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 role of protein kinase C (PKC) in the control of prostaglandin production by the human amnion was studied. Amnion membranes delivered spontaneously at term were minced and treated with phorbol esters, protein kinase inhibitors, cycloheximide, and actinomycin D; prostaglandin E2 (PGE2) output then was determined. Untreated tissue produced 3.97 +/- 1.13 ng PGE2/micrograms DNA/14 h (mean +/- SEM, n = 19). Phorbol dibutyrate and 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated PGE2 output up to 20-fold in a concentration-dependent manner with potencies corresponding to their efficacy as PKC activators. Four-beta-phorbol and 4-methoxy-TPA, which do not stimulate PKC, did not affect PGE2 output. Stimulation by TPA was blocked by staurosporine (IC50 = 57 nM) and H7; however, these PKC inhibitors did not decrease basal prostaglandin production. Cycloheximide inhibited basal and TPA-promoted PGE2 production and amino acid incorporation. Actinomycin D abolished TPA stimulation without decreasing unstimulated prostaglandin synthesis. These results show that amnion PGE2 production after labor is not maintained by PKC action, but PKC activation in this tissue causes a protein synthesis-dependent and RNA synthesis-dependent increase of PGE2 output. However, basal PGE2 production is dependent upon protein synthesis which, presumably, utilizes pre-existing mRNAs.
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PMID:Prostaglandin synthesis regulation in human amnion tissue: involvement of protein kinase C and dependence on ribonucleic acid and protein synthesis. 137 15

Studies reported here determined the effect of dietary fat level on membrane phospholipid composition, phosphoinositide labeling, 1,2-sn-diacylglycerol and protein kinase C activity in epidermal cells from female Sencar mice. Animals were fed either high fat (24.6 g/100 g diet) or control (5 g/100 g diet) diets at constant energy intake for 6 to 7 wk or 15 to 22 wk, and epidermal cells were isolated. The level of phosphatidylinositol was significantly lower in the animals fed the control diet than in the animals fed the high fat diet (0.6 vs. 1.2 nmol/10(6) cells). The fatty acid composition of the phospholipids showed significantly lower arachidonic acid level in phosphatidylinositol when the animals were fed the high fat diet. Protein kinase C activity in the solubilized particulate and soluble fraction of the cells was 131 +/- 18% and 62 +/- 14% greater, respectively, in animals fed the high fat diet compared with animals fed control diet. The level of 1,2-sn-diacylglycerol was significantly higher in animals fed the high fat diet (mean nmol/mg lipid +/- SEM: control, 4.5 +/- 0.5; high fat, 7.0 +/- 0.5). Incorporation of [3H]inositol into inositol lipid was not altered by diet. Because protein kinase C and 1,2-sn-diacylglycerol have been implicated in tumor promotion, the increase in protein kinase C activity and the elevation of 1,2-sn-diacylglycerol in cells from animals fed the high fat diet may be important in the high cancer rate observed with these diets.
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PMID:Protein kinase C is activated and diacylglycerol is elevated in epidermal cells from Sencar mice fed high fat diets. 145 16

To study the effect of the inflammatory mediator hydrogen peroxide (H2O2) on airway ciliary activity, we measured ciliary beat frequency (CBF) in cultured tracheal explants from sheep. Addition of H2O2 (10(-8) to 10(-4) M) produced a concentration-dependent mean (+/- SEM) decrease in CBF between 11.1 +/- 0.4% (P less than 0.01) and 100 +/- 0% (P less than 0.001); at each concentration, the maximal effect was reached by 20 to 25 min. Between 10(-8) and 10(-6) M H2O2, the decrease in CBF was reversible, lactate dehydrogenase (LDH) release was not significantly increased, and major morphologic lesions were not seen. At higher concentrations of H2O2, incomplete recovery of CBF (10(-5) M) or irreversible ciliostasis (10(-4) M) developed, and a significant increase in LDH and morphologic lesions were present. Catalase (2,000 U/ml) and H-7 (10(-5) M), a protein kinase inhibitor, abolished cilioinhibition produced by H2O2 at 10(-6) M and lower concentrations but not at 10(-5) M and higher concentrations. Phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, caused a dose-dependent (10(-11) to 10(-5) M), reversible decrease in CBF; this effect was abolished by H-7. We suggest that at nonlethal concentrations, H2O2 inhibits the beat frequency of airway epithelial cilia reversibly, through the activation of second messengers, including protein kinase C. This mechanism might contribute to the previously demonstrated impairment of mucociliary clearance in airway inflammation.
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PMID:Mechanism of hydrogen peroxide-induced inhibition of sheep airway cilia. 159 Oct 15

alpha-Adrenergic stimulation is known to enhance myocardial contractility. Adult rat left ventricular myocytes bathed in 1 mM [Ca2+] (Ca0) and electrically stimulated at 0.2 Hz responded to alpha-adrenergic stimulation with 50 microM phenylephrine and 1 microM propranolol with an increase in twitch amplitude to 177.1 +/- 25.6% of control (mean +/- SEM). In contrast, when cell Ca2+ loading was increased by bathing cells in 5 mM Ca0, alpha-adrenergic stimulation decreased twitch amplitude to 68.6 +/- 8.2% of control. Time-averaged cytosolic [Ca2+] of cells in 1.0 mM Ca0 is enhanced via an increase in the frequency of electrical stimulation. When myocytes were stimulated at 2 Hz in 1 mM Ca0, alpha-adrenergic stimulation did not increase twitch amplitude (103.8 +/- 12.4% of control). In myocytes loaded with the Ca2+ probe into-1, alpha-adrenergic effects during stimulation at 0.2 Hz (an increase in twitch amplitude in 1 mM Ca0 and a decrease in twitch amplitude in 5 mM Ca0) were associated with similar changes in the indo-1 transient. In 5 mM Ca0, spontaneous Ca2+ releases from the sarcoplasmic reticulum (SR) occurred in the diastolic interval between twitches (2.9 +/- 1.4 spontaneous SR Ca2+ oscillations/min; n = 7); alpha-adrenergic stimulation abolished these oscillations in six of seven cells. Thus, an increase in the frequency of spontaneous diastolic SR Ca2+ release (i.e., Ca2+ overload) is not the mechanism for the negative inotropic effect of alpha-adrenergic stimulation in 5 mM Ca0. In experiments with unstimulated myocytes, we determined whether the effect of alpha-adrenergic stimulation on cell Ca2+ homeostasis and oscillatory SR Ca2+ release observed in 5 mM Ca0 occurs only during electrical stimulation, when voltage-dependent currents are operative, or also at rest. Unstimulated rat ventricular myocytes in 5 mM Cao exhibit oscillatory SR Ca2+ release; alpha-adrenergic stimulation decreased the frequency of these oscillations to 53.9 +/- 8.9% of control, and this effect was blocked by 1 microM prazosin. In unstimulated indo-1-loaded myocytes alpha-adrenergic stimulation decreased the resting indo-1 fluorescence ratio in 5 mM Ca0, whereas it had no effect in 1 mM Ca0. Additional experiments were aimed at defining a role for Ca(2+)-activated, phospholipid-dependent protein kinase C (PKC) for the negative inotropic effect of alpha-adrenergic stimulation in 5 mM Ca0. Short-term preexposure to 0.1 microM 4 beta-phrobol 12-myristate 13-acetate (PMA) has been shown to maximally activate PKC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ca2+ dependence of alpha-adrenergic effects on the contractile properties and Ca2+ homeostasis of cardiac myocytes. 165 Feb 98

The goal of this study was to determine whether protein kinase C mediates bradykinin-induced increases in microvascular permeability. Permeability of the hamster cheek pouch was evaluated using intravital fluorescent microscopy and fluorescein isothiocyanate (FITC)-dextran (MW 70,000). We examined effects of sphingosine, a protein kinase C inhibitor, on bradykinin-induced increases in permeability. Increases in permeability were quantitated by counting the number of leaky sites and calculating the clearance of FITC-dextran. During bradykinin (10(-6) M), leaky sites increased from 0 to 40 +/- 4 (mean +/- SEM) sites/0.11 cm2, and clearance increased from 1.7 +/- 1.0 to 22 +/- 9 ml/sec x 10(-6). The bradykinin type-2 receptor antagonist D-Arg,[Hyp3,Thi5,8,D-Phe7]-bradykinin virtually abolished formation of leaky sites in response to bradykinin. To determine whether changes in microvascular pressure contribute to the increase in leaky sites, venular pressure was measured using a micropipette and survo-null device. Increases in cheek pouch venular pressure were similar during application of bradykinin and adenosine, which increased permeability, and isoproterenol, which did not increase permeability in the cheek pouch. Thus, increases in permeability were not linked to changes in microvascular pressure. The protein kinase C inhibitor, sphingosine (10(-6) M), markedly attenuated responses to bradykinin. Leaky sites increased from 0 to only 2 +/- 1 sites/0.11 cm2, and clearance increased from 3.9 +/- 1.4 to only 6.7 +/- 2.2 ml/sec x 10(-6). To test the specificity of sphingosine, we examined effects of adenosine (10(-6) M). Sphingosine did not significantly alter increases in microvascular permeability in responses to adenosine. We also examined effects of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), another protein kinase C inhibitor, on responses to bradykinin and adenosine. H-7 greatly attenuated formation of leaky sites during stimulation with bradykinin and did not alter the number of leaky sites produced during adenosine. The findings suggest that protein kinase C may mediate increases in vascular permeability in response to bradykinin.
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PMID:Role of protein kinase C in bradykinin-induced increases in microvascular permeability. 170 11

This manuscript describes experiments designed to investigate protein kinase C redistribution occurring during acquisition of the rabbit nictitating membrane (NM) conditioned response (CR). The first experiment defined the acquisition phase of the NM response for our laboratory. A group of rabbits (n = 6) was given 2 days of paired NM training; a second group (n = 6) was given 2 days of unpaired NM training. The data document a variable level of responding on day 1 for rabbits given paired training (mean +/- SEM, 21 +/- 11% CRs) but show that on day 2 most rabbits reached the behavioral asymptote (five of six rabbits responding with greater than 85% CRs). Rabbits responding at the behavioral asymptote were defined as having acquired the NM conditioned response. These data were interpreted to indicate that 1 day of training initiated processes necessary for behavioral acquisition (i.e., responding at the behavioral asymptote). A quantitative film autoradiographic study of [3H]phorbol 12,13-dibutyrate binding was then used to determine the distribution of hippocampal protein kinase C in rabbits sacrificed after receiving either 1 day of paired stimuli (n = 10), 1 day of unpaired stimuli (n = 6), or no stimuli (n = 6). Autoradiograms were analyzed by measuring binding in strictly defined regions of interest and from transept profiles. A significant increase in binding of the phorbol ester was found in the CA3 stratum oriens in the paired group relative to unpaired and naive controls. No other significant differences were found.
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PMID:Protein kinase C redistribution within CA3 stratum oriens during acquisition of nictitating membrane conditioning in the rabbit. 186 86

We determined the effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C, on pial arteriolar diameter and cerebrospinal fluid (CSF) prostanoid levels in newborn pigs. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy. In addition, CSF was sampled from under the window, and prostanoid levels (prostaglandin [PG] E2, 6-keto-PGF1 alpha, PGF2 alpha, and thromboxane B2) were determined by radioimmunoassay. Diameter and CSF prostanoid levels were determined during application of artificial CSF containing no drugs and during application of 10(-8), 10(-7), and 10(-6) M PDB. We also determined effects of 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), a phorbol ester that does not activate protein kinase C, and dimethyl sulfoxide, the vehicle for the phorbol esters, on pial arteriolar diameter and CSF prostanoid levels. Initial diameters were 100-200 microns. At 10(-8)-10(-6) M, PDB progressively constricted pial arterioles and increased CSF levels of prostanoids; the other phorbol ester and dimethyl sulfoxide had no such effects. Baseline arteriolar diameter was 147 +/- 17 microns (mean +/- SEM), and diameter was 140 +/- 17 microns at 10(-8) M PDB, 120 +/- 18 microns at 10(-7) M PDB (p less than 0.05), and 108 +/- 14 microns at 10(-6) M PDB (p less than 0.05) (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of phorbol esters on pial arteriolar diameter and brain production of prostanoids in piglets. 193 55

Human interferon-alpha (Hu-IFN alpha) and phorbol myristate acetate (PMA), a direct activator of protein kinase C (PK-C), induce the translocation of protein kinase C from the cytosol to the membrane fraction. By the use of transmission (TEM) and scanning (SEM) electron microscopy we have shown that treatment of human amniotic cells (UAC) with Hu-IFN alpha resulted in profound changes in the shape, volume and ultrastructure of the cells. Most treated cells had enlarged nuclei with marginal condensation of chromatin. Nucleolar segregation, disintegration and clumping of nucleolar components were also observed. The number of interdigitating cell processes decreased and the cell surface microvilli became shortened. Similar ultrastructural alterations were induced by PMA also. All these functional and morphological data strongly support the hypothesis that protein kinase C is a key factor in IFN-mediated cell reactions.
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PMID:Ultrastructural changes of human amniotic cells induced by natural human interferon-alpha. 209 71

Endothelin (ET-1) receptors were studied in the C-6 glia cell line. ET-1 binds to C-6 cells in a temperature- and time-dependent manner, with an apparent Kd of 1.16 +/- 0.07 10(-10) M and a Bmax of 96,500 +/- 6000 sites/cell (mean +/- SEM, n = 27). Stimulation of protein kinase C (PKC) with the diacylglycerol (DAG) analog phorbol 12-myristate 13-acetate (PMA) resulted in a decrease in the number of receptors in a dose-dependent manner. Inhibition of PKC with H-7 eliminated the effect of PMA on the reduction of binding sites. Treatment with exogenous 1-oleoyl-2-acetyl-sn-glycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG), release of endogenous DAG with phospholipase C, and inhibition of the metabolism of DAG with the diacylglycerol kinase inhibitor R 59022 also resulted in a decrease in the number of receptors. The effect of these agents was inhibited by H-7. ET-1-mediated down-regulation of receptors was also demonstrated, but the down-regulation was not affected by H-7 or by depletion of cellular PKC with chronic, high dose of PMA. Internalization constants of ET-1-receptor complex was also measured according to the model of Wiley and Cunningham (Cell 25 (1981) 433). PMA- and ET-1-mediated down-regulation of receptors was associated with an increase in the endocytosis constant for the hormone-receptor complex and a decrease in the rate of insertion of receptor into the plasma membrane. PMA, but not ET-1, increased the rate of endocytosis of unoccupied receptors. Radioiodinated ET-1 was crosslinked to the receptor after binding, extracted and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A band at 66 kDa was obtained. These studies show that ET-1 and PKC activation produce down-regulation of ET-1 membrane receptors and that ET-1-mediated down-regulation probably does not involve the activation of PKC.
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PMID:ET-1 receptors in C-6 cells: homologous down-regulation and modulation by protein kinase C. 216 63

We tested the hypothesis that protein kinase C might play a role in the biosynthesis of platelet-activating factor (paf-acether) in human neutrophils. PMA but not its inactive analog 4-alpha-phorbol-12,13-didecanoate induced lyso paf-acether production, followed by acetyltransferase activation, leading to paf-acether synthesis and release. Moreover, PMA was twice as powerful compared to opsonized zymosan (OPZ). 1-Oleoyl-2-acetyl-glycerol also induced acetyltransferase activation and paf and lyso paf production. The paf-acether formed by PMA or OPZ stimulation was composed of alkyl chains C16:0 (84.3 +/- 5% and 80.7 +/- 3.5%, respectively, and C18:0 (15.7 +/- 5% and 19.3 +/- 3.5%, respectively, means +/- SEM) as assessed by gas chromatography-electron capture detection. The inhibitor of protein kinase C, D-sphingosine, markedly decreased paf and lyso paf production and acetyltransferase activation in PMA- as well as OPZ-stimulated neutrophils. These results strongly suggest the involvement of protein kinase C in signal transduction during cell stimulation, leading to the paf biosynthesis.
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PMID:Biosynthesis of paf-acether. X. Phorbol myristate acetate-induced paf-acether biosynthesis and acetyltransferase activation in human neutrophils. 273 70


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