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)

Different bacterial toxins capable of modifying specific alpha-subunits of G-proteins were used to characterize the guanine nucleotide-binding protein (G-protein) dependency of the effects of endothelins (ETs) on PRL, LH, and FSH secretion. Primary cultures of anterior pituitary cells obtained from female rats were preincubated for 24 h with 20 ng/ml pertussis toxin (PTX) or 2 micrograms/ml cholera toxin (CTX) before challenge with ETs. Both ET-1 and ET-3 elicited a concentration-dependent inhibition of PRL secretion and stimulated the release of LH and FSH secretion on pituitary cells not treated with toxins. Based on the calculated ration of the half-maximal effective concentrations (EC50) of ET-1 and ET-3, ET-1 showed 7800, 20, and 14 times greater potency than ET-3 on PRL, LH, and FSH secretion, respectively. PTX, a selective inhibitor of Gi and several other G proteins, increased the basal secretion of PRL and completely eliminated the responsiveness of lactotroph cells to ET-1 and ET-3. Pretreatment with PTX caused a markedly different effect on LH and FSH secretion: while basal LH release was slightly increased, FSH secretion was markedly depressed by PTX. Moreover, while ET-induced LH secretion was enhanced by PTX, the effectiveness of ETs on FSH release was completely abolished. CTX, known as an activator of Gs proteins, decreased the basal secretory activity of lactotrophs but did not influence the ET-induced decrease of PRL release. CTX pretreatment (like PTX before) elicited a strikingly different effect on LH and FSH: while basal LH secretion was enhanced, basal FSH secretion was markedly inhibited by CTX. Moreover, while the effectiveness of ETs on LH secretion was not changed significantly, the stimulatory effect of ETs on FSH secretion was diminished after CTX pretreatment. Thus, the inhibition of PRL secretion by ETs requires a PTX-sensitive G protein while the ET-induced stimulation of FSH secretion involves both PTX- and CTX-sensitive elements. The fact that pretreatments with PTX or CTX influenced basal secretion of PRL, LH, and FSH suggests that PTX- and/or CTX-sensitive G proteins are directly involved in the process of exocytosis. Additionally, these findings might indicate an active paracrine/autocrine regulation of pituitary cells in culture that are impaired or enhanced by the bacterial toxins employed. Though the broad substrate specificity of PTX and CTX and the multiplicity of G protein families did not allow us to identify the specific G protein(s) involved, these data reveal the diversity of ET-induced intracellular signaling mechanisms in lactotrophs and gonadotrophs.
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PMID:The effects of endothelins on the secretion of prolactin, luteinizing hormone, and follicle-stimulating hormone are mediated by different guanine nucleotide-binding proteins. 193 91

Effects of endothelin (ET) homologues (ET-1, 2, 3 and sarafotoxin S6b) and its precursor (big ET-1) on phosphoinositide (PI) turnover were compared in neurally-related cell cultures. All ET-related peptides induced a robust increase of PI turnover in cerebellar astrocytes, C6-glioma and cerebellar granule cells. The rank order of potency in stimulating PI turnover was ET-1 = ET-2 greater than or equal to S6b greater than ET-3 greater than big ET-1 for granule cell neurons, while it was ET-1 greater than or equal to ET-2 greater than or equal to S6b greater than big ET-1 greater than ET-3 for astrocytes and C6-glioma cells. Short-term pretreatment with phorbol dibutyrate (PDBu) attenuated the ET-1-induced PI response in all three types of cultures. However, long-term pretreatment with PDBu attenuated the response in granule cells and C6-gliomas, but enhanced responses to ET and ATP in astrocytes. Long-term exposure of cells to pertussis toxin (PTX) attenuated the PI response to ET in astrocytes and C6-gliomas, but not in granule cells. Thus, phospholipase C-coupled ET receptors are expressed in both neurons and glial cells, but they differ considerably in their pharmacological selectivity and signal transduction mechanisms in stimulating PI hydrolysis.
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PMID:Comparative studies of phosphoinositide hydrolysis induced by endothelin-related peptides in cultured cerebellar astrocytes, C6-glioma and cerebellar granule cells. 215 94

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) peptides are potent growth factors that bind to G protein-coupled receptors. Although short-term signals activated by ET receptors have been extensively characterized, relatively little is known about mitogenic signal transduction. We investigated the ET receptor subtype involved in mitogenic signaling in glomerular mesangial cells and the role of protein kinase C (PKC) and protein tyrosine kinase (PTK) activity. Pertussis toxin attenuates increases in [Ca2+]i by ET-1 but not [3H]thymidine uptake. An ETA-selective receptor antagonist, BQ 123, blocks increments in [Ca2+]i by ET-1 and inhibits [3H]thymidine uptake. A nonselective ETA-ETB receptor antagonist (PD 142893) blocked [3H]thymidine uptake, but ETB receptor-selective agonists (S6c and [Ala1,Ala3,Ala11,Ala15]ET-1(6-21)) were unable to increase [Ca2+]i or [3H]thymidine uptake. Collectively, these data suggest that mitogenic signaling occurs through an ETA receptor subtype in mesangial cells. Experiments with both PKC inhibition and depletion demonstrate that PKC was necessary but not sufficient for mitogenic signaling. ET-1 increased tyrosine phosphorylation of cellular proteins in quiescent mesangial cells that was blocked by preincubation with herbimycin A. Two chemically and mechanistically dissimilar PTK inhibitors (herbimycin A and genistein) blocked [3H]thymidine uptake by ET-1. In addition, herbimycin A attenuated c-fos induction, AP-1 DNA binding, and transcription directed by an AP-1 cis-element in response to ET-1. Taken together, these data suggest that mitogenic signaling by ET-1 also involves a PTK-based mechanism. We further demonstrated that ET-1 stimulated autophosphorylation of pp60c-src and pp60c-src-catalyzed phosphorylation of a peptide substrate specific for PTK activity. That the dose-response relationship for ET-1-induced pp60c-src activation and [3H]thymidine uptake were similar suggests that these events might be functionally linked. Thus, cross-talk between G protein-coupled receptors and nonreceptor PTK such as pp60c-src might be involved in transcriptional regulation and mitogenic signaling by ET-1.
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PMID:Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1. Cross-talk between G protein-coupled receptors and pp60c-src. 768 50

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 endothelin (ET) family of peptides acts via two subtypes of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors termed ETA and ETB. ET-1 stimulated cAMP formation in Chinese hamster ovary (CHO) cells stably expressing human wild-type ETA (CHO/hETA cells) while it inhibited cAMP formation in CHO cells expressing human wild-type ETB (CHO/hETB cells), and pharmacological evidence indicated that the opposite effects were due to the selective coupling of each receptor subtype with G alpha s/G alpha i. To find out a receptor domain(s) that determined the selective coupling, a series of chimeric receptors between hETA and hETB was expressed on CHO cells, and the effect of ET-1 on cAMP formation in each cell line was tested. hETA with the replacement of second and/or third intracellular loop (ICLII and/or -III) to the corresponding region(s) of hETB failed to transmit the stimulatory effect of ET-1. hETB with the replacement of ICLIII to the corresponding region of hETA failed to transmit the inhibitory effect of ET-1. A chimeric receptor with ICLII of hETB and with ICLIII of hETA failed to transmit both effects. In cells expressing chimeric receptors with ICLII of hETA and with ICLIII of hETB, ET-1 inhibited cAMP formation while it stimulated cAMP formation when cells were pretreated with pertussis toxin. These results indicated the roles of ICLII and -III of hETR as a major determinant of the selective coupling of hETA and hETB with G alpha s/G alpha i, respectively. We also demonstrated that each receptor subtype expressed on the same cell could work independently, i.e. for hETA to activate G alpha s and for hETB to activate G alpha i, resulting in dose-dependent dual effects of ET-1 on cAMP formation.
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PMID:Structural basis of G protein specificity of human endothelin receptors. A study with endothelinA/B chimeras. 773 Mar 10

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

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