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 investigated the contribution of endothelin type A (ETA) and ETB receptors on ET-induced DNA synthesis in CCD-18Lu cells, a human lung cell line possessing both ETA and ETB (ETA/ETB ratio: 9:1). ET-1 (0.05-2 nM) potently induced [3H]thymidine incorporation by 2- to 14-fold over the basal level. An ETA-selective antagonist, FR139317, inhibited 0.2 nM ET-1-induced DNA synthesis dose dependently, showing complete inhibition at 1 microM. ET-3 was inactive up to 2 nM. In contrast, ETB-selective antagonists, 100 nM of BQ-788 or IRL 2500, partially (30-60%) inhibited 0.2 nM ET-1-induced DNA synthesis. Stimulation of either ETA or ETB evoked the increases in intracellular Ca2+ concentration ([Ca2+]i). ETB-mediated but not ET-1-induced [Ca2+]i increase was pertussis toxin (PTX) sensitive. Adenosine 3',5'-cyclic monophosphate (cAMP) formation via ETA was observed in PTX-treated cells, whereas the inhibition of isoproterenol-stimulated cAMP formation via ETB was observed in PTX-untreated cells. Like the ETB-selective antagonists, PTX treatment or dibutyryl cAMP partially (50-70%) inhibited ET-1-induced DNA synthesis. These data suggest that 1) ET-1 induces DNA synthesis predominantly through ETA, via PTX-insensitive G protein; 2) ETA-mediated cAMP formation inhibits DNA synthesis; and 3) stimulation of ETB coupling to Gi protein modulates ETA-mediated DNA synthesis by inhibiting cAMP formation.
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PMID:ETA and ETB receptors cooperate in DNA synthesis via opposing regulations of cAMP in human lung cell line. 884 84

The aim of this study was to characterize the properties of endothelin (ET)-receptor subtypes mediating inositol phosphate (IP)-formation in rat kidney and their regulation during ontogenesis. In renal cortical slices of adult rats (12-16 weeks old) ET's concentration-dependently increased IP-formation with an order of potency ET-1 >> ET-3. While the non-selective ET-receptor antagonist bosentan (10 microM) completely suppressed ET-induced IP-formation, the ETA-receptor antagonist BQ-123 (10 microM) inhibited it only by 70%, the ETB-receptor antagonist IRL 1038 (1 microM) by 25%; combined application of BQ-123 + IRL 1038 caused complete inhibition of ET-1-induced IP-formation. Pretreatment of isolated renal cells with pertussis toxin (PTX, 500 ng/ml) overnight did not attenuate but significantly increased ET-1-induced IP-formation. Ontogenetic studies in renal sites from neonatal, 1, 2, 3, 6, 12 and 24 weeks old rats revealed that ET-1-induced IP-formation maturation-dependently declined being highest in neonatal rats (increase: 169% over basal) and lowest in 24 weeks old rats (increase: 47% over basal). This decline in ET-induced IP-formation was accompanied by a decrease in renal ET-receptor number and the amount of immunodetectable Gq/11 (assessed by Western-blotting using the QL-antiserum). Moreover, ET-receptor subtypes changed during the maturation process: from neonates to 12 weeks old rats number and functional responsiveness of ETA-receptors declined, while that of ETB-receptors increased. We conclude that in adult rat renal cortex ET-induced IP-formation is mediated by activation of both ETA- and ETB-receptors and does not involve a PTX-sensitive G-protein. ET-induced IP-formation declines during the maturation process; this is associated with a decrease in ET-receptor number and the immunodetectable amount of Gq/11.
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PMID:Endothelin-induced inositol phosphate formation in rat kidney. Studies on receptor subtypes, G-proteins and regulation during ontogenesis. 893 54

In primary cultures of mouse striatal astrocytes prelabeled with [3H]myristic acid, endothelin (ET)-1 induced a time-dependent formation of [3H]phosphatidic acid and [3H]diacylglycerol. In the presence of ethanol, a production of [3H]phosphatidylethanol was observed, indicating the activation of a phospholipase D (PLD). ET-1 and ET-3 were equipotent in stimulating PLD activity (EC50 = 2-5 nM). Pretreatment of the cells with pertussis toxin partially abolished the effect of ET-1, indicating the involvement of a Gi/G(o) protein. Inhibition of protein kinase C by Ro 31-8220 or down-regulation of the kinase by a long-time treatment with phorbol 12-myristate 13-acetate (PMA) totally abolished the ET-1-induced stimulation of PLD. In contrast, a cyclic AMP-dependent process is not involved in the activation of PLD, because the ET-1-evoked formation of [3H]phosphatidylethanol was not affected when cells were coincubated with either isoproterenol, 8-bromo-cyclic AMP, or forskolin. Acute treatment with PMA also stimulated PLD through a protein kinase C-dependent process. However, the ET-1 and PMA responses were additive. Furthermore, the ET-1-evoked response, contrary to that of PMA, totally dependent on the presence of extracellular calcium. These results suggest that at least two distinct mechanisms are involved in the control of PLD activity in striatal astrocytes. Finally, ET-1, ET-3, and PMA also stimulated PLD in astrocytes from the mesencephalon, the cerebral cortex, and the hippocampus.
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PMID:Endothelin stimulates phospholipase D in striatal astrocytes. 897 12

Endothelins (ETs) are potent regulators of renal, cardiovascular and endocrine functions and act as neurotransmitters in the CNS. Here we report that immortalized Schwann cells express receptors for ETs and characterize some of the cellular events triggered by their activation. Specific binding of [125I]-ET-1 to Schwann cell membranes was inhibited by ET-1 and ETB-selective agonists ET-3, sarafotoxin 6c and [Ala1,3,11,15]-ET-1 with IC50cor values ranging between 2 and 20 nM. No competition was observed with the ETA receptor-selective antagonist BQ123. Incubation of [3H]-inositol pre-labeled Schwann cells with ET-1, ET-3 or sarafotoxin 6c elicited a concentration-dependent increase in the release of [P1 that reached a plateau at approximately 100 nM. The efficacy of [Ala1,3,11,15]-ET-1 (a linear peptide analog of ET-1) was half of that corresponding to ET-1. These stimulatory effects were partially blocked by pre-incubation with pertussis toxin. When Schwann cells were incubated in the presence of 100 nM ET-1 or ET-3 there was a significant inhibition of basal and isoproterenol-stimulated cAMP levels. The inhibitory effects of sarafotoxin 6c and [Ala1,3,11,15]-ET-1 on isoproterenol-stimulated cAMP levels were similar to that observed with ET-1. Pre-incubation with pertussis toxin completely prevented this effect. These observations indicate that immortalized Schwann cells express receptors for ET peptides (predominantly ETB) coupled to modulation of phospholipase C and adenylyl cyclase activities. The actions of ETs on Schwann cells provide a novel example of the influence of vascular factors on nerve function.
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PMID:Immortalized schwann cells express endothelin receptors coupled to adenylyl cyclase and phospholipase C. 913 Feb 51

1. Angiotensin II (AII) and the endothelins (ET) are known to be potent trophic stimuli in various cells including cardiomyocytes. In order to characterize further these effects we studied, in neonatal rat ventricular cardiomyocytes, the effects of several endothelin-receptor antagonists and the AT1-receptor antagonist losartan on AII- and endothelin-induced inositol phosphate (IP)-formation (assessed as accumulation of total [3H]-IPs in myo-[3H]-inositol prelabelled cells) and increase in rate of protein synthesis (assessed as [3H]-phenylalanine incorporation). 2. Endothelin (10 pM-1 microM) concentration-dependently increased IP-formation (max. increase at 100 nM ET-1: 130 +/- 14% above basal, n = 25) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 52 +/- 4% above basal, n = 16) with an order of potency: ET-1 > > ET-3. Both effects were antagonized by the ETA/ETB-receptor antagonist bosentan and the ETA-receptor antagonist BQ-123, but not affected by the ETB-receptor antagonist IRL 1038 and the AT1-receptor antagonist losartan. 3. Pretreatment of the cells with 500 ng ml-1 pertussis toxin (PTX) overnight that completely inactivated PTX-sensitive G-proteins did not attenuate but rather enhance ET-1-induced IP-formation. On the other hand, in PTX-pretreated cardiomyocytes ET-1-induced [3H]-phenylalanine incorporation was decreased by 39 +/- 5% (n = 5). 4. All (1 nM-1 microM) concentration-dependently increased IP-formation (max. increase at 1 microM: 42 +/- 7% above basal, n = 16) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 29 +/- 2%, n = 9). These effects were antagonized by losartan, but they were also antagonized by bosentan and BQ-123. 5. In well-defined cultures of cardiomyocytes (not contaminated with non-myocyte cells) All failed to increase [3H]-phenylalanine incorporation: addition of non-myocyte cells to the cardiomyocytes restored All-induced increase in [3H]-phenylalanine incorporation. 6. We conclude that, in rat neonatal ventricular cardiomyocytes, (a) the ET-1-induced increase in rate of protein synthesis (through ETA-receptor stimulation) involves at least two signalling pathways: one via a PTX-insensitive G-protein coupled to IP-formation, and the other one via a PTX-sensitive G-protein, and (b) the trophic effects of All are brought about via local ET-1 secretion upon AT1-receptor stimulation in neonatal rat ventricular non-myocyte cells.
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PMID:Trophic effect of angiotensin II in neonatal rat cardiomyocytes: role of endothelin-1 and non-myocyte cells. 914 95

1. Endothelin (ET) receptors, and their cellular signal transduction mechanism, were characterized in a primary culture of human prostatic smooth muscle cells (HP cell). 2. [125I]-ET-1 and [125I]-ET-3 binding studies revealed that both ETA and ETB receptors were present in the HP cells, and the ratio of ETA to ETB receptors was 1.4:1. 3. Analysis of ET receptor mRNA by reverse transcription-polymerase chain reaction also demonstrated that HP cells express both ETA and ETB receptors. 4. ET-1 and ET-3 increased intracellular free Ca2+ concentration ([Ca2+]i) in the HP cells in a concentration-dependent manner. Use of subtype selective antagonists BQ-123 and BQ-788, indicated that both ETA and ETB receptors were coupled to an increase in [Ca2+]i. 5. Pretreatment of the cells with pertussis toxin resulted in a significant but partial attenuation of the [Ca2+]i increase mediated through the ETA and ETB receptors. However, sensitivity to pertussis toxin (PTX) was significantly different between them. 6. In conclusion, HP cells possess ETA and ETB receptors. Further, these two endothelin receptor subtypes evoke an increase in [Ca2+]i possibly via the action of different GTP-binding proteins.
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PMID:Endothelin receptors and their cellular signal transduction mechanism in human cultured prostatic smooth muscle cells. 920 35

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.
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PMID:Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle. 924 82

We demonstrate that the human endothelin-B (ETB) receptor incorporates [3H]palmitic acid. Mutation of three putative palmitoylated cysteine residues (amino acids 402, 403 and 405) in the carboxyl terminus into serine residues (C2/3/5S) completely prevented palmitoylation of ETB. When expressed in CHO cells, C2/3/5S was localized on the cell surface, retained high affinity for ET-1 and ET-3, and was rapidly internalized when bound to the ligand. However, unlike the wild-type ETB, C2/3/5S transmitted neither an inhibitory effect on adenylate cyclase nor a stimulatory effect on phospholipase C, indicating a critical role of palmitoylation in the coupling with G-proteins, regardless of the G-protein subtype. Truncation of the carboxyl terminus, including all or a part of the three cysteine residues, gave palmitoylation-negative and -positive deletion mutants, delta 402 and delta 403. Despite the absence of the cytoplasmic tail, both delta 402 and delta 403 showed essentially the same features as C2/3/5S, except that delta 403 did transmit a stimulatory effect on phospholipase C via a pertussis toxin-insensitive G-protein, most likely a member(s) of the Gq family. These results indicated a differential requirement for the carboxyl terminus downstream from the palmitoylation site in the coupling with G-protein subtypes, i.e., it is required for the coupling with Gi but not for that with Gq.
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PMID:Cysteine residues in the carboxyl terminal domain of the endothelin-B receptor are required for coupling with G-proteins. 959 45

The mechanism underlying endothelin-1 (ET-1)-induced increases in intracellular Ca2+ concentrations in the human neuroblastoma cell-line SK-N-MC was investigated. ET-receptor agonists increased inositol phosphate (IP)-formation (assessed as accumulation of total [3H]-IPs in [3H]-myo-inositol prelabelled cells) and intracellular Ca2+ (assessed by the FURA-2 method) with an order of potency: ET-1 > sarafotoxin 6b (S6b)> ET-3 = S6c; the ETA-receptor antagonist BQ-123 inhibited both responses with apparent pKi-values of 8.3 and 8.6, respectively, while the ETB-receptor antagonist BQ-788 did not. Pretreatment of the cells with pertussis toxin (PTX, 500 ng ml(-1) overnight) reduced ET-1-induced Ca2+ increases by 46+/-5%, but rather enhanced ET-1-induced IP-formation. Chelation of extracellular Ca2+ by 5 mM EGTA did not affect ET-1-induced IP-formation. However, in the presence of 5 mM EGTA or SKF 96365, an inhibitor of receptor mediated Ca2+ influx (1.0-3.0 x 10(-5) M) ET-1-induced Ca2+ increases were inhibited in normal, but not in PTX-treated cells. [125I]-ET-1 binding studies as well as mRNA expression studies (by RT-PCR) detected only ETA-receptors whereas expression of ETB-receptor mRNA was marginal. ET-1 (10(-8) M) inhibited isoprenaline-evoked cyclic AMP increases; this was antagonized by BQ-123, not affected by BQ-788 and abolished by PTX-treatment. We conclude that SK-N-MC cells contain a homogeneous population of ETA-receptors that couple to IP-formation and inhibition of cyclic AMP formation. Stimulation of these ETA-receptors increases intracellular Ca2+ by at least two mechanisms: a PTX-insensitive IP-mediated Ca2+ mobilization from intracellular stores and a PTX-sensitive influx of extracellular Ca2+.
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PMID:Mechanism of ET(A)-receptor stimulation-induced increases in intracellular Ca2+ in SK-N-MC cells. 986 48

Endothelins (ETs) promote cytoskeletal actin reorganization of cultured astrocytes (Koyama and Baba, Neuroscience 61:1007-1016, 1994; Koyama and Baba, Glia 16:342-350, 1996). In this study, we examined the signal transduction involved in that activity of ETs. Immunoblot analysis with an anti-phosphotyrosine antibody showed that ET-3 (1 nM) increased tyrosine phosphorylation of 120 Kda and 70 Kda astrocytic proteins. The tyrosine phosphorylations of both proteins reached a maximum at 1 nM ET-3. In morphological examinations, ET-3 (1 nM) induced stress fibers, an organized F-actin structure, and focal adhesions in 0.5 mM dibutyryl cAMP (DBcAMP)-treated astrocytes within 30 min. Immunochemical staining of phosphotyrosine revealed that the newly formed focal adhesions possessed phosphotyrosine immunoreactivity. Phorbol 12-myristate 13 acetate (PMA, 100 nM), bradykinin (1 microM), angiotensin II (100 nM), and A23187 (5 microM) did not induce astrocytic stress fibers and had no obvious effects on tyrosine phosphorylation of 120 Kda and 70 Kda proteins. Tyrosine phosphorylation of astrocytic 120 Kda and 70 Kda proteins was stimulated by 1 mM sodium orthovanadate (VO4(3-)), a protein tyrosine phosphatase inhibitor. VO4(3-) promoted reorganization of stress fibers and focal adhesions in DBcAMP-treated astrocytes. Neither chelation of intra- and extracellular Ca2+ nor pre-treatment with pertussis toxin (PTX) affected the ET-induced tyrosine phosphorylation and stress fiber formation in cultured astrocytes. These results suggest a relationship between cytoskeletal actin reorganization and the tyrosine phosphorylation of astrocytic proteins by ETs.
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PMID:Endothelin-induced protein tyrosine phosphorylation of cultured astrocytes: its relationship to cytoskeletal actin organization. 1038 51


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