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)

Modulation of immunoreactive endothelin-1 (IR-ET-1) production by vasoactive substances was investigated in cultured endothelial cells (EC) derived from capillaries and microvessels of human brain. Peptides, catecholamines, thrombin, protein kinase C-activating phorbol ester, and calcium ionophore enhanced the secretion of IR-ET-1. The known vasoconstrictive peptides, angiotensin II (Ang II) and arginine-vasopressin (AVP) dose-dependently stimulated the endothelial secretion of IR-ET-1. The angiotensin and vasopressin-inducible production of IR-ET-1 was completely inhibited by their respective receptor antagonists [Sar1, Ala8]-angiotensin II and [1-6 (beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-O-methyl-tyrosine]. The results indicate that the peptide-stimulated secretion of IR-ET-1 is receptor-mediated in EC which have specific angiotensin II and arginine-vasopressin receptors. These findings represent the first demonstration of IR-ET-1 production by capillary and microvascular endothelium of human brain.
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PMID:Secretion of immunoreactive endothelin-1 by capillary and microvascular endothelium of human brain. 140 66

Endothelins are a family of three peptides that act as local hormones released by the endothelium. They were found to inhibit rabbit and dog platelet aggregation in vivo, but no effect was observed in vitro. In order to investigate the possible interaction between endothelins and human platelet serotonin receptors, their effects on platelet aggregation induced by serotonin was studied. Endothelin-1, -2 and -3 had a dual action, on platelet aggregation and calcium mobilization induced by serotonin. When added at the same time as serotonin, endothelin potentiated the response to the amine. On the contrary, preincubation of platelet suspension with endothelin resulted in a concentration-dependent inhibition of the serotonin-mediated platelet response. Moreover, endothelin-1 inhibited serotonergic amplification of epinephrine-induced aggregation of platelets. We hypothesize that endothelins can bind to the platelet membrane and interact with serotonin receptors. The diverse effect of endothelins on serotonin-induced aggregation and calcium mobilization may be due to stimulation of protein kinase C.
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PMID:Endothelins inhibit serotonin-induced platelet aggregation via a mechanism involving protein kinase C. 142 54

We have studied whether a novel vasoconstrictor, endothelin-1 (ET-1), is synthesized by and released from human decidual cells in early pregnancy, and whether ET-1 acts directly on their own cells. It was observed that ET-1-like immunoreactivity (ET-1-LI) was released from cultured decidual, but not villous, cells, as a function of time. Reverse-phase high-pressure liquid chromatography of the conditioned media from the decidual cells revealed a major peak of ET-1-LI coeluting with standard ET-1. Phorbol myristate acetate, a protein kinase C activator, dose-dependently increased the release of ET-1-LI from the decidual cells, while a protein kinase C inhibitor, H7, significantly attenuated the stimulatory effect of phorbol myristate acetate on ET-1-LI release. Northern blot analysis demonstrated the expression of messenger RNA for prepro-ET-1 in the decidual tissue, but no such messenger RNA was observed in the villous tissue. The human decidual tissue contained a noninteracting, single class of binding sites demonstrating higher affinity for ET-1 and ET-2 than ET-3. This would be most consistent with the ETA receptor subtype. An ET-1-induced, dose-dependent accumulation of total inositol phosphates was also observed in human decidual cells prelabeled with myo-[3H]inositol. The present results demonstrate for the first time that human decidual cells in early pregnancy can synthesize and release ET-1. These cells also possess specific functional receptors for ET-1 which are coupled to phosphoinositide hydrolysis. Thus our data suggest a possible role for ET-1 in autocrine and/or paracrine function in human decidual cells.
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PMID:Synthesis and release of endothelin-1 by human decidual cells. 143 83

This study was designed to examine how protein kinase C (PKC) regulates the release of endothelin-1 (ET-1) from cultured porcine aortic endothelial cells. We measured the release of immunoreactive (IR)-ET-1 from cells cultured for up to 72 h in the presence or absence of a phorbol ester TPA. The release of IR-ET-1 from control cells (no TPA) increased according to time for up to 72 h. In the presence of TPA, the release of IR-ET-1 from the cells was higher than the control level for up to 8 h, but was lower thereafter and reached a plateau after 48 h. TPA dose-dependently stimulated IR-ET-1 release during incubation for 4 h, but suppressed it after incubation for 72 h. Stimulation of PKC by diacylglycerol mimicked the early (4 h) action of TPA. On the other hand, pretreatment of cells with TPA to downregulate PKC significantly suppressed basal and thrombin- or FCS-stimulated IR-ET-1 release. These findings suggest that the activation of PKC is related to the stimulation of ET-1 release and that down-regulation of PKC leads to the suppression of ET-1 release from cultured endothelial cells.
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PMID:Effect of a phorbol ester on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells. 144 49

The stimulation of phospholipase D (PLD) activity by endothelin-1 (ET1) was investigated in rabbit iris sphincter prelabelled with [3H]myristic acid. In the presence of 0.5% ethanol, ET1 caused a time- and dose-dependent increase in the production of [3H]phosphatidylethanol ([3H]PEt). Within 30 s the peptide increased PEt formation by 30% and after 5 min increased it by 140%. The EC50 value for ET1-stimulated PEt formation was found to be 30 nM. This value is appreciably lower than the EC50 we previously obtained for ET1-induced inositol trisphosphate production (45 nM), but considerably higher than that for arachidonic acid release (1 nM). PEt formation was significantly stimulated by prostaglandin F20, phorbol 12,13-dibutyrate (PDBu), chloroform, A23187 and A1F4-, but it was not affected by carbachol or the platelet-activating factor. PDBu-stimulated PEt formation was blocked by staurosporine and it was not potentiated by A23187. Staurosporine had no effect on ET1-stimulated PEt formation. Our data indicate that ET1 stimulation of PLD occurs independently of protein kinase C activation, phospholipase C activation and intracellular Ca2+ mobilization, and phospholipase A2 activation. In this tissue the ET1 receptor is probably coupled to the three phospholipases through several G-proteins, and this appears to be species and receptor type specific.
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PMID:Activation of phospholipase D by endothelin-1 and other pharmacological agents in rabbit iris sphincter smooth muscle. 148 66

We have previously reported that endothelin-1 stimulates phospholipase C-induced hydrolysis of phosphatidylinositol-4,5-bisphosphate. Other signal transduction pathways that hydrolyze alternative phospholipids through phospholipase D may also mediate endothelin-stimulated cellular responses. We initially evaluated endothelin-dependent generation of 32P-phosphatidic acid as an indirect indication of phospholipase D activity in rat mesangial cells. Endothelin (10(-7) M) induced an elevation of phosphatidic acid that was maximal at 15 min and persisted upward of 60 min. Pretreatment with the diacylglycerol-kinase inhibitor, R59022, did not reduce formation of endothelin-stimulated 32P-phosphatidic acid, demonstrating that the sequential actions of phospholipase C/diacylglycerol kinase do not contribute to endothelin-stimulated phosphatidic acid formation. We next conclusively identified a role for phospholipase D in the generation of phosphatidic acid by assessing the formation of 3H-phosphatidylethanol from 3H-alkyl lyso glycerophosphocholine and exogenous ethanol. Endothelin stimulated 3H-alkyl phosphatidylethanol formation in the presence but not the absence of 0.5% ethanol. Also, endothelin induced a concomitant elevation of 3H-alkyl-phosphatidic acid that was significantly reduced when the cells were exposed to exogenous ethanol, reflecting the formation of phosphatidylethanol. In addition, endothelin stimulated the release of 3H-choline and 3H-ethanolamine, demonstrating that additional phospholipids may serve as substrates for phospholipase D. Phorbol esters and synthetic diglycerides mimicked the effects of endothelin to stimulate phospholipase D and inhibitors of protein kinase C significantly reduced endothelin-stimulated phospholipase D. In addition, endothelin did not stimulate phosphatidylethanol formation in protein kinase C down-regulated cells. The calcium ionophore, ionomycin, did not stimulate phospholipase D and mesangial cells pretreated with BAPTA to chelate cytosolic calcium did not show a diminished endothelin-stimulated phospholipase D. Thus these data demonstrate that mesangial cells possess a protein kinase C-regulated phospholipase D activity that can be stimulated with endothelin.
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PMID:Endothelin stimulates phosphatidic acid formation in cultured rat mesangial cells: role of a protein kinase C-regulated phospholipase D. 153 86

The effects of endothelin, a novel vasoconstrictive peptide, on the delayed rectifier K+ current (IK) were examined in single dialyzed cells from guinea pig ventricles. Either big endothelin or endothelin-1 enhanced IK at a dissociation constant of 2 nM with L-type Ca2+ current being unaffected. Under intracellular perfusion with pCa 7.6 solution, 3 nM big endothelin increased IK by 55 +/- 38.5%. Either pretreatment with 10 microM 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7) or a low Ca2+ [10 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and minus CaCl2] internal solution diminished the enhancement. Preceding stimulation of protein kinase C (PKC) by 10-20 nM 12-O-tetradecanoylphorbol-13-acetate also reduced the degree of enhancement. When Na+ was eliminated from the solutions, endothelin increased IK distinctively in cells internally dialyzed with a low Ca2+ solution. This enhancement was not abolished by either pretreatment with H 7 or by removal of Ca2+ from the external perfusate but by increasing the internal EGTA concentration to 40 mM. Preincubation with ryanodine or internal perfusion with heparin also reduced the IK enhancement under Na(+)-free conditions. Intracellular application of 200 microM guanosine 5'-O-(3-thiotriphosphate) effectively attenuated the effect of endothelin. It is concluded that endothelin enhances IK via phospholipase C-mediated PKC activation and intracellular Ca2+ mobilization. GTP-binding protein is involved in these reactions.
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PMID:Endothelin enhances delayed potassium current via phospholipase C in guinea pig ventricular myocytes. 153 93

Cultured porcine endothelial cells (EC) released immunoreactive endothelin-1 (ir-endothelin-1) and big endothelin-1 (ir-big endothelin-1) into the medium in a time-dependent way. Reverse-phase high-pressure liquid chromatography coupled with radioimmunoassay showed that the major component of ir-endothelin-1 corresponded to standard endothelin-1 (1-21) and that the major component of ir-big endothelin-1 corresponded to standard big endothelin-1 (porcine 1-39). This release was strongly inhibited by cycloheximide and was, therefore, related to de novo protein synthesis. The release of greater amounts was stimulated by thrombin. The protein kinase C (PKC) inhibitors from two chemical classes, H7 and staurosporine, inhibited release following such stimulation in a relatively dose-dependent way. Neither H7 nor staurosporine affected the basal release of both endothelin-1 and big endothelin-1. Phorbol myristate acetate, which activates PKC and the Ca2+ ionophore A23187, stimulated the release of ir-endothelin-1 and ir-big endothelin-1 in a dose-dependent way, respectively. In addition, the combination of both compounds had a synergistic effect. An inactive enantiomer of phorbol ester, 4 alpha-phorbol-12,13-didecanoate had no effect on the release of ir-endothelin-1 and ir-big endothelin-1. These results suggest that cultured EC release endothelin-1 and big endothelin-1 simultaneously, and that thrombin stimulates this release by a mechanism that probably involves intracellular Ca2+ mobilization and the activation of PKC.
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PMID:Release mechanism of endothelin-1 and big endothelin-1 after stimulation with thrombin in cultured porcine endothelial cells. 157 76

Endothelins are a family of three peptides that act as local hormones in all mammalian species. They were found to inhibit rabbit and dog platelet aggregation in vivo, whereas no effect was observed in vitro. In order to investigate the possible interaction between endothelins and human platelet serotonergic receptors, their effect on the platelet aggregation, induced by serotonin, was studied. Endothelin-1, -2 and -3 had a dual action for platelet aggregation induced by serotonin. When added simultaneously to serotonin endothelins aggregatory response to this amine was potentiated. On the contrary, preincubation of platelet suspension with endothelins resulted in a concentration-dependent inhibition of serotonin-promoted platelet response. Moreover, endothelin-1 inhibited serotonergic amplification of epinephrine-induced aggregation of platelets. It is proposed that endothelins bind to the platelet membrane and interact with serotonergic receptors and/or G proteins. The diverse effect of eodothelins on serotonin-induced aggregation of platelets may be due to stimulation of protein kinase C.
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PMID:[Inhibition of serotonin-induced platelet aggregation by endothelins]. 161 85

Effects of endothelin-3 on the secretion of endothelin-1 and other endothelium-derived substances were investigated in cultured human umbilical vein endothelial cells. The present binding study showed two distinct subpopulations of binding sites for endothelin-3 with higher and lower affinities in cultured human endothelial cells. Endothelin-3 caused an increase in intracellular Ca2+ and inositol 1,4,5-trisphosphate levels and activated protein kinase C in a dose-dependent manner. Endothelin-3 also caused an increase in [3H]thymidine incorporation into cellular DNA and stimulated the production of cyclic guanosine 3',5'-monophosphate, 6-ketoprostaglandin F1 alpha, and immunoreactive endothelin-1 in cultured human endothelial cells. NG-Monomethyl L-arginine (3 x 10(-4) mol/l) and indomethacin (10(-5) mol/l) enhanced endothelin-3-induced endothelin-1 production. These results suggest that endothelin-3 bound to its specific receptors and then caused phosphoinositide breakdown, subsequently mobilizing intracellular Ca2+ and leading to protein kinase C activation and the initiation of DNA synthesis, resulting in the stimulation of endothelin-1 production by human endothelial cells. Furthermore, this endothelin-1 production may be suppressed by endothelium-derived relaxing factor and prostacyclin produced in response to endothelin-3 in cultured human endothelial cells.
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PMID:Endothelin-3 regulates endothelin-1 production in cultured human endothelial cells. 165 67


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