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 purpose of this investigation was to assess whether alterations in the fatty acid composition of rat liver epithelial (WB-F344) cell phospholipids would modulate gap junction-mediated intercellular communication (GJIC). WB-F344 cells were grown to confluency in culture medium supplemented with one of seven different fatty acids at a concentration of 50 microM for 48 h. Only alpha-linoleate (18:3 n-3) significantly inhibited GJIC. Saturated fatty acids (12:0, 16:0, and 18:0), a monounsaturated fatty acid (18:1 n-9), and n-6 polyunsaturated fatty acids (18:2 and 20:4) did not affect GJIC. The alpha-linolenate-induced inhibition of GJIC was not due to the activation of protein kinase C or intracellular hydroperoxide production, two lipid-dependent parameters previously shown to inhibit GJIC. In addition, alpha-linolenate did not alter membrane fluidity. Although the mechanism by which alpha-linolenate inhibits GJIC is unclear, changes in the fatty acid composition of cell phospholipids may be of critical importance. Subsequent to supplementation with alpha-linolenate, WB-F344 cell phospholipids had reduced 20:4 n-6 and elevated n-3 fatty acids. The results of this investigation emphasize the importance of current research into the influence of lipids on cell function and identify a new mechanism by which gap junctions can be modulated.
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PMID:Inhibition of gap junction-mediated intercellular communication by alpha-linolenate. 167 33

This study has investigated the effect of supplementation of vascular endothelial cells with arachidonate and other polyunsaturated fatty acids on the agonist-stimulated synthesis of platelet activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; 1-alkyl-2-acetyl-GPC). Incubation of calf pulmonary artery endothelial cells for 48 h in medium containing 40 microM arachidonate resulted in a 2-3-fold enhancement of [3H]acetate incorporation into 1-radyl-2[3H]acetyl-GPC in response to either bradykinin or calcium ionophore A23187. The effects of arachidonate supplementation were both dose- and time-dependent, requiring a minimum exogenous arachidonate concentration of 2.5 microM and an incubation time of 4-6 h. Eicosapentaenoate and docosahexaenoate also enhanced the synthesis of 1-radyl-2-[3H]acetyl-GPC, but were less potent than arachidonate; alpha-linolenate, linoleate and oleate were without effect. Although not effective as an agonist, phorbol myristate acetate potentiated A23187- and bradykinin-stimulated synthesis of 1-radyl-2-[3H]acetyl-GPC. The effects of arachidonate supplementation were synergistic with potentiation by phorbol myristate acetate. Sphingosine inhibited agonist-stimulated incorporation of [3H]acetate into 1-radyl-2-[3H]acetyl-GPC both in the presence and absence of PMA. Characterization of the radiolabeled material indicated that the primary product was the acyl analogue of PAF (1-acyl-2-acetyl-GPC) rather than PAF. The results from this study suggest that agonist-stimulated synthesis of 1-radyl-2-acetyl-GPC in vascular endothelial cells is modulated both by cellular fatty acyl composition and activation of protein kinase C. Enrichment of vascular endothelial cells with fatty acids, which are mobilized by agonist-stimulated phospholipase A2, may enhance subsequent deacylation of choline phospholipids and, thus, increase synthesis of both 1-acyl-2-acetyl-GPC and PAF.
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PMID:C20 polyunsaturated fatty acids and phorbol myristate acetate enhance agonist-stimulated synthesis of 1-radyl-2-acetyl-sn-glycero-3-phosphocholine in vascular endothelial cells. 190 5

The base exchange enzymes catalyze the incorporation of L-serine, ethanolamine and choline into their corresponding phospholipids. The L-serine base enzyme activity was increased 120% by 0.1 mM sphingosine. There was a modest increase of the ethanolamine base exchange enzyme activity but the choline base exchange enzyme activity was unaffected. Na-arachadonate, Na-oleate and Na-linolenate at 0.2 mM concentration increased the activity of the L-serine and ethanolamine base exchange enzymes but inhibited the choline base exchange enzyme activity. A model is proposed suggesting that modulations of the L-serine base exchange enzyme may participate in the regulation of the calcium phospholipid-dependent protein kinase C.
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PMID:Sphingosine and unsaturated fatty acids modulate the base exchange enzyme activities of rat brain membranes. 193 52

Oleate, linoleate, linolenate, arachidonate and eicosapentaenoate, but not myristate, palmitate and stearate, stimulated glycogen phosphorylase activity by 2-8-fold when added to cultured rat hepatocytes. Addition of BSA or Ca2- to the incubation medium decreased the stimulating effects of the unsaturated fatty acids. The combination of oleate or linolenate, with corticosterone, testosterone or estradiol produced synergistic stimulations of phosphorylase activity. The stimulation of glycogen phosphorylase activity by linolenate was inhibited by staurosporine or sphingosine. Staurosporine (80 nM) alone also decreased basal phosphorylase activities by about 60%. The results show that unsaturated fatty acids can be used as model agonists to stimulate phosphorylase activity by a mechanism that probably involves protein kinase C. On the basis of the fatty acid: BSA ratios used, this stimulation should only occur in vivo at high fatty acid concentrations when accompanied by hypoalbuminaemia.
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PMID:Unsaturated fatty acids activate glycogen phosphorylase in cultured rat hepatocytes. 203 70

Unlike unsaturated fatty acids, which almost fully activated purified brain protein kinase C in a phosphatidylserine- and Ca2(+)-free reaction, related methyl esters were poorly active in vitro. In contrast, methyl arachidonate was revealed to be as potent as arachidonic acid in activating protein kinase C in intact platelets. Arachidonic acid-mediated activation peaked at 20 s while methyl arachidonate-mediated activation plateaued at 2 min when both lipids were added at 50 microM. At concentrations higher than 0.3 mM, all tested unsaturated fatty acids and related methyl esters were weak activators of the enzyme, with the exception of linolenic acid and methyl linolenate which evoked strong enzyme activation. However, inhibitors of arachidonate metabolism blocked both arachidonic-acid and methyl-arachidonate-induced responses. At 5 microM arachidonic acid and methyl arachidonate, protein kinase C activation was due to a cyclooxygenase product(s) whereas at 50 microM the lipoxygenase pathway was mostly involved in the reaction. Therefore, arachidonic acid and its methyl ester activate protein kinase C in platelets mainly through action of their metabolites and eicosanoid synthesis. It is suggested that such indirect protein kinase C activation may account for the tumor-promoting activity of unsaturated fatty acids and related methyl esters.
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PMID:Arachidonic acid and related methyl ester mediate protein kinase C activation in intact platelets through the arachidonate metabolism pathways. 211 10

1. Activation of protein kinase C (PKC) by phorbol esters or diacylglycerols has been shown to modulate a number of ionic currents carried by Ca2+, K+ and Cl-. Recently, it has been demonstrated that PKC may be activated by cis-fatty acids in the absence of either phospholipid or Ca2+. We wished to determine if this new class of PKC-activating compound would also modulate ionic currents. To this end we applied the whole-cell voltage-clamp technique to N1E-115 neuroblastoma cells. 2. Analysis of families of currents evoked under voltage clamp by depolarizing steps from a holding potential of -85 mV during external application of 5 microM-oleate (a cis-fatty acid) showed a 36% reduction of the peak inward current with no shift in either the peak or the reversal potential of the current-voltage relation and no alteration of outward current. 3. External application of the cis-fatty acids oleate, linoleate and linolenate reversibly attenuated voltage-dependent Na+ current with approximate half-maximal dose values of 2, 3, and 10 microM respectively. Oleate was approximately 2 times more potent when applied internally (ED50 = 1 microM). Externally applied elaidate (a trans-isomer of oleate) and stearate (a saturated fatty acid) which do not activate PKC, had no effect. Since cis-fatty acids are known to fluidize membranes, as well as to activate PKC, we sought to dissociate these functions by applying compounds that fluidize membranes but do not activate PKC: methyloleate and lysophosphatidylcholine. Neither compound affected Na+ current when applied externally at concentrations of 1-50 microM. 4. In contrast to cis-fatty acids, three classical PKC activators, phorbol-12.13-dibutyrate (PDB), phorbol-12.13-diacetate (PDA), and 1.2-oleoylacetylglycerol (OAG) were found to have no effect on the voltage-dependent Na+ current when applied externally at 10 nM-1 microM (phorbol esters) or 1-150 microM (OAG) for incubation periods up to 1 h. 5. External application of the PKC inhibitors polymyxin B, H-7, sphingosine and staurosporine blocked the attenuation of the Na+ current by cis-fatty acid in a dose-dependent manner, with maximal inhibition occurring at doses of 50, 10, 200 and 0.1 microM, respectively. The cyclic nucleotide-dependent protein kinase inhibitor H-8 was much less effective in blocking the cis-fatty acid effect. Polymyxin B and staurosporine were more potent when applied internally. 6. Chronic (24 h) exposure to 1 microM phorbol-12-myristate-13-acetate (TPA) was employed to down-regulate PKC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:cis-Fatty acids, which activate protein kinase C, attenuate Na+ and Ca2+ currents in mouse neuroblastoma cells. 255 78

The influence of lipids on gap-junction-mediated intercellular communication (i.e., metabolic cooperation) between Chinese hamster V79 cells was investigated. Unsaturated free fatty acids (oleate, linoleate, linolenate, palmitoleate, myristoleate, and arachidonate) inhibited metabolic cooperation between 6-thioguanine-resistant, hypoxanthine guanine phosphoribosyltransferase-deficient and 6-thioguanine-sensitive, hypoxanthine guanine phosphoribosyltransferase-proficient V79 cells. Saturated fatty acids (stearate, palmitate, myristate, and arachidate) had no effect. Further characterization of the effects of fatty acids on metabolic cooperation is summarized as follows: a relationship between the degree of unsaturation and the ability of unsaturated fatty acids to inhibit metabolic cooperation could not be established (i.e., inhibition of metabolic cooperation by 18:1 greater than 18:2 = 18:3); longer carbon chain monounsaturated fatty acids are more effective in inhibiting metabolic cooperation (i.e., inhibition of metabolic cooperation by 18:1 greater than 16:1 greater than or equal to 14:1); geometric isomerism is of some importance in determining the efficacy of monounsaturated fatty acids to inhibit metabolic cooperation (i.e., inhibition of metabolic cooperation by cis 18:1 greater than trans 18:1 and cis 16:1 greater than trans 16:1); and the position of the double bond(s) is relatively unimportant (i.e., inhibition of metabolic cooperation by 18:3 = gamma 18:3). Unsaturated diacylglycerol compounds (diolein, dilinolein, and 1-oleoyl-2-acetyl glycerol) inhibit metabolic cooperation; a saturated diacylglycerol compound (distearin) had no effect. The position of the unsaturated fatty acid groups is not of importance in the inhibition of metabolic cooperation by diacylglycerols containing unsaturated fatty acid moieties (i.e., 1,2-diolein and 1,3-diolein are equally efficacious in inhibiting metabolic cooperation; relative inhibition of metabolic cooperation by 18:1 greater than 1-oleoyl-2-acetyl glycerol greater than 1,2-diolein). Alterations of membrane biophysical properties and protein kinase C involvement are discussed as possible mechanisms involved in the inhibition of metabolic cooperation by unsaturated lipid.
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PMID:Influence of lipids on gap-junction-mediated intercellular communication between Chinese hamster cells in vitro. 373 Nov 6

The arachidonic acid content of plasma lipoproteins is altered during dietary magnesium deficiency, although the tissue arachidonic acid content seems to be unchanged. The primary event triggering these changes is probably the loss of extracellular Mg2+, as it is not clear whether dietary magnesium deficiency produces loss of intracellular Mg2+. In the isolated rabbit heart, in vitro perfusion conditions which produce loss of intracellular Mg2+ also result in disturbances of arachidonic acid metabolism. The metabolism of exogenous arachidonic acid to prostaglandins is increased without changing the Km or Vmax of cyclo-oxygenase. The incorporation of arachidonic acid into tissue phospholipids is significantly reduced, although the incorporation of oleate, stearate, and linolenate is either increased or unchanged. These data indicate that the activity of the enzymes (CoA synthetases and acyl transferases) which mediate arachidonate incorporation is reduced during Mg2+ depletion. Since protein-kinase-C-mediated phosphorylation of both CoA synthetase and acyl transferase reduces their activity, and since protein kinase C has an Mg2+ binding site, it is possible to speculate that loss of intracellular Mg2+ may lead to the activation of protein kinase C, with the consequent reduction of arachidonic acid reacylation enzyme activity.
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PMID:Magnesium and arachidonic acid metabolism. 827 64

The effects of changing the composition of membrane lipids on protein kinase C (PKC) activation were studied in MCF-7 human breast cancer cells. The supply of linoleate or alpha-linolenate to MCF-7 cells altered cell membranes fatty acid composition but did not affect PKC activity. When the cells were additionally exposed to IGF-1, the same fatty acids caused a dramatic increase in membrane-bound PKC activity. We also found that the mitogenic response induced by IGF-1 was not enhanced in those conditions when PKC becomes activated by linoleate and alpha-linolenate. These data show that these fatty acids elicit a distinct route for the transmission of IGF-1 signal by inducing the PKC pathway. They suggest that linoleate and alpha-linolenate could control the biological response of MCF-7 cells to IGF-1.
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PMID:Supplementation of MCF-7 cells with essential fatty acids induces the activation of protein kinase C in response to IGF-1. 924 7