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)

1. The recent localization of endothelin synthesis and receptors in the thick ascending limb (TAL) prompted us to investigate a possible autocrine and/or paracrine effect of this agent. The net chloride flux (JCl) has been determined in isolated cortical and medullary TALs by the in vitro microperfusion technique. 2. In both segments, endothelin 1 (ET-1) at 10(-8) M in the bath significantly decreased JCl, an effect which was partially reversible and observed at concentrations equal to or greater than 10(-13) M. 3. This JCl inhibition (by 33.9 +/- 3.2%) was blocked by BQ788 and was also observed with sarafotoxin 6C and ET-3, indicating that endothelin receptor B (ETB) are present in TAL. 4. ET-1 did not affect cAMP content under basal or hormone-stimulated conditions. The presence of a prostaglandin synthesis inhibitor also did not prevent the ET-1 action on JCl. 5. The ET-1-induced inhibition of JCl was prevented by protein kinase C inhibitors (staurosporine or GF 109203) and was reproduced by diacylglycerol analogues (OAG and DiC8). However, ET-1 failed to increase intracellular Ca2+ concentration. 6. Addition of ET-1 or ET-3 to the apical surface induced a decrease of JCl throgh ETB receptors, an effect which was not additive with that induced by basolateral ET-1, and was not concomitant with an increase in intracellular Ca2+ concentration. 7. It is concluded that the basolateral and luminal inhibitions of JCl by ET-1 in TAL, through ETB receptors, is mediated by a protein kinase C activation which is independent of intracellular Ca2+ increase.
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PMID:Luminal and basolateral endothelin inhibit chloride reabsorption in the mouse thick ascending limb via a Ca(2+)-independent pathway. 945 49

This study examined the role of endothelins (ETs) and their receptor subtypes ETA and ETB in the regulation of vascular tone in the in situ perfused rat left adrenal gland. Endothelin-1 (ET-1), which binds both ETA and ETB receptors, decreased adrenal flow rate of the perfusion medium, and its effect was reversed by the ETA antagonist BQ-123 and enhanced by the ETB antagonist BQ-788. ET-3, which preferentially binds ETB, and the selective ETB agonist BQ-3020 increased adrenal flow rate of perfusate, and their effects were annulled by BQ-788. BQ-123 magnified the effect of ET-3 and did not affect that of BQ-3020. The ETA-mediated decrease and the ETB-mediated rise in the rate of collection of perfusate were abolished by Ro-31-8220, an inhibitor of protein kinase C (PKC), and by N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase (NOS), respectively. Collectively, these findings suggest that ETs can regulate vascular tone in the in situ perfused rat adrenals via both PKC-coupled ETA and NOS-coupled ETB receptors, the activation of which evokes vasoconstriction and vasodilation, respectively.
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PMID:Role of endothelins in regulation of vascular tone in the in situ perfused rat adrenals. 945 40

Endothelin (ET) peptides are potent growth factors binding to G protein-coupled receptors. Sarafotoxins (S6) isolated from Atractaspis engaddensis are highly homologous to endothelins. In this study, we have investigated the effects of endothelin/sarafotoxin peptides on the prostaglandin synthesizing system in an osteoblast-like cell line, MC3T3-E1. ET-1, ET-2, beta-ET, and S6b rapidly stimulated prostaglandin E2 production within 5 min, whereas ET-3, S6a, and S6c did not. ET-1, ET-2, beta-ET, S6b, and S6a induced prostaglandin synthesis after 3 h of incubation. Antagonizing these effects with BQ-123, PD 142893, BQ-788, and S6c suggests signaling through an ET(A) receptor subtype in osteoblasts. Long-term prostaglandin synthesis was blocked by NS-398, and reduced to short-term levels by cycloheximide and actinomycin D, indicating induction of PGHS-2. There was only minor enhancement of cAMP accumulation by the agonists, which had no effect on prostaglandin synthesis. Induction of PGHS-2 was furthermore demonstrated by Northern blot analysis of PGHS-2 messenger RNA. Depletion of protein kinase C with TPA largely blunted the response. Genistein, an inhibitor of protein tyrosine kinases, also blocked long-term prostaglandin E2 formation. We conclude that in osteoblast-like MC3T3-E1 cells, ET-1, ET-2, beta-ET, S6b, and S6a peptides induce PGHS-2 through a protein tyrosine kinase-dependent and protein kinase C-dependent pathway, signaling through ET(A) receptor occupancy.
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PMID:Prostaglandin endoperoxide synthase-2 contributes to the endothelin/sarafotoxin-induced prostaglandin E2 synthesis in mouse osteoblastic cells (MC3T3-E1): evidence for a protein tyrosine kinase-signaling pathway and involvement of protein kinase C. 949 62

Depletion of intracellular calcium stores by agonist stimulation is coupled to calcium influx across the plasma membrane, a process termed capacitative calcium entry. Capacitative calcium entry was examined in cultured guinea pig enteric glial cells exposed to endothelin 3. Endothelin 3 (10 nM) caused mobilization of intracellular calcium stores followed by influx of extracellular calcium. This capacitative calcium influx was inhibited by Ni2+ (89 +/- 2%) and by La3+ (78 +/- 2%) but was not affected by L-, N-, or P-type calcium channel blockers. Chelerythrine, a specific antagonist of protein kinase C, dose-dependently inhibited capacitative calcium entry. The nitric oxide synthase inhibitor NG-nitro-L-arginine decreased calcium influx in a dose-dependent manner. The combination of chelerythrine and NG-nitro-L-arginine produced synergistic inhibitory effects. Capacitative calcium entry occurs in enteric glial cells via lanthanum-inhibitable channels through a process regulated by protein kinase C and nitric oxide.
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PMID:Endothelin-stimulated capacitative calcium entry in enteric glial cells: synergistic effects of protein kinase C activity and nitric oxide. 964 67

This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured endothelium derived from capillaries of human brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl- cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ET(A) but not ET(B) receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ET(A) receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC.
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PMID:Human brain capillary endothelium: modulation of K+ efflux and K+, Ca2+ uptake by endothelin. 970 3

This study showed that endothelins (ETs) stimulate DNA and proteoglycan synthesis in monolayer culture of rat articular chondrocytes (AC) by interacting with specific cell surface receptors. The high affinity receptors bound [125I]ET-1 with a Kd of 0.54 nM and Bmax of 81.4 pM/microgram DNA (approximately 40 000 binding sites per cell) was demonstrated. [125I]ET-1 binding was completely inhibited by unlabelled ET-1 or ET-2, and by BQ123 (ETA receptor antagonist), whereas ET-3 and IRL1038 (ETB receptor antagonist) did so only weakly. SDS-PAGE of cell extracts containing [125I]ET-1 cross-linked to the receptors, followed by autoradiography of the gels revealed a single 50-kDa band. These findings indicate that most of the receptors are subtype ETA. Although mRNA transcripts specific for both ETA and ETB receptors were found by RT-PCR, the ETA mRNA was more abundant. ET-1 increased the production of cAMP, cGMP and prostaglandin E2 (PGE2) and protein kinase C (PKC) activity in a concentration- and time-dependent manner. ET-1, and to a lesser degree ET-2, stimulated DNA synthesis, whereas ET-3 was inactive. Stimulation of DNA synthesis by ET-1 was strongly inhibited in a concentration-dependent manner by BQ123 and, to a much lesser degree, by IRL1038, which is consistent with an ETA receptor. ET-1 also stimulated proteoglycan synthesis and increased the amount of mRNA specific for the aggrecan gene. These findings strongly suggest that ET-1 is involved in regulating chondrocyte proliferation and metabolism in health, and presumably in disease.
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PMID:Endothelin 1 receptors, signal transduction and effects on DNA and proteoglycan synthesis in rat articular chondrocytes. 977 Mar 28

Endothelin-1 (ET-1) is a peptide classically produced by endothelial cells and known for its powerful vasoconstrictor activity. However, recent data suggest an involvement of ET-1 also in reproductive function. This study was designed to examine the possible presence and role of ET-1 in human luteal cells. Purified luteal cells were incubated for different times with ET-1 (10(-9)-10(-6) M) or ET-3 (10(-9)-10(-6)) alone or associated with human chorionic gonadotrophin (HCG) (100 ng/ml). Both basal and HCG-induced progesterone production were significantly reduced by ET-1 at all examined times whereas preincubation of luteal cells with BQ485 (10(-9)-10(-6) M), an ET-A receptor antagonist, prevented the inhibitory effect of ET-1. Conversely, no effect on progesterone synthesis was observed when ET-3 was added to the cultures. Luteal cells were then incubated for 24 h with phorbol 12-myristate-13 acetate (PMA) (100 ng/ml), an activator of protein kinase C. Inhibition of progesterone synthesis by PMA was similar to that induced by ET-1 alone. This study demonstrates that ET-1 negatively affects, at physiological concentrations, basal and HCG-induced progesterone synthesis. These effects seem to be exerted through the ET-A receptors and the protein kinase C pathway. Conversely, ET-3 was not able to influence human luteal steroidogenesis.
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PMID:Endothelin-1 inhibits basal and human chorionic gonadotrophin-stimulated progesterone production. 980 62

Endothelin (ET) is one of the active endogenous substances regulating the functions of astrocytes. In the present study, we examined effects of ET on cyclooxygenase (COX) expression in cultured astrocytes. ET-3 (100 nM) caused transient increases in the expression of both COX2 mRNA and protein, but not those of COX1, in cultured astrocytes. ET-induced COX2 mRNA expression was suppressed by 5 microg/ml actinomycin D, 30 microM BAPTA/AM, inhibitors of protein kinase C (1-100 nM staurosporin and 100 microM H-7), 2 microM dexamethasone, and prolonged treatment with 100 nM phorbol 12-myristate 13-acetate. ET-3 stimulated production of prostaglandin (PG) E2 in cultured astrocytes. The effect of ET-3 on the PGE2 production was diminished by actinomycin D. Indomethacin and NS398, a selective COX2 inhibitor, comparably decreased both the basal and the ET-stimulated PGE2 production. Proliferation of cultured astrocytes was stimulated by 100 nM ET-3, and the increased proliferation was reduced by co-addition of 1 microM PGE2. Treatment with 1 microM PGE2 caused astrocytic morphological changes accompanied by disappearance of stress fibers, a prominent structure of organized cytoskeletal actin in cultured astrocytes. In the presence of 10 nM ET-3, PGE2 did not show an effect on astrocytic actin organization. The present study shows that ET is an inducer of astrocytic COX2 and suggests that ET-induced PGE2 production through COX2 may be involved in the regulation of astrocytic functions.
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PMID:Endothelins stimulate expression of cyclooxygenase 2 in rat cultured astrocytes. 1046 89

Endothelin (ET)-1 is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca(2+) in the myocardium. The object of this study was to examine 1) the influence of ET(A) and ET(B) receptor subtypes, and 2) the role of the phospholipase C (PLC) pathway in mediating ET-1-induced contraction. Left ventricular cardiomyocytes were isolated from the hearts of New Zealand White rabbits (2-2.5 kg) by the use of Langendorff perfusion with collagenase. Cardiomyocyte function was examined during unloaded, electrically stimulated (0.5 Hz) contractions with a video-edge detection system. ET-1 increased cell shortening with greater potency than ET-3: mean EC(50) values were 1.1 x 10(-11) and 2.6 x 10(-10) M, respectively. With the same order of potency, ET-1 and ET-3 increased (P <.05) velocity of cell shortening. The ET(A) receptor-selective antagonist ABT-627 shifted the ET-1-induced cell shortening response curve to the right with a pA(2) value of 10.3. The ET(B) receptor-selective antagonist A-192621 (10(-8)-10(-7) M) did not alter the concentration-response of ET-1. Moreover, the ET(B) receptor-selective agonist sarafotoxin 6c did not have any effect on cell shortening over the concentration range of 10(-11) to 10(-7) M. ET-1 in the presence of the PLC inhibitor U-73122 did not alter the contractile amplitude. However, ET-1 in the presence of the protein kinase C inhibitor bisindolylmalemide increased cell shortening. These findings indicate that 1) the ET(A) receptor subtype, and not the ET(B) receptor subtype, mediates the positive inotropic effect of ET-1, and 2) the response of ET-1 is mediated by a PLC pathway, but not through protein kinase C, in ventricular cardiomyocytes isolated from rabbit myocardium.
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PMID:Endothelin(A) receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium. 1094 58

Alteration of endothelins (ET) and/or their receptors may be important in mediating vascular dysfunction in diabetes. We investigated mechanisms regulating ET-1 expression in human umbilical vein endothelial cells (HUVEC) in response to glucose and the functional significance of these mechanisms. Permeability across HUVEC, grown in medium containing either low (5 mmol/l) or high (25 mmol/l) D-glucose were investigated. L-glucose was used as a control. ET-1, ET(A), and ET(B) mRNA were assessed by semiquantitative RT-PCR. ET-1 immunoreactivity and F-actin microfilament assembly were investigated using confocal microscopy. Increased transendothelial permeability was noted in cells cultured in high glucose or when the cells grown in low (physiologic) glucose were incubated with ET-1, vascular endothelial growth factor (VEGF), or N (G) -nitro-L-arginine methyl ester but not when they were incubated with ET-3, N(G)-nitro-D-arginine methyl ester, or L-glucose. Increased permeability was associated with increased ET-1, ET(A), and ET(B) mRNA expression and augmented ET-1 immunoreactivity. High glucose induced increased permeability, increased ET-1, ET(A), and ET(B) mRNA expression. ET-1 immunoreactivity was blocked by the protein kinase C (PKC) inhibitor chelerythrine, the specific PKC isoform inhibitor 379196, VEGF-neutralizing antibody, or the ET(A) blocker TBC11251, but was not blocked by the specific ET(B) blocker BQ788 or by a VEGF-non-neutralizing antibody. Increased permeability was also associated with deranged F-actin assembly in the endothelial cells and by derangement of endothelial cell junctions as assessed by electron microscopy. Data from this study suggest that high glucose-induced increased permeability may be induced through increased ET-1 expression and disorganization of F-actin assembly. ET-1 expression and increased permeability may occur secondary to PKC isoform activation and may be modulated by VEGF and nitric oxide.
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PMID:Interaction of endothelin-1 with vasoactive factors in mediating glucose-induced increased permeability in endothelial cells. 1095 Jan 22


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