Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using ROS17/2 rat osteosarcoma cells as a model system, we examined the possibility that endothelin (ET)-induced down-regulation of ETB receptor was accompanied by a decrease in levels of ETB receptor mRNA. Northern blot analysis showed that low doses of ET-1 and ET-3 caused a transient decrease in ETB receptor mRNA in the cells. The maximum decrease in the levels of ETB receptor mRNA (80%) occurred after 2-4 h of exposure of the cells to ETs and was followed by a gradual recovery to control levels by 24 h. The effects were dose-dependent (EC50-1 nM), and ET-1 and ET-3 were almost equipotent in eliciting the response. The addition of either ionomycin, a Ca2+ ionophore, or phorbol dibutyrate, a protein kinase C activator, mimicked the effect of ETs. These results suggested that ETs-induced down-regulation of ETB receptor mRNA was mediated by the activation of ETB receptor and that it may have involved ETB receptor coupled second messenger pathways. We also showed that ETB receptor mRNA had a long intracellular life span which suggested that ETs-induced down-regulation of ETB receptor mRNA may have been due to a decrease in the stability of mRNA, rather than inactivation of the transcription of mRNA.
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PMID:Level of ETB receptor mRNA is down-regulated by endothelins through decreasing the intracellular stability of mRNA molecules. 132 7

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
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PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

Endothelins are a novel group of potent vasoconstrictor peptides originally isolated from cultured porcine endothelial cells. We and others have previously reported the presence of endothelin receptors in the central nervous system, and this study was designed to further characterize endothelin receptors and their transduction mechanism in cultured neurohybrid NG108-15 cells. Specific binding of [125I]endothelin-1 to NG108-15 cells reached saturation within 60 min at 22 degrees C and was only partially reversible. Scatchard analysis of the saturation binding revealed the presence of one class of high-affinity binding sites with an apparent dissociation constant of 160 pM and a maximal binding capacity of 3.3 x 10(4) sites/cell. Unlabeled endothelin analogues competitively inhibited [125I]endothelin-1 binding to NG108-15 cells and the apparent dissociation constant values obtained from the competition curves correlated well with the EC50 values obtained for inducing elevation of intracellular free Ca2+ level. Endothelin stimulated phosphoinositide metabolism in a dose-dependent manner with an EC50 value of 5.4 nM for inositol trisphosphate formation. The protein kinase C-activator phorbol ester dose-dependently inhibited endothelin-induced phosphoinositide turnover and intracellular free Ca2+ increase, suggesting the involvement of protein kinase C in the regulation of endothelin-induced responses. Neither endothelin-induced phosphoinositide hydrolysis nor endothelin-induced increase in intracellular free Ca2+ were affected by pertussis toxin. These data indicate that endothelin receptors are present on NG108-15 cells and the G protein coupled to endothelin receptor for inducing activation of phospholipase C and increase of free intracellular Ca2+ is insensitive to pertussis toxin.
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PMID:Endothelin receptor binding and cellular signal transduction in neurohybrid NG108-15 cells. 166 18

Endothelial cells from brain microvessels express two types of endothelin (ET) receptor. The first receptor subtype (defined as E alpha) shows a high affinity for ET-1, a low affinity for ET-3, and it is coupled to phospholipase C. The second subtype (E beta) shows a high affinity for both ET-1 and ET-3. It is not coupled to phospholipase C, but its activation leads to an increased activity of the Na+/H+ exchanger via a protein kinase C-independent mechanism. Brain astrocytes also express a high-affinity ET-3 receptor. However, unlike that of brain capillary endothelial cells, this receptor is coupled to phospholipase C and it may be a third type of endothelin receptor (E gamma). Thus, it seems that by using both binding and functional criteria, at least three subtypes of endothelin receptor can be distinguished: a low-affinity ET-3 receptor and two high-affinity ET-3 receptors that are coupled to different intracellular signaling pathways.
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PMID:Functional properties of high- and low-affinity receptor subtypes for endothelin-3. 172 8

Endothelins (ETs) are a family of vasoactive peptides with profound biological actions in diverse cell systems. Among its varied actions, ET stimulates phospholipase C (PLC) in cultured mesangial cells. We investigated the presence of specific ET receptors in rat mesangial cells in culture, and studied the role of GTP-binding proteins (G proteins) in coupling PLC to the endothelin receptor. [125I]ET binding was time- and temperature-dependent, and Scatchard analysis of saturation data showed a single class of high-affinity binding sites. Heterologous displacement with two related peptides, ET-3 and sarafotoxin (SFTX), revealed the presence of two binding sites for these isopeptides. Preincubation of cells with ET-1 reduced the receptor number without affecting Kd, and this effect was not prevented by protein kinase C inhibition or downregulation. We confirmed the presence of a 41- to 43-kDa pertussis toxin substrate in rat mesangial cell membranes in an ADP ribosylation assay. ET-1 inhibits and GDP beta S enhances toxin-catalyzed transfer of ADP-ribose to this substrate. ET-1 potentiated GTP gamma S-induced phosphatidylinositol (PI) hydrolysis in a concentration-dependent manner. In addition, pertussis toxin partially inhibited ET-stimulated PI hydrolysis in intact mesangial cells. Pertussis toxin also reduced the magnitude of ET-stimulated intracellular free calcium [( Ca2+ )i]. Thus, ET-1 binds to specific receptors on rat mesangial cells and activates PLC, in part, through a pertussis toxin-sensitive G-protein.
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PMID:Endothelin receptors and coupled GTP-binding proteins in glomerular mesangial cells. 172 39

Endothelin, originally identified as a vasoconstrictive peptide derived from vascular endothelial cells, is now known to exert diverse biological effects on a wide variety of tissues and cell types through its own receptor(s). One of the outstanding actions of endothelin is a cell growth promoting activity which is demonstrated in several cell types including cultured vascular smooth muscle cells, fibroblasts, glomerular mesangial cells and osteoblasts. The mitogenic effect is likely mediated by stimulation of phospholipase C via receptor-G-protein coupling, and subsequent activation of protein kinase C. The effect of endothelin may contribute to the cell-proliferation response under various physiological and pathological conditions, such as wound healing and development of atherosclerosis and glomerulonephritis. Recently, three distinct endothelin-related genes have been cloned, suggesting that mammals, including humans, produce three members of this peptide family, endothelin (ET)-1 (the 'classical' endothelin), ET-2 and ET-3, which may act on distinct subtypes of endothelin receptor to induce different cellular responses.
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PMID:Endothelin, its diverse biological activities and mechanisms of action. 249 Dec 62

The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I2) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI2 synthesis, measured as immunoreactive 6-keto-PGF1 alpha, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ETA and ETB receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ETB receptor agonist, enhanced 6-keto-PGF1 alpha synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF1 alpha synthesis. Moreover, the selective ETB receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF1 alpha synthesis. Furthermore, ET-1-induced 6-keto-PGF1 alpha synthesis was attenuated by an ETA receptor antagonist, BQ-123, in a dose-dependent manner but not by an ETB receptor antagonist, BQ-788. Depletion of extracellular Ca2+ or addition of Ca2+ channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1-mediated 6-keto-PGF1 alpha synthesis, while a Ca2+ channel agonist, S(-)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1-induced 6-keto-PGF1 alpha synthesis. These data suggest that PGI2 synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca2+ via activation of an ETA receptor and is independent of protein kinase C.
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PMID:Prostacyclin synthesis elicited by endothelin-1 in rat aorta is mediated by an ETA receptor via influx of calcium and is independent of protein kinase C. 749 63

Stimulation of human platelets with endothelin raises cytosolic pH (pHi). In order to determine whether this effect is mediated via protein kinase C and Na(+)-H+ linked pathways, the effects of staurosporine and calphostin C (protein kinase C inhibitors) and 5-(N,N-hexamethylene) amiloride (Na(+)-H+ exchange blocker) on endothelin-induced pHi responses in human platelets were assessed. In addition, platelet endothelin receptor subtypes were determined pharmacologically using the selective ETA receptor antagonist BQ-123 and the ETB receptor agonist sarafotoxin S6c. pHi was measured spectrofluorometrically using the fluorescent probe BCECF-AM in platelets obtained from 15 healthy subjects. Endothelin-1 at a fixed concentration of 10(-9) M significantly increased pHi from 7.11 +/- 0.01 ([H+]i = 77 +/- 0.9 nM) to 7.19 +/- 0.04 ([H+]i = 64 +/- 0.9 nM) (p < 0.01). The pHi-stimulating effect of endothelin-1 was inhibited by 10(-7) M staurosporine, calphostin C and 5-(N,N-hexamethylene) amiloride. BQ-123 (10(-7) M) abolished the pHi responses to endothelin-1, whereas sarafotoxin S6c had no effect on platelet pHi. These data suggest that in vitro effects of endothelin-1 on platelet pHi are receptor-mediated via a pathway involving protein kinase C. Platelet endothelin receptors appear to be of the ETA subtype.
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PMID:Endothelin influences pHi of human platelets through protein kinase C mediated pathways. 777 66

Endothelins are potent peptide mediators that elicit glycogenolytic and vasoconstrictor actions in the liver. Endothelins were found to stimulate the synthesis and release of the lipid mediator platelet-activating factor in cultured rat Kupffer cells. Endothelin-mediated synthesis of platelet-activating factor required extracellular calcium in that the calcium chelator, EGTA and nifedipine, a calcium ion channel blocker, inhibited platelet-activating factor synthesis. The phospholipase A2 inhibitor, 4-bromophenacyl bromide, strongly inhibited endothelin-induced platelet activating factor synthesis. Endothelin-stimulated platelet activating factor synthesis was inhibited after treatment of Kupffer cells with cholera toxin, whereas pertussis toxin inhibited only this response to endothelin-1. Agents that elevate intracellular cyclic AMP levels were found to inhibit endothelin-induced platelet-activating factor synthesis in Kupffer cells. Staurosporine, a protein kinase C inhibitor minimized endothelin-induced platelet-activating factor synthesis but phorbol myristate acetate, an activator of protein kinase C, did not affect endothelin-induced platelet activating factor synthesis. Thus, the current study demonstrates that activation of an endothelin receptor in cultured rat Kupffer cells results in the synthesis and release of platelet-activating factor. The importance of endothelin-mediated platelet-activating factor synthesis relates to the mechanism of intercellular signaling occurring between endothelial cells (i.e., the site of endothelin synthesis) and Kupffer cells (i.e., the site of formation of secondary mediators such as platelet-activating factor and eicosanoids) within the rat liver exposed to various types of pathophysiological episodes.
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PMID:Endothelin stimulates platelet-activating factor synthesis by cultured rat Kupffer cells. 784 29

Endothelin-1 (ET-1) is a potent stimulator of atrial natriuretic factor (ANF) secretion from myocardial cells. In heart tissue there are two ET receptor subtypes (ETA-R and ETB-R), which can be pharmacologically distinguished by the ET isopeptides ET-1 and ET-3. However, the identification of the ET-R subtype responsible for the rapid enhancement of ANF release, which occurs within minutes of exposing cardiac myocytes to ET, has not been investigated. In the present study ET-1 was about 100-fold more potent than ET-3 at stimulating membrane phosphoinositide hydrolysis, protein kinase C activation, and ANF release from purified primary atrial myocytes. These responses were completely abolished by BQ123, an ETA-R antagonist. Radioligand binding analyses showed that competitor peptides displaced 125I-ET-1 binding to atrial myocyte ET-Rs with a rank order of potency of ET-1 >> BQ123 > ET-3, a characteristic ETA-R pharmacological profile. While neither ET-1 or ET-3 altered forskolin-stimulated cAMP levels, suggesting the absence of the ETB-R, basal cAMP levels were also unaffected by the ETs. Northern analysis using ET-R subtype-specific probes demonstrated that the ETA-R transcript was present in the cultures at levels at least 50-fold greater than the ETB-R transcript. These findings demonstrate that the stimulation of the phosphatidylinositol/protein kinase C pathway, which is required for maximal ET-stimulated ANF release from primary atrial myocytes, is associated with the activation of only the ETA-R, thus defining a specific function for an endogenous ET-R in myocardial cells.
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PMID:Identification of the receptor subtype responsible for endothelin-mediated protein kinase C activation and atrial natriuretic factor secretion from atrial myocytes. 822 66


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