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)

We have previously shown that myocardium from experimental autoimmune myocarditis expresses H1 receptors not present in normal mice heart. ThEA acting via H1 receptors, augments cyclic AMP production in atria from autoimmune myocarditis mice without any effect on atria from control mice. Addition of mepyramine before ThEA caused cyclic AMP levels to fall to a level similar to basal, confirming the H1 receptor participation. Histamine at low concentrations mimicked the ThEA action on H1 receptor-stimulation of cyclic AMP production by autoimmune myocardium. The fact that the inhibition of phospholipase C blocked the cyclic AMP stimulation by ThEA, supports the assumption that this action is secondary to receptor-mediated hydrolysis of phosphoinositides, generating some oxidative metabolites (IP3-DAG), which in turn may be responsible for the cyclic AMP effect. So, the inhibition of protein kinase C and calcium/calmodulin partially prevented the stimulatory action of ThEA on cyclic AMP levels in autoimmune myocardium, suggesting that both pathways are implicated in this effect. Data shows that the stimulation of H1 receptors by specific agonist in atria from autoimmune myocarditis mice, augments the cyclic AMP, requiring the hydrolysis of phosphoinositide cycle. The role of this cyclic AMP augmentation in myocardium from autoimmune myocarditis mice, will provide a basis to assess the role of this second messenger as an important factor in the regulation and/or modulation of the physiological behaviour of the heart in the course of autoimmune myocarditis.
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PMID:Increases in cyclic AMP levels couple to H1 receptors in atria from autoimmune myocarditis mice. 859 44

In our previous study (A. Balogh et al, Cell. Signalling 5 (6), 795-802, 1993.), we have shown that epidermal growth factor (EGF) increased protein kinase C (PKC) activities in colon carcinoma cell line (HT29), possibly through the increased 1,2-diacylglycerol (1,2-DAG) production via phosphatidylcholine (PC). Here we investigate the effect of well-known PKC activator 12-O-tetradecanoyl-2 phorbol-13-acetate (TPA), on the levels of 32P incorporation into EGF induced phosphatidylinositols (PI, PI4P, PI4, 5P2) and different phospholipids (PC, PA, PS) as well as on induced tyrosine kinase activity. TPA significantly decreased the effects of EGF and it had the biggest inhibitory effect on EGF induced PC level. These data support our contention that PC plays an important role in the activation of PKC via 1,2-DAG production in the EGF stimulated pathway.
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PMID:Phosphatidylcholine could be the source of 1,2-DAG which activates protein kinase C in EGF-stimulated colon carcinoma cells (HT29). 859 48

Based on marked differences in the enzymatic properties of diacylglycerols compared with phorbol ester-activated protein kinase C (PKC), we recently proposed that activation induced by these compounds may not be equivalent (Slater, S. J., Kelly, M. B., Taddeo, F. J., Rubin, E., and Stubbs, C. D. (1994) J. Biol. Chem. 269, 17160-17165). In the present study, direct evidence is provided showing that phorbol esters and diacylglycerols bind simultaneously to PKC alpha. Using a novel binding assay employing the fluorescent phorbol ester, sapintoxin-D (SAPD), evidence for two sites of high and low affinity was obtained. Thus, both binding and activation dose-response curves for SAPD were double sigmoidal, which was also observed for dose-dependent activation by the commonly used phorbol ester, 4beta-12-O-tetradecanoylphorbol-13-acetate (TPA). TPA removed high affinity SAPD binding and also competed for the low affinity site. By contrast with TPA, low affinity binding of SAPD was inhibited by sn-1,2-dioleoylglycerol (DAG), while binding to the high affinity site was markedly enhanced. Again contrasting with both TPA and DAG, the potent PKC activator, bryostatin-I (B-I), inhibited SAPD binding to its high affinity site, while low affinity binding was unaffected. Based on these findings, a model for PKC activation is proposed in which binding of one activator to the low affinity site allosterically promotes binding of a second activator to the high affinity site, resulting in an enhanced level of activity. Overall, the results provide direct evidence that PKCalpha contains two distinct binding sites, with affinities that differ for each activator in the order: DAG > phorbol ester > B-I and B-I > phorbol ester > DAG, respectively.
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PMID:Protein kinase Calpha contains two activator binding sites that bind phorbol esters and diacylglycerols with opposite affinities. 861 24

Insulin and glucose increase the synthesis of 1,2-diacylglycerol (1,2-DAG), the physiological activator of protein kinase C (PKC) in a variety of tissues and cells. The effects of insulin and glucose on the abundance and fatty acid composition of 1,2-DAG were investigated in isolated perfused rat hearts with the use of capillary gas chromatography and 1,2-dipentadecanoin as an internal standard. A high concentration of insulin (25 mU/ mL) significantly increased cardiac contractility and reduced coronary flow. In addition, perfusion with 25 mU/mL insulin induced significant increases of 18.2% and 26.4% in 1,2-DAG mass after 5 and 30 minutes, respectively, in the presence of 8.6 mmol/L glucose, whereas there was no increase in 1,2-DAG with 2.5 mU/mL insulin. Analysis of the fatty acid composition of 1,2-DAG showed that only species containing specific fatty acids (16:0, 18:1, and 18:2) were increased in response to insulin. In contrast, an increase in glucose concentration in the perfusion medium from 3 to 17 mmol/L had no effect on the total mass or fatty acid composition of 1,2-DAG, cardiac contractility, or coronary flow. Addition of a high insulin concentration to the high-glucose medium increased the abundance of 1,2-DAG containing 16:0, 18:1, and 18:2 fatty acids, as well as cardiac contractility. It is concluded that the effect of insulin on cardiac contractility may be related to the associated increase in 1,2-DAG abundance.
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PMID:Insulin increases distinct species of 1,2-diacylglycerol in isolated perfused rat heart. 863 54

The involvement of phospholipids and in particular polyphosphoinositides in cellular signalling has been documented in detail in the last 20 years. In addition to the plasma membrane localization also the nucleus is shown to be a site for both synthesis and hydrolysis of the phosphorylated forms of phosphatidylinositol. Previous observation have established that the nucleus possesses a specific PLC for inositol lipids, i.e., the PLC beta 1 isoform, which undergoes rapid and transient activation after IGF-I stimulation of quiescent Swiss 3T3 cells and is down-regulated after treatment of Friend erythroleukemia cells with DMSO. Here we have reviewed: (i) the potential of nuclear PLC beta 1 to be a target for anti-cancer drug, (ii) the capability of this PLC isoform, when activated by IGF-I, to be a key signalling molecule in the onset of DNA synthesis, via DAG generation and PKC alpha translocation to the nucleus, (iii) the chromosome mapping of PLC beta 1 gene. The differentiation program of Friend cells can be activated by other agents besides DMSO including tiazofurin, an anti-tumor drug, also capable of affecting the nuclear inositol lipid cycle. Tiazofurin induces a lowering of the activity of PLC beta 1 due to down regulation of this isoform as revealed by both Western blotting and Northern blotting analyses. Using Swiss 3T3 cells stably transformed with an antisense PLC beta 1 construct, the knock-out of the PLC beta 1 gene induces both a loss of PLC beta 1 expression, as determined by Western blots, and a loss of the mitogenic responsiveness to IGF-I. These events show a direct relationship between nuclear PLC beta 1 evoked signals and IGF-I induced cell proliferation. Finally, the assignment of the PLC beta 1 gene to the band q35-36 of rat chromosome 3 paves the way for further genetic studies given the fact that the region where PLC beta 1 gene maps is a hot spot for genetic alterations in a number of experimentally induced rat tumors. Taken as a whole, these results assign a key role to the regulation of nuclear PLC activity and expression both in growth-factor activated mitogenesis and in in vitro erythroid differentiation.
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PMID:Inositol lipid cycle and autonomous nuclear signalling. 886 43

1. A pharmacological characterization was made of the effects of lysophosphatidyl-inositol (lysoPI) and -ethanolamine (lysoPE) on the Ca(2+)-sensitivity of contraction in alpha-toxin permeabilized rat mesenteric arteries. The effect of GTP gamma S (G-protein activator), diacylglycerols (DAGs, dioctanoyl glycerol (diC8) and 1-stearoyl-2-arachidonoyl-sn-glycerol) and phorbol myristate acetate (PMA, protein kinase C (PKC) activator) on Ca(2+)-sensitivity was also assessed. 2. LysoPI increased the Ca(2+)-sensitivity, demonstrated by both an increase in tension induced by 1 microM [Ca2+]free and an increase in the Ca(2+)-sensitivity of Ca2+ concentration-tension curves. LysoPE did not enhance force or Ca(2+)-sensitivity. 3. GTP gamma S enhanced force at constant Ca2+, increased the Ca(2+)-sensitivity, and increased force under Ca(2+)-free conditions. PMA also increased force at constant Ca2+ and increased Ca(2+)-sensitivity, but caused no force development under Ca(2+)-free conditions. 4. DAGs, both diC8 and the more physiological relevant DAG, 1-stearoyl-2-arachidonoyl-sn-glycerol, enhanced force at constant Ca2+ and increased the Ca(2+)-sensitivity. DiC8, in contrast to 1-stearoyl-2-arachidonoyl-sn-glycerol, caused force development under Ca(2+)-free conditions and substantially enhanced force at maximal Ca(2+)-induced contraction. GDP-beta-S abolished the increased Ca(2+)-sensitization induced by noradrenaline, but not that by DAGs. 5. The PKC inhibitor calphostin C completely abolished Ca(2+)-sensitization induced by all of the Ca(2+)-sensitizing agents. 6. These results show that lysoPI can increase the Ca(2+)-sensitivity of smooth muscle contraction, and the Ca(2+)-sensitization induced by DAGs was not completely G-protein mediated, because it was not inhibited by GDP-beta-S. A central role for PKC in regulation of Ca(2+)-sensitization in rat mesenteric small arteries was indicated by the abolishment of Ca(2+)-sensitization by calphostin C.
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PMID:Calphostin C-sensitive enhancements of force by lysophosphatidylinositol and diacylglycerols in mesenteric arteries from the rat. 887 51

The lateral membrane organization of phosphatidylserine, diacylglycerol, substrate, and Ca(2+)-dependent protein kinase C in large unilamellar vesicles was investigated by using fluorescence digital imaging microscopy. The formation of phosphatidylserine domains could be induced by either Ca2+, the MARCKS peptide, or protein kinase C. However, only Ca2+ could induce diacylglycerol to partition into the phosphatidylserine domains. In the complete protein kinase C assay mixture, two separate triple-labeling experiments demonstrated the colocalization of phosphatidylserine, protein kinase C, diacylglycerol, and the MARCKS peptide in domains. The amounts of all the labeled components in whole vesicles and in domains were measured at various concentrations of either phosphatidylserine, Ca2+, diacylglycerol, or the MARCKS peptide or with the addition of polylysine. The role of each component in forming membrane domains and in mediating the enzyme activity was analyzed. The results indicated that the inclusion of the MARCKS peptide in the domains, not just the binding of the substrate to vesicles, was especially important for PKC activity. The formation of PKC domains required the presence of DAG and Ca2+ at physiological ionic strength. The PKC activity was proportional to the amounts of PKC and substrate in the domains. The results also showed that the MARCKS peptide left the domains after being phosphorylated. A model for the activation of protein kinase C involving sequestering of the reaction components into membrane domains is proposed. The efficiency of the reaction was greatly increased by concentrating the activators, the enzyme, and the substrate into domains.
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PMID:Formation of membrane domains during the activation of protein kinase C. 890 94

Unopsonised zymosan particles bind to the CD11b/CD18 integrin on human neutrophils (PMN) and are phagocytosed. Binding stimulates the release of leukotriene (LT) B4. The present study examined the effect on this interaction of two agents that 'prime' PMN for augmented responses to a variety of agonists. The cell permeable diacyl glycerol, 1,2-dioctanoyl-glycerol (DiC8) and TNF alpha each increased CD11b/CD18 expression on PMN [maximal at 10-9 M TNF alpha or 10-8 M DiC8]. There was a decrease, however, in CD11b/CD18 expression above 10-8 M DiC8, which was not observed at high concentrations of TNF alpha. Pre-treatment with either DiC8 or TNF alpha dose-dependently augmented the zymosan-stimulated release of LTB4 from PMN. DiC8 and TNF alpha in combination, however, synergistically increased LTB4 release. In contrast, at concentrations above 10-8 M DiC8, whether in the presence or absence of TNF alpha, LTB4 release was inhibited and this was ameliorated by protein kinase C inhibitors. The response to neither TNF alpha nor DiC8 (below 10-8 M) was kinase inhibitor sensitive. Doses of DAG, which activate protein kinase C, inhibit CD11b/CD18-dependent responses by down-regulating receptor expression. In contrast, the mechanisms of TNF alpha and low dose DAG 'priming' are not clear but are independent of PKC activation. The synergy between these two priming agents, however, suggests independent, complementary signalling pathways that provide a novel, potentially important mechanism for the control of PMN CD11b/CD18 integrin-dependent activation.
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PMID:CD11b/CD18-dependent stimulation of leukotriene B4 synthesis by human neutrophils (PMN) is synergistically enhanced by tumour necrosis factor alpha and low dose diacylglycerol. 892 7

Growth hormone (GH; 500 ng/ml) rapidly doubled cytosolic free Ca2+ concentration ([Ca2+]i) in rat adipocytes as determined with the Ca2+ indicator fura 2. No response was seen in Ca(2+)-free medium, suggesting that the increase in [Ca2+]i was due to Ca2+ influx. GH also doubled the influx of Mn2- as inferred from the rate of fluorescence quenching. Depolarization with 30 mMK+ also increased [Ca2+]i, and the increase in [Ca2+]i due to either GH or 30 mMK+ was blocked by 100 nM nimodipine, suggesting that GH increases [Ca2+]i by activating voltage-sensitive L-type Ca2+ channels. GH increased [Ca2+]i even when K+ channels were blocked, suggesting that activation of Ca2+ uptake was not secondary to closure of K+ channels and consequent depolarization. A diacylglycerol (PAG) analogue, 1,2-dioctanoyl-sn-glycerol (50 microM), duplicated, and the protein kinase C(PKC) inhibitors calphostin C (100 nM), chelerythrine (1 microM), and bis-indolylmaleimide (250 nM) inhibited the effects of GH on [Ca2+]i. Xanthogenate tricyclodecan-9-yl (D609), a specific inhibitor of phospholipase C(PLC), abolished the increase in [Ca2+]i due to GH but not to DAG. The results suggest that GH increases [Ca2+]i by activation of PLC, release of DAG, and activation of a Ca(2+)-independent isoform of PKC. PKC-catalyzed phosphorylation of either the Ca2+ channels or a protein that regulates them may account for the influx of Ca2+ produced by GH.
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PMID:Growth hormone increases calcium uptake in rat fat cells by a mechanism dependent on protein kinase C. 896 51

Lipid soluble psychotropics inhibit brain PKC-catalyzed phosphorylation of exogenous and endogenous proteins to varying degrees. These drugs were better inhibitors of Ca2+/PL-dependent phosphorylation of histones (H) than that of Ca2+/PL-independent protamine sulfate (PrSO4): antidepressants/antipsychotics displayed IC50 of 0.1 to 0.16 mM towards H and 0.3 to 4.0 mM towards PrSO4 phosphorylation. Sedatives/anesthetics were less efficient inhibitors with much higher IC50 of 1.3 to 40 mM. Phosphorylation of a Ca(2+)-dependent but PL-independent p80 protein and of a cluster of Ca2+/PL-dependent proteins, p16-20, in brain was also inhibited by the antidepressants/antipsychotics but not by the sedatives/anesthetics. Phorbol ester binding studies revealed that these inhibitors do not compete for DAG binding site(s) on PKC. However, both drug-PL and drug-PKC interactions seem to be relevant in their mechanism of action. Furthermore, our data suggest that the hydrophobic nature of the propanamine side chain or its N-methylated version as well as the tricyclic nucleus influence drug-PKC interaction. Although many of these drugs have other accepted modes of action, modulation of PKC activity in brain, may be yet another aspect to be considered in their mechanism of action.
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PMID:Inhibition of rat brain protein kinase C by lipid soluble psychotropics. 902 54


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