Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of guinea pig enteric glia to respond to endothelins was examined using fura 2-based digital microscopy in glial cells derived from guinea pig taenia coli. Each isoform of endothelin (ET-1, ET-2, ET-3) evoked dose-dependent and equipotent increases in intracellular Ca2+ concentration ([Ca2+]i) and in percentage of cells responding, 4alaEt-1, an ETB receptor agonist, elicited similar [Ca2+]i increments. BQ-788, an ETB antagonist, inhibited [Ca2+]i responses to endothelin. Preincubation of glia with U-73122 a phospholipase C inhibitor, abolished the [Ca2+]i response to ET-3 exposure. Thapsigargin also eliminated ET-3-evoked Ca2+ signaling. The inositol 1,4,5-trisphosphate (IP3) receptor antagonist heparin, introduced into glial cells by radio frequency electroporation, blocked [Ca2+]i responses to ET-3 (100 nM) in 63% of glia. Sustained elevation in [Ca2+]i was abolished by removal of Ca2+ from the buffer and inhibited 85. -3% by Ni2+ (1 mM). Preincubation of glia with 100 nM phorbol 12-myristate 13-acetate (24 h) also inhibited sustained increments in [Ca2+]i by 87%. The presence of IP3 receptors in enteric glia was confirmed by immunofluorescent confocal microscopy.
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PMID:Endothelin-activated calcium signaling in enteric glia derived from neonatal guinea pig. 917 28

We previously reported that endothelin-1 (ET-1) stimulates phosphatidylcholine-hydrolyzing phospholipase D independently of phosphoinositide hydrolysis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the characteristics of the receptors mediating ET-1-induced intracellular signaling pathway in MC3T3-E1 cells. Cyclo-D-Trp-D-Asp-Pro-D-Val-Leu (BQ123), a selective ETA receptor antagonist, significantly inhibited the ET-1-induced formation of inositol phosphates in a dose-dependent manner in the range between 22 nmol/L (IC50) and 2.2 mumol/L (IC50 x 100). On the contrary, N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma MeLeu-D-Trp(COOMe)-D-Nle-ONa (BQ788), a selective ETB receptor antagonist, had no effect on the ET-1-induced formation of inositol phosphates in the range between 1.2 nmol/L (IC50) and 120 nmol/L (IC50 x 100). BQ123 significantly suppressed the ET-1-induced formation of choline dose-dependently, however, BQ788 did not affect the choline formation. BQ123 also inhibited the ET-1-induced release of arachidonic acid, but BQ788 had little effect. The results strongly suggest that ETA receptor mediates the three intracellular signaling pathways of ET-1: (1) phosphoinositide hydrolysis by phospholipase C; (2) phosphatidylcholine hydrolysis by phospholipase D; (3) arachidonic acid release in osteoblast-like cells.
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PMID:ETA receptor mediates the signaling of endothelin-1 in osteoblast-like cells. 926 89

This report describes the effects of endothelins (ET-1 and ET-3) on ion transport systems expressed on cultured rat brain capillary endothelial cells (RBEC) and includes investigation of pharmacological properties of ET receptors, their reactivity and induction of signal transduction pathways. ET-1 stimulated IP3 formation and Ca2+ uptake with half-maximal effective concentrations (EC50) of 0.68 and 0.93 nM, respectively; the effects of ET-3 on these responses were much weaker. ET-1-stimulated IP3 formation and Ca2+ uptake were inhibited by an ETA antagonist (BQ123) and a phospholipase C (PLC) inhibitor (U73122), indicating the presence of ETA receptors coupled to PLC. ET-1 stimulated K+ efflux (through a quinine-sensitive mechanism) and K+ uptake (through both ouabain-sensitive and bumetanide-sensitive mechanisms) with EC50 of 0.59 and 0.68 nM, respectively. The potencies of ET-3 on these responses were considerably lower than those of ET-1. By contrast, ET-1 or ET-3 stimulated Na+ uptake with similarly high potencies (EC50 = 0.80 and 1.89 nM, respectively) through EIPA (a Na+/H+ exchange inhibitor)-sensitive mechanisms. ET-stimulated K+ efflux, K+ uptake and Na+ uptake activities were all inhibited by BQ123 (but not by BQ788), suggesting the involvement of ETA (and not ETB) receptors in all these responses. ET-1 stimulated K+ uptake and efflux were inhibited by either U73122 or an intracellular Ca2+ chelator, suggesting that these two responses were mediated via PLC. In contrast, ET stimulation of Na+ uptake was unaffected by PLC inhibition or intracellular Ca2+ chelation. These data suggest the presence of two distinct subtypes of ETA receptors on RBEC; one appears to be a typical ETA receptor which is coupled to PLC and has higher binding affinity for ET-1 than ET-3. The other (ETA-like) receptor is similarly activated by ET-1 and ET-3 with high potencies but is independent of PLC. This possibility was further confirmed by the [125I]ET-1 binding studies demonstrating the presence of high- and low-affinity ET-3 binding sites.
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PMID:Functional characterization of endothelin receptors on cultured brain capillary endothelial cells of the rat. 930 10

The mechanism of an endothelin-1- (ET-1-) induced intracellular Ca2+ ([Ca2+]i) increase and the receptor subtype(s) responsible for this effect in single human melanocytes were studied using fura-2/AM. ET-1 induced a transient increase in [Ca2+]i in a concentration-dependent manner. The transient [Ca2+]i increase was followed by a sustained plateau level of [Ca2+]i which was higher than the initial [Ca2+]i level. IRL-1620, a specific ET-B receptor agonist, increased [Ca2+]i in a dose-dependent manner. BQ-788, a specific ET-B receptor antagonist, abolished the ET-1-induced [Ca2+]i increase, but BQ-123, a specific ET-A receptor antagonist, failed to prevent it. U73122, an inhibitor of phospholipase C (PLC), inhibited the ET-1-induced [Ca2+]i rise in a dose-dependent manner. Prior depletion of intracellular Ca2+ stores with thapsigargin, an inhibitor of Ca2+-ATPase of the endoplasmic reticulum, abolished the ET-1-induced Ca2+ transient, whereas removal of extracellular Ca2+ with EGTA eliminated the sustained rise. These results suggest that in cultured human melanocytes the binding of ET-1 to ET-B receptors and the subsequent activation of PLC mediate ET-1-induced [Ca2+]i increase. The transient [Ca2+]i increase is attributed to mobilization of Ca2+ from inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ stores, and the sustained [Ca2+]i level may be related to the influx of extracellular Ca2+.
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PMID:Endothelin-B receptor-mediated Ca2+ signaling in human melanocytes. 942 89

Endothelin (ET) is a potent peptide mediator exhibiting a wide variety of effects in both the parenchymal and nonparenchymal hepatic cells. In the Kupffer cell, ET activates several transmembrane signaling pathways to generate numerous second messengers including the phospholipase C-generated products inositol-1,4,5-trisphosphate and diacylglycerol and the cyclooxygenase product prostaglandin E2 via specific ETB-type receptors. In addition to these findings, we have now demonstrated that endothelin stimulates the production of nitric oxide (NO) in the Kupffer cell in a time- and concentration-dependent manner. Western blot analysis indicates that ET-stimulated NO production occurs though activation of the inducible form of the nitric oxide synthase enzyme. These findings have important implications as the stimulation of NO production by ET may be part of the physiological response to inflammation or infection. Elevated levels of ET and NO have been found to be associated with numerous hepatic pathophysiological conditions that may contribute to derangements in the vascular system seen in these conditions.
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PMID:Endothelin-stimulated nitric oxide production in the isolated Kupffer cell. 944 9

Endothelin (ET)-1 is an endothelium-derived vasoconstrictor as well as a mitogen. We have recently described a novel role of ET-1 as a survival factor for rat endothelial cells from serum deprivation-induced apoptosis. The present study was designed to determine which receptor subtype (ETA or ETB) is responsible for and what intracellular mediators are involved in endothelial apoptosis. Apoptotic cell death was evaluated by nucleosomal ladders on agarose gel electrophoresis and immunohistochemical study using anti-single-stranded DNA antiserum. ET-1 and an ETB receptor agonist suppressed endothelial apoptosis, whose effects were abrogated by an ETB receptor antagonist but not by an ETA receptor antagonist. Addition of an ETB receptor antagonist or nonselective ETA/B receptor antagonists, but not an ETA receptor antagonist, enhanced the apoptotic events caused by serum deprivation, suggesting an autocrine/paracrine role of endogenous ET-1 in protecting against endothelial apoptosis. The effect of ET-1 in suppressing apoptosis was unaffected by any of the following reagents: a phospholipase C inhibitor (U73122), a tyrosine kinase inhibitor (ST638), an MEK inhibitor (PD98059), a phosphatidylinositol-3 kinase inhibitors (wortmannin, LY294002). Taken together, these results confirm a role for ET-1 as an autocrine/paracrine survival factor for rat endothelial cells, in which neither phospholipase C, tyrosine kinase, MAP kinase, nor phosphatidylinositol-3 kinase is involved in mediating the antiapoptotic effect of ET-1.
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PMID:Endothelin-B receptor-mediated suppression of endothelial apoptosis. 959 22

In the rat cardiovascular system endothelin-1 (ET-1) elicits prolonged physiologic responses mediated by the ETA receptor, whereas the effects mediated by the ETB receptor are transient. The molecular mechanisms for the subtype-specific responses are not yet clear. However, post-translational modifications such as phosphorylation and palmitoylation may play an important role. In Sf9 cells overexpressing the human ETA and ETB receptors, both subtypes are palmitoylated. However, only the ETB but not the ETA receptor is phosphorylated in a ligand-dependent manner. Because phosphorylation is believed to play an important role in ligand-dependent receptor inactivation, we analyzed whether the differential phosphorylation of the ETA and ETB receptors reflects a differential mechanism of receptor inactivation. Using a modified inositol phosphate accumulation assay, we analyzed CHO cells that expressed the ETA or ETB receptor. The ETB receptor was deactivated almost completely within 5 min after agonist stimulation, whereas stimulation of the ETA receptor resulted in sustained activation, i.e., > 90% of the initial activity was maintained after 5 min of ligand stimulation and > 30% after 20 min. A strong correlation was observed between the time course of ETA receptor inactivation and ETA receptor internalization. The endogenous ETA receptor in Rat-1 cells produced a prolonged stimulation of phospholipase C similar to that seen in CHO cells. Therefore, the sustained signaling activity of the ETA receptor is not a property only of recombinant cell lines. Together, our data suggest rapid ETB receptor inactivation due to phosphorylation and delayed ETA receptor inactivation by internalization. These mechanisms adequately reflect the differential response patterns of the ET receptors under physiologic conditions.
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PMID:Subtype-specific endothelin-A and endothelin-B receptor desensitization correlates with differential receptor phosphorylation. 959 38

We investigated the functional importance and signal transduction pathways of endothelin (ET)-B receptors in mediating ET-1-induced vasoconstriction in pig skin. Skin vasoconstriction was studied by monitoring the perfusion pressure of isolated perfused pig skin flaps (6 x 16 cm) at a constant flow rate. Intra-arterial infusion of the ETA/B receptor agonist ET-1, the ETB receptor agonists sarafotoxin 6C (S6c) and BQ-3020, or the thromboxane A2 mimetic U-46619 (n = 4 or 5) caused a concentration-dependent skin vasoconstriction. The vasoconstrictor potency of ET-1 (EC50 3.1 x 10(-9) M) was lower (P < 0.05) than that of S6c (EC50 1.8 x 10(-9) M) and similar to that of BQ-3020 (EC50 2.6 x 10(-9) M). The vasoconstrictor potency of ET-1, S6c, and BQ-3020 was at least 300-fold higher than that of U-46619 (EC50 0.9 x 10(-6) M). The skin vasoconstrictor effect of ET-1 (10(-9)-10(-8) M) was partially inhibited by 10(-5) M BQ-123, an ETA receptor antagonist. Further inhibition was achieved with the combination of 10(-5) M BQ-123 and BQ-788 (an ETB receptor antagonist) or with an ETA/B receptor antagonist (10(-5) M bosentan or PD-145065) (n = 5; P < 0.05). In addition, the skin vasoconstrictor effect of the ETB receptor agonist BQ-3020 was completely blocked by 5 x 10(-6) M BQ-788 and partially inhibited by 5 x 10(-6) M of the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyl-N,N-diphenylcarbamate (NCDC), an L-type Ca2+ channel antagonist (nifedipine), a protein kinase C (PKC) inhibitor (chelerythrine), or removal of Ca2+ from the perfusate (n = 4 or 5; P < 0.05). The vasoconstrictor effect of S6c was also partially blocked by 5 x 10(-6) M of NCDC, nifedipine, or chelerythrine or by removal of Ca2+ from the perfusate (n = 4; P < 0. 01). We conclude that ETB receptors play a central role in mediating ET-1-induced vasoconstriction in pig skin, and the mechanism probably involves L-type Ca2+ channels, PLC, and PKC.
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PMID:Role and mechanism of endothelin-B receptors in mediating ET-1-induced vasoconstriction in pig skin. 975 35

Compelling evidence indicates that endothelins (ETs) stimulates aldosterone secretion from rat zona glomerulosa (ZG) cells, acting through the ETB receptor subtype. We have investigated the mechanisms transducing the aldosterone secretagogue signal elicited by the pure activation of ETB receptors. Aldosterone response of dispersed rat ZG cells to the selective ETB-receptor agonist BQ-3020 was not affected by inhibitors of adenylate cyclase/protein kinase (PK)A, tyrosine kinase-, mitogen-activated PK-, cyclooxygenase- and lipoxygenase-dependent pathways. In contrast, the inhibitor of phospholipase C (PLC) U-73122 abrogated, and the inhibitors of PKC, phosphatidylinositol trisphosphate (IP(3))-kinase and calmodulin (calphostin-C, wortmannin and W-7, respectively) partially prevented aldosterone response to BQ-3020. When added together, calphostin-C and wortmannin or W-7 abolished the secretagogue effect of BQ-3020. BQ-3020 elicited a marked increase in the intracellular Ca2+ concentration ([Ca2+]i) in dispersed rat ZG cells, and the effect was abolished by the Ca(2+)-release inhibitor dantrolene. The Ca2+ channel blocker nifedipine affected neither aldosterone nor Ca2+ response to BQ-3020. Collectively, our findings suggest that (1) ETs stimulate aldosterone secretion from rat ZG cells through the activation of PLC-coupled ETB receptors; (2) PLC stimulation leads to the activation of PKC and to the rise in [Ca2+]i with the ensuing activation of calmodulin; and (3) the increase in [Ca2+] is exclusively dependent on the stimulation of IP(3)-dependent Ca2+ release from intracellular stores.
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PMID:Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signaling pathway. 1117 5

We studied the mechanism by which endothelin-1 (ET-1) affects the mobility of intracellular free Ca2+ ([Ca2+]i) in cultured A7r5 aortic smooth muscle cells. ET-1 at 10(-9) to 10(-7) M increased [Ca2+]i in Ca2+-containing buffer and Ca2+-free buffer. Pretreatment with ET-1 inhibited thapsigargin- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-induced [Ca2+]i increases in Ca2+-free buffer. Pretreatment with thapsigargin and CCCP partially abolished the [Ca2+]i increase induced by ET-1. The ET-1-induced Ca2+ signal was partially suppressed by the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788 and nifedipine. Pretreatment of cells with the phospholipase C inhibitor U73122 reduced the ET-1-induced [Ca2+]i increase. These results suggest that the ET-1-induced [Ca2+]i increase in A7r5 smooth muscle cells initially activates the ETA receptor, leading to Ca2+ influx and increased internal Ca2+ release from endoplasmic reticulum and mitochondrial Ca2+ stores. The ETB receptor and L-type Ca2+ channel are involved in maintaining further extracellular Ca2+ influx. ET-1-induced intracellular Ca2+ release was also modulated by phospholipase C-coupled events.
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PMID:Possible mechanism of endothelin-induced Ca2+ mobility in A7r5 cultured vascular smooth muscle cells. 1251 1


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