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)

Endothelin acts via specific membrane-bound receptors through signal transduction pathways that include increases in intracellular free calcium and inositol triphosphate generation. Two endothelin receptors have been cloned. The ETA receptor is ET-1 selective, and the ETB receptor is isopeptide nonselective. Both receptor subtypes are widely distributed throughout the body, although ETA receptors predominate in vascular smooth muscle, whereas ETB receptors predominate in the brain. The presence of mixed receptor subtypes makes functional screening of subtype-specific analogues difficult. A eukaryotic expression vector was constructed by inserting the cloned coding region of the human ETB receptor downstream from the Rous sarcoma promoter. COS-7 cells were transfected with this construct, and cell lines were isolated with stably integrated copies of the relevant gene. One line, 1C7, was shown to specifically bind 125I-ET-1. Scatchard analysis indicated a Kd value of 8.8 pM and a Bmax value of 1.02 pM/mg. ET-1 stimulated phosphoinositide hydrolysis in a dose-dependent manner, as did ET-3, sarafotoxin 6c, and [1,3,13,15Ala]ET-1, whereas BQ123, a selective ETA receptor antagonist, did not inhibit the action of ET-1. The transfected receptor stimulates phosphoinositide (PI) hydrolysis via a pertussis-sensitive pathway. Pretreatment of the membrane from 1C7 cells with dithio-bis-nitrobenzoic acid (DTNB) a negatively charged, nonpenetrating agent capable of oxidizing sulfhydryl groups, and N-ethyl-maleimide (NEM), a penetrating agent that causes irreversible alkylation of sulfhydryl groups, significantly reduces Bmax but has no effect on Kd. In whole cells, DTNB pretreatment abolishes the ability of ET-1 to stimulate PI hydrolysis.
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PMID:COS-7 cells stably transfected to express the human ETB receptor provide a useful screen for endothelin receptor antagonists. 750 82

Using front-surface fluorometry and fura-2, the effect of endothelin (ET) on the cytosolic Ca concentration, (Ca)i, in smooth muscle cells and endothelial cells was determined. Both the contraction of smooth muscle cells and the release of endothelium-derived relaxing factor (EDRF) from endothelial cells are regulated by changes in (Ca)i. During contractions induced by U-46619, a thromboxane A2 analog, low doses of ET-1 induced an EDRF-dependent reduction of (Ca)i and force in porcine coronary arterial smooth muscles. Using porcine aortic valvular strips, we recorded the signals of (Ca)i in endothelial cells in situ. ET-1 induced an influx of Ca, which was markedly inhibited by pertussis toxin (IAP), thus indicating that this influx was regulated by an IAP-sensitive G-protein. BQ-123, a selective ETA receptor antagonist, partially inhibited the elevation of (Ca)i induced by ET-1, but did not affect the elevation of (Ca)i induced by ET-3. The sequence of cDNA encoding the porcine ETA receptor has been previously determined, and RT-PCR confirmed that ETA receptor mRNA was present in the endothelial cells on the aortic side of the valvular strips. Therefore, in addition to ETB receptors, functioning ETA receptors and ETA receptor mRNA can also be found in endothelial cells in situ. Thus, ET-1 may play an important role in controlling the coronary artery tonus not only by acting directly on smooth muscle cells to increase the force in a paracrine manner, but also by acting on endothelial cells to release EDRF in an autocrine manner, resulting in relaxation of smooth muscle cells.
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PMID:The effects of endothelin on vascular tonus. 758 Oct 32

The purpose of the present study was to determine the influence of pertussis toxin (PTX) on the pulmonary and systemic vasodilator responses to endothelin (ET) isopeptides in the intact cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by an intralobar arterial infusion of U-46619, intralobar arterial bolus injections of ET-1, ET-2, and ET-3 decreased lobar arterial pressure and systemic vascular resistance in a dose-related manner. The vasodilator responses to ET-1 and ET-2 in the cat lung were abolished by PTX pretreatment, whereas PTX pretreatment did not alter the pulmonary vasodilator response to ET-3 and cromakalim, a specific ATP-sensitive potassium (KATP) channel activator, and the systemic vasodilator responses to all ET isopeptides studied. Glipizide, an inhibitor of KATP channels, inhibited the pulmonary vasodilator responses to ET-1, ET-2, and ET-3, whereas the systemic vasodilator responses to these isopeptides were not changed. The present data are the first to provide a functional correlate in vivo suggesting the existence of different signal transduction mechanisms for two pulmonary vascular ET receptor subtypes, ETA-like that is PTX sensitive and has greater sensitivity to ET-1 and ET-2 (than to ET-3) and ETc-like that is PTX insensitive and has sensitivity to ET-3 (than to ET-1 and ET-2). However, both ET-receptor subtypes promote vasodilation in the adult pulmonary vascular bed by activating KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of G proteins in the vasodilator response to endothelin isopeptides in vivo. 766

We have studied whether endothelin (ET) isopeptides have any effects on adenylate cyclase activity via different guanyl nucleotide-binding proteins (G-proteins) in cultured rat vascular smooth muscle cells (VSMC) and bovine endothelial cells (EC). Northern blot analysis clearly demonstrated gene expression of ETA receptors in VSMC and ETB receptors in EC. ET-1 dose-dependently (10(-9)-10(-6) M) stimulated cAMP formation in VSMC, whose effect was inhibited completely by ETA receptor antagonist (BQ-123) but not by indomethacin or quinacrine. The ET-1-induced cAMP formation was additive with isoproterenol but not with cholera toxin. In contrast, ET-3 and ETB receptor agonist (BQ-3020) dose-dependently (10(-9)-10(-6) M) inhibited forskolin-stimulated cAMP formation in EC, whose effect was completely abolished by pertussis toxin. Cholera toxin ADP ribosylated 45- and 52-kilodalton proteins in VSMC, whereas pertussis toxin ADP ribosylated the 41-kilodalton protein in EC. These data suggest that, in addition to phospholipase C via Gq, ETA and ETB receptor subtypes are functionally coupled to adenylate cyclase, possibly via Gs in VSMC and Gi in EC, respectively.
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PMID:Endothelin receptor subtypes are coupled to adenylate cyclase via different guanyl nucleotide-binding proteins in vasculature. 767 93

Endothelin (ET) potently inhibits arginine vasopressin (AVP)-induced adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and Na-K-adenosinetriphosphatase (Na-K-ATPase) activity in the inner medullary collecting duct (IMCD). At least two types of ET receptors exist: ETA [binds ET-1 > ET-3 = sarafotoxin S6c (S6c)] and ETB (binds ET-1 = ET-3 = S6c). We examined which of these receptors mediates biological actions of ET in freshly isolated rat IMCD cells. Binding studies revealed comparable displacement of 125I-ET-3 by ET-1, ET-3, and S6c, whereas 125I-ET-1 was displaced by ET-1 >> ET-3 = S6c. Together, these studies confirm the presence of receptors in the IMCD with ETA and ETB binding characteristics. ET-1, ET-3, and S6c were equipotent in reducing AVP-stimulated cAMP accumulation. BQ-123, at concentrations selective for ETA receptor antagonism, did not alter the effect of ET-1, ET-3, or S6c. Pertussis toxin or protein kinase C blockade, but not indomethacin, inhibited the effect of ET-1 and S6c on AVP-stimulated cAMP accumulation, consistent with activation of the same signal transduction pathways. ET-1 and S6c were equipotent in reducing forskolin-stimulated cAMP accumulation, ruling out inhibition of AVP-receptor interaction as a common mechanism of action. Finally, ET-1, ET-3, and S6c caused comparable stimulation of prostaglandin E2 (PGE2) accumulation, an effect that was not blocked by BQ-123. These data indicate that an ETB-like receptor mediates ET stimulation of PGE2 and inhibition of AVP-enhanced cAMP accumulation in the IMCD. The function of the ETA-like receptor in the IMCD remains to be determined.
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PMID:Endothelin B receptor mediates ET-1 effects on cAMP and PGE2 accumulation in rat IMCD. 769 6

The possible involvement of a cAMP pathway in endothelin (ET) signal transduction was explored using rat atrial slices. We show that ET-1 induces both stimulation and inhibition of cAMP formation, depending on its concentration. Unexpectedly, the effects of ET-3 and of sarafotoxins b and c (SRTX-b and SRTX-c) on this pathway differ from that of ET-1. Moreover, we show that the ET-1-induced formation of cAMP results from catecholamine release in a process mediated by a Ca2+ channel coupled to a pertussis toxin sensitive G-protein. It is concluded that this pathway is mediated by a new ETA receptor subtype (probably presynaptic), for which ET-1 is an agonist and ET-3, SRTX-b, and SRTX-c are antagonists.
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PMID:Ligand-specific stimulation/inhibition of cAMP formation by a novel endothelin receptor subtype. 791 54

We characterized the endothelin (ET) receptor subtypes responsible for signal transduction in cultured porcine kidney epithelial LLC-PK1 cells. Both ET-1 (IC50, 43 pM) and ET-3 (IC50, 46 pM) inhibited the binding of [125I]ET-1 to LLC-PK1 cells to a similar extent. The binding affinity of LLC-PK1 cells was about 10,000 times higher for the ETB antagonist BQ-788 [N-cis-2,6-dimethyl-piperidinocarbonyl-L-tau-metylleucyl-D-+ ++Nin- methoxycarbonyltryptophanyl-D-norleucine] (IC50, 1.3 nM) than for the ETA antagonist BQ-123 [cyclo-(D-Trp-D-Asp-Pro-D-Val-Leu)] (IC50, 14 microM). ET-1 enhanced cyclic GMP (cGMP) production, but reduced vasopressin- and forskolin-stimulated cyclic AMP (cAMP) production. Both effects of ET-1 were antagonized by BQ-788, but not by BQ-123. The cAMP decrease, but not the cGMP increase, in response to ET-1 was inhibited by pertussis toxin, suggesting that the former response is mediated by pertussis toxin-sensitive Gi, whereas the latter is mediated by a pertussis toxin-insensitive G-protein. Therefore, the ETB receptors in LLC-PK1 cells couple to the two types of signal transduction cascades to reduce cAMP production and stimulate cGMP production via distinct G-proteins. ET-1 and probably also ET-3 may play a role in the regulation of renal epithelial transport by decreasing cAMP and increasing cGMP.
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PMID:Endothelin ETB receptors couple to two distinct signaling pathways in porcine kidney epithelial LLC-PK1 cells. 793 50

In estradiol-dominated rat myometrium, endothelin (ET)-1 caused contraction and increased the accumulation of [3H]inositol phosphates (EC50 = 70 nM), with the sequential generation of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate. There was a coincident early decrease in phosphatidyl-inositol bisphosphate. The ET-1 stimulatory effect was pertussis toxin insensitive, suggesting an activation of phospholipase C via Gq/G11 proteins. ET-1 also inhibited the generation of cAMP induced by forskolin (EC50 = 30 nM). The inhibition was maintained in Ca(2+)-depleted medium and was prevented by pertussis toxin, suggesting G(i)-mediated inhibition of adenylyl cyclase. The rank order of potency for these various ET-1 effects [ET-1 > (Thr2)-sarafotoxin-b >> ET-3], as well as the inhibitory effect displayed by BQ123, a specific ETA receptor antagonist, provided evidence for the involvement of the ETA receptor subtype. Exposure to ET-1 (15 min) resulted in concentration-dependent and homologous desensitization (40%) of the inositol phosphate response triggered by ET-1. There was virtually no recovery of ET-1-mediated inositol phosphate responses in the desensitized tissue even after 180 min of incubation. In contrast, the persistent low level of ET-1 activity that was observed in spite of several washings and in the absence of rechallenge with ET-1 was progressively revsersed and totally eliminated by BQ123. The ET-1 inhibitory effect on cAMP was also desensitized, as evidenced by the attenuation of the inhibitory effect of ET-1 after 15 min of ET-1 pretreatment. The data indicate that in rat myometrium the ETA receptor is coupled, via two distinct G proteins, to two main signal transduction cascades, which both undergo rapid desensitization.
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PMID:Endothelin receptor type A signals both the accumulation of inositol phosphates and the inhibition of cyclic AMP generation in rat myometrium: stimulation and desensitization. 793 29

Involvement of a cyclic GMP pathway in signal transduction stimulated by endothelins (ETs) and sarafotoxins (SRTXs) was explored using rat cerebellar slices. These peptides activated the same receptor binding sites (ET-1 and SRTX-b at the picomolar sites; ET-3 and SRTX-c at the nanomolar sites) to produce cyclic GMP, but their signaling pathways differed. The endothelins (ET-1 and ET-3) were found to signal via nitric oxide formation and to involve pertussis toxin-sensitive G-protein(s). The SRTXs (b and c), while also stimulating cyclic GMP production, did so via a pathway which is not L-arginine-dependent, i.e., carbon monoxide formation, and did not involve pertussis-toxin-sensitive G-protein(s). This is the first demonstration that the signaling pathways of endothelins and sarafotoxins may differ, even though they share the same binding sites.
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PMID:Cyclic GMP formation in rat cerebellar slices is stimulated by endothelins via nitric oxide formation and by sarafotoxins via formation of carbon monoxide. 799 93

In adult rat cardiac myocytes, endothelin (ET) receptors couple to multiple signaling pathways, including stimulation of phosphoinositide hydrolysis (pertussis toxin insensitive) and inhibition of adenylyl cyclase via Gi. We have used ET-1 and congeners to characterize the subtypes of ET receptors on isolated rat myocytes. The rank orders of potency for stimulating phosphoinositide hydrolysis, inhibiting hormone-sensitive adenylyl cyclase, and competing with 125I-ET-1 for binding to myocytes are the same and show the pattern characteristic of an ETA receptor interaction, i.e., ET-1 approximately ET-2 > sarafotoxin 6b > ET-3; the corresponding EC50 values for the effects of ET on signal transduction are approximately 0.5 nM (ET-1), 0.7 nM (ET-2), 7 nM (sarafotoxin 6b), and 60 nM (ET-3). The ETA receptor antagonist BQ-123 abolishes the cellular responses to ET-1 and competes fully for 125I-ET-1 binding in a concentration-dependent manner. Sarafotoxin 6c, an ETB-specific agonist, does not diminish the responses to ET-1 or compete for 125I-ET-1 binding; no specific binding of the ETB-specific ligand 125I-IRL-1620 is detectable on myocytes. Myocytes express approximately 4 x 10(5) ET-1 binding sites/cell. The association of 125I-ET-1 with myocytes is largely irreversible, as are the biochemical responses to ET-1; thus, constants derived from analyses that assume reversible equilibria are in error. We conclude that the effects of ET on transmembrane signaling in rat ventricular myocytes result from occupation of ETA receptors and that the responses are likely to be long lived, compared with those of the readily dissociable neurotransmitters released by the autonomic nervous system.
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PMID:Coupling of the type A endothelin receptor to multiple responses in adult rat cardiac myocytes. 802 11


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