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)

The present study examined the possible interaction of platelet-derived growth factor (PDGF) and atrial or brain natriuretic peptides (ANP and BNP, respectively) on cellular proliferation and secretion of endothelin-1 in cultured rat mesangial cells. PDGF increased cellular proliferation and endothelin-1 secretion. The protein kinase C (PKC) inhibitors, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, staurosporine, and PKC inhibitor peptide, inhibited such stimulation. Rat ANP-(1-28) and rat BNP-45 exhibited clearly dose-related inhibition of PDGF-stimulated cellular proliferation and endothelin-1 secretion. This inhibition by ANP and BNP was paralleled by an increase in the cellular level of guanosine 3',5'-cyclic monophosphate (cGMP). Results indicate that PDGF stimulates cellular proliferation and endothelin-1 secretion in cultured rat mesangial cells by a mechanism probably involving activation of PKC and that ANP and BNP inhibit such stimulation through a cGMP-dependent process.
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PMID:Interaction of PDGF and natriuretic peptides on mesangial cell proliferation and endothelin secretion. 823 92

Addition of endothelin-1 or endothelin-3 to rat renal papillary tubules produced a dose-dependent inhibition of the cAMP response to vasopressin stimulation. The average EC50 values were 1.1 +/- 0.6 and 2.6 +/- 1.1 nM, respectively, indicating mediation by an endothelin ETB receptor. Phorbol myristate acetate (1 microM) also inhibited the vasopressin-cAMP response and this inhibition was not additive with that to endothelin, indicating that the endothelin inhibition is mediated by activation of protein kinase C. These findings demonstrate functionally relevant endothelin ETB receptors on renal papillary tubules. Such receptors are a possible target for endothelin-3 produced within the kidney.
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PMID:Functional endothelin ETB receptors on renal papillary tubules. 825 66

The kinetic properties of endothelin-1 (ET-1) binding sites and the production of inositol phosphates (IPs; IP1, IP2, IP3), cyclic AMP, thromboxane B2, and prostaglandin F2 alpha induced by various endothelins (ET-1, ET-2, ET-3, and sarafotoxin S6b) were examined in endothelial cells derived from human brain microvessels (HBECs). The presence of both high- and low-affinity binding sites for ET-1 with KD1 = 122 pM and KD2 = 31 nM, and Bmax1 = 124 fmol/mg of protein and Bmax2 = 909 fmol/mg of protein, respectively, was demonstrated on intact HBECs. ET-1 dose-dependently stimulated IP accumulation with EC50 (IP3) = 0.79 nM, whereas ET-3 was ineffective. The order of potency for displacing ET-1 from high-affinity binding sites (ET-1 > ET-2 > sarafotoxin S6b > ET-3) correlated exponentially with the ability of respective ligands to induce IP3 formation. ET-1-induced IP3 formation by HBEC was inhibited by the ETA receptor antagonist, BQ123. The protein kinase C activator phorbol myristate ester dose-dependently inhibited the ET-1-stimulated production of IPs, whereas pertussis toxin was ineffective. Cyclic AMP production by HBECs was enhanced by both phorbol myristate ester and ET-1, and potentiated by combined treatment with ET-1 and phorbol myristate ester. Data indicate that protein kinase C plays a role in regulating the ET-1-induced activation of phospholipase C, whereas interaction of different messenger systems may regulate ET-1-induced accumulation of cyclic AMP. ET-1 also stimulated endothelial prostaglandin F2 alpha production, suggesting that activation of phospholipase A2 is most likely secondary to IP3-mediated intracellular calcium mobilization because both ET-1-induced IP3 and prostaglandin F2 alpha were inhibited by BQ123. These findings are the first demonstration of ET-1 (ETA-type) receptors linked to phospholipase C and phospholipase A2 activation in HBECs.
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PMID:Endothelin-1 receptor binding and cellular signal transduction in cultured human brain endothelial cells. 829 22

Previous studies from this laboratory have demonstrated that endothelin-1 (ET) stimulates phosphatidylinositol (PI) hydrolysis, activates dihydropyridine-insensitive Ca2+ channels, and promotes prostaglandin E2 (PGE2) accumulation in cultured rat renal medullary interstitial cells (RMIC). The mechanism whereby ET augments PGE2 production was explored in the current study. ET-evoked PGE2 accumulation proceeded independent of large increments in cytosolic free Ca2+ concentration ([Ca2+]i), derived from either extracellular or intracellular sources. Chelation of intracellular Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid eliminated ET-evoked PGE2 production, indicating that eicosanoid production was nonetheless a Ca(2+)-requiring process. Nanomolar concentrations of phorbol 12-myristate 13-acetate (PMA) alone did not stimulate PGE2 production, nor did PMA alter ET-stimulated PGE2 accumulation. Furthermore, downregulation of protein kinase C (PKC) by prolonged exposure of cells to PMA did not mitigate ET-mediated PGE2 production, demonstrating that PKC stimulation was not required for PGE2 production. ET stimulated PGE2 accumulation despite PI-specific phospholipase C (PI-PLC) inhibition by nanomolar concentrations of PMA, indicating that eicosanoid production was not a downstream event of PI hydrolysis. ET stimulated arachidonic acid metabolite release in parallel with a loss of label from membrane phospholipids. Phosphatidylethanolamine was the preferred substrate for ET-mediated activation of phospholipase A2 (PLA2). Immunocytochemical studies including immunostaining, immunoblotting, and immunoprecipitation confirmed the presence of cytosolic PLA2 (cPLA2) in RMIC. In summary, ET stimulation of PGE2 production in RMIC is mediated via agonist activation of cPLA2 independent of activation of PI-PLC, suggesting direct coupling to the ET receptor. Constitutive levels of [Ca2+]i rather than abrupt increments in [Ca2+]i are sufficient for activation of this receptor-effector system, with no obligatory requirement for PKC.
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PMID:Mechanism of endothelin activation of phospholipase A2 in rat renal medullary interstitial cells. 830 84

1. It has been shown that receptor agonists and activators of protein kinase C, phorbol esters, increase Ca2+ sensitivity of contractile elements in vascular smooth muscle. To discover if protein kinase C is involved in the agonist-mediated Ca2+ sensitization, we examined the effects of receptor agonists in the rat isolated aorta in which protein kinase C activity had been diminished by pretreatment with phorbol 12-myristate 13-acetate for 24 h. 2. In the aorta with protein kinase C activity, a high concentration (1 microM) of 12-deoxyphorbol 13-isobutyrate induced contraction and a low concentration (100 nM) potentiated high K(+)-induced contraction. In addition, prostaglandin F2 alpha induced greater contractions than high K+ at a given cytosolic Ca2+ level. The maximally effective concentrations of noradrenaline and endothelin-1 also induced greater contraction than high K+. In the aorta without protein kinase C activity, the contraction induced by 12-deoxyphorbol 13-isobutyrate and its potentiation of the high K(+)-induced contraction were abolished. However, prostaglandin F2 alpha, noradrenaline and endothelin-1 still induced a greater contraction than high K+. 3. In the aorta without protein kinase C activity, noradrenaline, endothelin-1 and prostaglandin F 2 alpha, but not 12-deoxyphorbol 13-isobutyrate, induced contractions in the presence of the Ca2+ channel blocker, verapamil, or in the absence of external Ca2+, by increasing Ca2+ sensitivity. 4. In the permeabilized preparations, inhibition of protein kinase C activity abolished the effect of potentiation of the Ca(2+)-induced contraction by 12-deoxyphorbol 13-isobutyrate although the potentiation of the contraction by prostaglandin F2 alpha did not change. 5. These results suggest that there are two pathways for Ca2+ sensitization in rat aorta; a protein kinase C-dependent pathway which is activated by phorbol esters, and a protein kinase C-independent pathway which is activated by receptor agonists.
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PMID:Different pathways of calcium sensitization activated by receptor agonists and phorbol esters in vascular smooth muscle. 830 97

To elucidate the cellular mechanism by which angiotensin II (ANG II) induces cardiac hypertrophy, we investigated the possible autocrine/paracrine role of endogenous endothelin-1 (ET-1) in ANG II-induced hypertrophy of neonatal rat cardiomyocytes by use of synthetic ET-1 receptor antagonist and antisense oligonucleotides to preproET-1 (ppET-1) mRNA. Northern blot analysis and in situ hybridization revealed that ppET-1 mRNA was expressed in cardiomyocytes, but, to a lesser extent, in nonmyocytes as well. ANG II upregulated ppET-1 mRNA level by threefold over control level as early as 30 min, and it stimulated release of immunoreactive ET-1 from cardiomyocytes in a dose- and time-dependent manner. ET-1 stimulated ppET-1 mRNA levels after 30 min in a similar fashion as ANG II. Tetradecanoylphorbol-acetate (10(-7) M) mimicked the effects of ANG II and ET-1 on induction of ppET-1 mRNA. ANG II-induced ppET-1 gene expression was completely blocked by protein kinase C inhibitor H-7 or by down-regulation of endogenous protein kinase C by pretreatment with phorbol ester. ET-1 and ANG II stimulated twofold increase [3H]leucine incorporation into cardiomyocytes, whose effects were similarly and dose dependently inhibited by endothelin A receptor antagonist (BQ123). Introduction of antisense sequence against coding region of ppET-1 mRNA into cardiomyocytes resulted in complete blockade with ppET-1 mRNA levels and [3H]leucine incorporation stimulated by ANG II. These results suggest that endogenous ET-1 locally generated and secreted by cardiomyocytes may contribute to ANG II-induced cardiac hypertrophy via an autocrine/paracrine fashion.
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PMID:Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. 832 7

Nanomolar concentrations of leukotriene C4 and phorbol 12-myristate acetate, a protein kinase C activator, stimulated endothelin-1 release by vascular endothelial but not smooth muscle cells. For both agonists, attenuation of this stimulatory effect was observed at higher concentrations, concomitant with but independent of enhanced prostacyclin biosynthesis.
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PMID:Differential effects of leukotriene C4 on endothelin-1 and prostacyclin release by cultured vascular cells. 832 7

To evaluate the role of protein kinase C (PKC) in regulation of cellular responsiveness to mitogens, we used rat 6 (R6) fibroblasts that stably overexpress the beta 1 isoenzyme of protein kinase C (PKC-beta 1). The potent vasoconstrictor and mitogen endothelin-1 (ET-1; 100 nM) was substantially more effective in stimulating InsP3 accumulation in PKC-beta 1-overexpressing fibroblasts (PKC3 cells) than in control fibroblasts lacking the PKC-beta 1 cDNA insert. PKC3 cells were found to express a 7-fold greater number of endothelin receptors than did control cells, whereas both cell lines showed equivalent Kd values. These receptors were of the ETA subtype, as defined by a 1000-fold greater affinity for ET-1 than for ET-3. Changes in intracellular free Ca2+ levels ([Ca2+]i) in response to ET-1 measured with the fluorescent Ca2+ indicator fura-2 showed that ET-1 was more potent and efficacious in stimulating [Ca2+]i in PKC3 cells than in control fibroblasts. The ET-1-induced Ca2+ rise was completely blocked by the selective ETA antagonist BQ123, but only slightly diminished by extracellular application of 2 mM EGTA. In contrast with the effects of PKC-beta 1 overexpression on responsiveness to ET-1, alpha-thrombin, which was previously found to have a weaker effect on InsP3 accumulation in PKC-beta 1-overexpressing cells, was also a less effective stimulator of [Ca2+]i in PKC3 cells than in control cells. These results demonstrate that, although the Ca2+ response to alpha-thrombin is diminished by PKC-beta 1 overexpression, ETA receptor number and cellular responsiveness to ET-1 are increased in PKC-beta 1-overexpressing cells.
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PMID:Endothelin (ETA) receptor number and calcium signalling are up-regulated by protein kinase C-beta 1 overexpression. 836 66

We examined the effects of cyclical strain on endothelin-1 (Et-1) secretion and Et-1 mRNA levels in human umbilical vein endothelial cells. Cultured endothelial cells grown on a flexible membrane base were deformed by vacuum to 20% of maximum strain, at 60 cycles/min, for various time periods. The rate of Et-1 release from strain- treated cells and their Et-1 mRNA levels were measured. Cells subjected to strain increased their Et-1 secretion into the culture medium from 0.17 ng/hr/10(6) cells to 0.44 ng/hr/10(6) cells. Concomitantly, the Et-1 mRNA levels in strained cells increased 1.4-, 2.1- or 2.6- fold (vs control unstrained cells) after 0.25, 0.5 or 6 hours of strain, respectively. Cells exposed to longer periods of strain (> 6 hrs) did not further increase their mRNA expression. Pretreatment with calphostin C, a specific inhibitor of protein kinase C, before straining completely abolished Et-1 mRNA expression. These results indicate that mechanical strain can modulate the secretion of Et-1 from endothelial cells by increasing Et-1 mRNA levels via the protein kinase C pathway. Elevation of Et-1 secretion and gene expression in endothelial cells under physiological strain might influence normal or pathological states of the vasculature and cardiac growth.
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PMID:Cyclical strain increases endothelin-1 secretion and gene expression in human endothelial cells. 837 84

The growth factor-activated Na+/H+ exchanger is regulated by numerous stimuli, including polypeptide hormones, phorbol esters, cell acidity, and cell shrinkage. To determine whether this regulation occurs at a common site on the cytoplasmic domain of the Na+/H+ exchanger, we microinjected polyclonal antibodies (RP1-c28) to the C-terminal 157 amino acids of the molecule and measured cell pH changes after application of a variety of stimuli known to activate the Na+/H+ exchanger. Microinjection of approximately 10 fg of RP1-c28 antibody, but not control IgG, into single cultured fibroblasts blocked subsequent activation of the exchanger by both endothelin and alpha-thrombin. In contrast, microinjected RP1-c28 did not prevent activation of Na+/H+ exchange by phorbol esters, consistent with the observation that both endothelin-1 and alpha-thrombin retained the ability to activate exchange activity in protein kinase C-depleted cells. Finally, activation of Na+/H+ exchange by both cell acidity and osmotic shrinkage was also unaffected by microinjected RP1-c28 antibody. These data indicate that activation of Na+/H+ exchange by endothelin-1 and alpha-thrombin is mechanistically distinct both from activation by protein kinase C and activation by physical factors and probably occurs at a separate site on the exchanger molecule.
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PMID:Role of cytoplasmic domain of the Na+/H+ exchanger in hormonal activation. 838 29


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