicked the effects of ENBA alone i.e. produced protection against PDBu and enhanced ET-1 contractions. Incubation of the arteries with ENBA alone caused an accumulation of PKC levels, whereas, incubation with CGS 21680 had no significant effect on PKC levels. To study the coupling of adenosine receptor with G-protein, the tissue was incubated for one day with cholera (CT) or pertussis toxin (PT) in the presence or absence or ENBA and PDBu as described above. Incubation with PT blocked the protective effect of ENBA against PDBu as well as the elevation of ET-1 response when incubated with ENBA alone. On the contrary, incubation with CT did not produce any significant effect on ENBA responses. These results indicate that PKC is modulated by adenosine via A1 adenosine receptors and through a PT sensitive G-protein.
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PMID:Modulation of protein kinase C by adenosine: involvement of adenosine A1 receptor-pertussis toxin sensitive nucleotide binding protein system. 856 49

To investigate the action of endothelin-1 (ET-1) on L-type Ca currents (ICa,L) in guinea-pig ventricular cells, whole-cell currents were recorded at approximately 36-37 degrees C in enzymatically isolated myocytes. ET-1 (> or =10 nM) suppressed the basal ICa,L to 79+/-8% of control at 20 nM. Bath application of isoproterenol (ISO; 10 nM) enhanced ICa,L to 192+/-28% with about a -10-mV shift of its relationship with membrane potential. ET-1 concentration dependently inhibited this ISO-enhanced ICa,L with a half-maximally inhibitory concentration (IC50) of 168 pM. The inhibitory actions of ET-1 were antagonised by BQ-123 (300 nM), cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp), a specific ETA receptor antagonist. Histamine-enhanced ICa,L was also suppressed by ET-1, but ICa, L potentiated by internal adenosine 3',5'-cyclic monophosphate (cAMP) was unaffected. Preincubation of myocytes with pertussis toxin (PTX, at 5 microgram/ml for >60 min at 36 degrees C) completely occluded the ET-1 action. Thus, stimulation of ETA receptors by subnanomolar ET-1 inhibits ICa,L via PTX-sensitive G-proteins.
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PMID:Endothelin-1 inhibits L-type Ca currents enhanced by isoproterenol in guinea-pig ventricular myocytes. 859 96

The aims of this study were to determine whether endothelin-1 (ET-1), a positive inotropic agent, altered the production of cyclic AMP (cAMP) in adult feline cardiac myocytes and to characterize the effect with respect to G-protein-coupling and calcium regulation of adenylyl cyclase. ET-1 inhibited basal and/or stimulated cAMP accumulation in the intact cardiac myocyte and in membrane preparations in a dose-dependent manner. In intact cells, maximal inhibition of forskolin-stimulated cAMP accumulation was 90-95% with an EC50 of 5 x 10(-10) M. Inhibition of isoproterenol-stimulated cAMP was biphasic with maximal inhibition of 70% observed by 10(-11)M; at higher doses inhibition was not consistently observed. The inhibitory response to ET-1 occurred in the absence or presence of isobutylmethylxanthine suggesting that activation of cAMP phosphodiesterases was not the means for reducing cAMP levels. Prior exposure of cardiac myocytes to 100ng/ml pertussis toxin blocked the inhibitory action of ET-1, indicating that this response is mediated through the involvement of a pertussis toxin-sensitive G-protein such as Gi. Studies carried out in the absence of extracellular calcium and under conditions of cell-loading with the intracellular calcium chelator, 1,2-bis-(2-aminophenoxy)-ethane-N,N,N'N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM), suggest that the mechanism by which ET-1 inhibits cAMP accumulation is not calcium-dependent. Thus, inhibition of cAMP accumulation by ET-1 appears to be mediated through a pertussis toxin sensitive protein rather than by activation of phosphodiesterases or calcium inhibition of cardiac forms of adenylyl cyclase. Though unlikely to play a role in the positive inotropic effect of ET-1, transduction of ET-1 responses through Gi suggests another means for regulation of growth in these adult cardiac myocytes.
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PMID:Inhibition of cyclic AMP accumulation by endothelin is pertussis toxin sensitive and calcium independent in isolated adult feline cardiac myocytes. 860 20

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