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)

Interaction of protein kinase C with chromaffin granule membranes has been studied as a means of investigating the translocation of protein kinase C from cytosol to intracellular membrane surfaces, which is believed to occur during secretion. Protein kinase C in an adrenal medullary soluble fraction was found to bind reversibly to granule membranes in a Ca2+-dependent fashion. Association and dissociation events were sensitive to Ca2+ concentrations in the low micromolar range, and the Ca2+ sensitivity of both processes was increased when the membranes had been preincubated with the protein kinase C-activating phorbol ester, 4 beta-phorbol 12-myristate 13-acetate (TPA). Binding of protein kinase C to granule membranes occurred at 0 and 37 degrees C, irrespective of whether the membranes had been preincubated with TPA. However, dissociation of protein kinase C from granule membranes that had been preincubated with TPA occurred only at 37 degrees C and not at 0 degree C, even though dissociation of the enzyme from membranes which had not been preincubated with TPA would occur at both 37 and 0 degrees C. These effects of TPA were not reproduced by 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD), a phorbol ester which does not activate protein kinase C. Soluble protein kinase C activity also associated with chromaffin granules in a Ca2+-dependent manner in an adrenal medullary homogenate, indicating that granules can compete with other intracellular membranes for the binding of protein kinase C. Results obtained with this model system differ from other systems where the interaction of protein kinase C with plasma membranes has been studied and have general implications for studies performed on the translocation of protein kinase C in intact cells and for the role of protein kinase C in stimulus-secretion coupling in the chromaffin cell.
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PMID:Interaction of protein kinase C with chromaffin granule membranes: effects of Ca2+, phorbol esters and temperature reveal differences in the properties of the association and dissociation events. 292 75

Phorbol 12-myristate 13-acetate (PMA) has been shown to stimulate DNA synthesis and cell proliferation in a population of glial cells isolated from newborn rat brain. The non-tumor promoter 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), on the other hand, was without an effect. The cultures treated with PMA displayed an extensive process formation and an increase in cell content. The tumor promoter-induced [3H]thymidine incorporation into acid-precipitable material was completely blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of protein kinase C (PKC), thereby suggesting a role for PKC in the control of DNA synthesis in glial cells. Subcellular fractionation and in vitro assay of PKC activity revealed a translocation of the enzyme from cytosol to particulate fraction in PMA-treated cultures.
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PMID:Role of protein kinase C in glial cell proliferation. 292 38

The hydro-osmotic response of the toad urinary bladder to antidiuretic hormone (ADH) and cyclic AMP was inhibited by phorbol myristate acetate (PMA) and 4 beta- phorbol dideconate (4 beta-PDD), activators of protein kinase C (PKC). The inactive epimer of 4 beta-PDD, had no effect on the ADH response. The osmotic transfer of water in the absence of ADH was unaffected by PMA. PKC activity, localized in the soluble fraction of isolated toad bladder cells, was activated by PMA. ADH initially inhibited and subsequently stimulated 32Pi incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI). Carbachol, which inhibits ADH-induced water flow, also stimulated 32P incorporation into PA and PI. It is suggested that phosphoinositide breakdown to diacylglycerol may activate PKC which functions to attenuate the hormone-mediated permeability response.
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PMID:Calcium/phospholipid-dependent protein kinase and its relationship to antidiuretic hormone in toad urinary bladder epithelium. 300 55

Protein phosphorylation mediated by cAMP-dependent protein kinase is instrumental in maintaining meiotic arrest of mouse oocytes. To assess whether protein phosphorylation mediated by calcium/phospholipid-dependent protein kinase (protein kinase C) might also inhibit the resumption of meiosis, we treated oocytes with activators of this enzyme. The active phorbol esters 12-O-tetra-decanoyl phorbol-13-acetate (TPA) and 4 beta-phorbol 12,13-didecanoate (4 beta-PDD) inhibited germinal vesicle breakdown (GVBD), as did a more natural activator of protein kinase, C, sn-1,2-dioctanoylglycerol (diC8). An inactive phorbol ester, 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), did not inhibit GVBD. We then examined whether protein kinase C activators inhibit a step in the cAMP-modulated pathway that regulates resumption of meiosis. TPA did not inhibit the maturation-associated decrease in oocyte cAMP. Microinjected heat-stable protein inhibitor of cAMP-dependent protein kinase failed to induce GVBD in the presence of TPA. Both TPA and diC8 partially inhibited specific changes in oocyte phosphoprotein metabolism that are tightly correlated with resumption of meiosis; these agents also induced the apparent phosphorylation of specific oocyte proteins. These results suggest that protein kinase C activators may inhibit resumption of meiosis by acting distal to a decrease in cAMP-dependent protein kinase activity, but prior to changes in oocyte phosphoprotein metabolism that are presumably required for resumption of meiosis. Finally, we compared the effects of db-cAMP and protein kinase C activators on polar body emission following GVBD. TPA, 4 beta-PDD or diC8, but not 4 alpha-PDD or db-cAMP, inhibited polar body emission in a dose-dependent manner. The morphology and cytology of oocytes in which polar body emission was inhibited by TPA or 4 beta-PDD differed from that of oocytes treated with diC8. Thirty to 60% of the former were round in shape and exhibited a clump of chromosomes but no spindle; the remainder were distended in shape and exhibited a metaphase I spindle. All oocytes treated with diC8, however, were round, had dispersed chromosomes, and no spindle. These results suggest that, in contrast to resumption of meiosis, polar body emission is inhibited by activation of protein kinase C but not cAMP-dependent protein kinase.
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PMID:Effects of protein kinase C activators on germinal vesicle breakdown and polar body emission of mouse oocytes. 301 65

Many recent reports have indicated that the effect of the phorbol ester tumor promoters is mediated through the Ca2+/phospholipid dependent protein kinase C. We have investigated the effect of two biologically active phorbol esters, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) and 4 beta-phorbol 12 beta,13 alpha-didecanoate (beta PDD) on muscarinic agonist binding and receptor-stimulated phosphoinositide breakdown in cultured human neuroblastoma (SH-SY5Y) cells. Preincubation of these cells with phorbol esters significantly reduced the carbachol-stimulated breakdown of inositol phospholipids and caused a decrease of agonist affinity for [3H](-)methyl quinuclidinyl benzilate ([3H](-)MQNB) binding without affecting the affinity of antagonist to the muscarinic receptor. The nontumor promoting 4 alpha-phorbol 12 beta,12 alpha-didecanoate (alpha PDD) was ineffective in our studies. These results suggest that the activation of protein kinase C may play an important role in regulating the muscarinic receptor system.
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PMID:Phorbol esters alter muscarinic receptor binding and inhibit polyphosphoinositide breakdown in human neuroblastoma (SH-SY5Y) cells. 302 14

Several tumor promoters exert their effects by activating a Ca2+-phospholipid-dependent protein kinase (protein kinase C). To study the role of this protein kinase in the regulation of Sertoli cell function, we have evaluated the effect of phorbol esters, mezerein, and teleocidin on the response of the Sertoli cell to FSH. Cells were treated for different time intervals with the tumor promoters, and cell response was measured by stimulating the cell with FSH. 12-O-Tetradecanoylphorbol 13-acetate (TPA) had no significant effect on basal cAMP production but markedly inhibited the cAMP response to FSH. Significant inhibition of cAMP accumulation was observed after 15 min treatment with 100 nM TPA, and maximal inhibition developed within 1 h. The decrease in cAMP accumulation was dependent on the dose of phorbol ester used, with an estimated ED50 of 10-20 nM TPA. In a manner similar to TPA, mezerein and teleocidin also inhibited the cAMP response of the Sertoli cell, while the phorbol ester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), inactive as a tumor promoter and unable to stimulate protein kinase C activity, was devoid of effect. The promoters that inhibited cAMP response also inhibited the FSH-stimulated androgen aromatization. The dose of TPA producing half-maximal inhibition of estrogen accumulation was again 10-20 nM TPA, mezerein, and teleocidin inhibited estrogen accumulation whether FSH, forskolin or cholera toxin was used to stimulate the Sertoli cell. In contrast, only FSH-dependent cAMP accumulation was inhibited by the tumor promoters, while forskolin and cholera toxin stimulations were not affected. These data suggest that tumor promoters which activate protein kinase C act at two sites of the Sertoli cell response. They alter receptor-mediated signal transduction across the membrane and affect steroidogenesis at a site distal to cAMP accumulation.
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PMID:Inhibition by phorbol esters and other tumor promoters of the response of the Sertoli cell to FSH: evidence for dual site of action. 303 Aug 55

The role that protein kinase C (PKC) may play on insulin regulation of glucose metabolism was investigated in rat adipocytes and Zajdela hepatoma cultured (ZHC) cells which are two cell types highly responsive to insulin. In rat adipocytes, 4 beta-phorbol 12 beta-myristate, 13 alpha-acetate (PMA, 0.1-1,000 ng/ml), a potent tumor promoter acting as a substitute for diacylglycerol which directly activates PKC, stimulated basal 2-deoxyglucose (2-DG) transport in a time- and dose-dependent manner, but decreased the activation of this process elicited by submaximal concentrations of insulin. PMA (0.1-1,000 ng/ml) also stimulated basal lipogenesis from [3-3H] glucose in a dose-dependent manner. Maximal PMA and insulin effects on both processes were not additive. The specificity of the insulin-like effects of PMA was assessed by the finding that 4 beta-phorbol 12, 13 dibutyrate (PDBu), mezerein, 1-oleyl-2-acetyl glycerol (OAG) and 1, 2 diolein, know as PKC activators, also markedly stimulated glucose metabolism whereas 4 alpha-phorbol 12, 13 didecanoate (4 alpha-PDD) and 4 beta-phorbol 13-monoacetate, shown not to activate PKC, were ineffective. PMA and insulin biological effects exhibited several similarities: both agents stimulated glucose transport and lipogenesis in a calcium-dependent manner, both activated glucose transport through an energy-requiring process, and the effects of both were markedly decreased by mellitin, a PKC inhibitor. Finally, fat cells made PKC-deficient by a chronic treatment with PMA exhibited a marked decrease in insulin responsiveness for stimulation of glucose transport and lipogenesis, with no change in either the hormone sensitivity or the insulin receptor affinity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Regulation of glucose metabolism by insulin: dual role of protein kinase C]. 305 80

The phorbol ester TPA activates the protein kinase C in a similar way as 1,2-diacylglycerol. The effect of TPA on prolactin (PRL) secretion and electrical properties of rat pituitary cells in culture (GH4C1 cells) were compared with the effects of thyroliberin (TRH) on the corresponding parameters. The rate of hormone release was measured using a parafusion system optimized to give high time resolution. Samples for PRL measurements were taken every 4 s. The TRH evoked a biphasic PRL release, with a transient peak after about 30 s followed by a lower but sustained enhancement of the secretion. The TPA mimicked the late phase of the secretory response to TRH. The TPA analogue, 4 alpha-PDD, had no effect on the PRL release. The TRH also evoked biphasic membrane potential changes in the GH4C1 cells; the late phase consisting of membrane depolarisation associated with increased input resistance and enhanced firing of Ca2+ dependent action potentials. The TPA mimicked to a great extent these late phase effects of TRH, whereas the inactive analogue 4 alpha-PDD was ineffective. Continuous exposure to TPA masked the late phase of the electrophysiological response to TRH, suggesting that TPA and TRH share common mechanisms in their action on GH4C1 cells. We suggest that TRH enhances the electrical activity in these cells due to protein phosphorylation induced by diacylglycerol activation of protein kinase C, which in turn suppresses the membrane permeability to K+.
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PMID:The phorbol ester TPA induces hormone release and electrical activity in clonal rat pituitary cells. 308 38

Histamine-induced endothelium-dependent relaxation (EDR) in the pulmonary artery was inhibited in a concentration-dependent manner by the phorbolester phorbol 12,13-dibutyrate (PDBu) (IC50: 70 nM) whereas EDR occurring in response to ionophore A 23187 was not affected by PDBu. The phorbolester 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), which does not activate protein kinase C (PKC), was without effect on receptor- or ionophore-induced EDR. The observed inhibition of signal transduction by PKC activation is suggested to reflect phosphorylation of the GTP binding protein Ni.
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PMID:Interference of phorbolesters with endothelium-dependent vascular smooth muscle relaxation. 309 74

The involvement of protein kinase C in the release of [3H]acetylcholine (ACh) and [3H]norepinephrine (NE) was studied in strips of guinea pig small intestine. 12-O-tetradecanoyl phorbol 13-acetate (TPA), but not 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) potentiated the A23187-evoked release of [3H]ACh and [3H]NE from the strips of small intestine preloaded with [3H]choline and [3H]NE, and the potentiating effect of TPA was inhibited by polymyxin B. High K+-evoked releases of [3H]ACh and [3H]NE in the presence of tetrodotoxin were also potentiated by TPA. These TPA-induced potentiations of the evoked release were greater at a low concentration of external Ca2+ (0.5 mM) than at a high concentration (2 mM). Ouabain induced the release of these neurotransmitters both in the absence and presence of the low concentration of external Ca2+. The ouabain-evoked release was not altered by TPA. These results indicate that the activation of protein kinase C potentiates the vesicular release of ACh and NE at low Ca2+ concentration from the nerve terminals of enteric neurons in the guinea pig small intestine.
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PMID:Role of protein kinase C in the vesicular release of acetylcholine and norepinephrine from enteric neurons of the guinea pig small intestine. 314 63


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