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)

1. The present experiments were designed to determine the effect of melittin on renin secretion. Melittin is a polypeptide component of bee venom which stimulates phospholipase A2 activity, thereby increasing arachidonic acid release and prostaglandin (PG) synthesis, and which inhibits protein kinase C activity. Either of these actions might be expected to stimulate renin secretion, since renin secretion is stimulated by arachidonic acid and by several PGs, and since renin secretion is inhibited by several activators of protein kinase C. 2. In rat renin cortical slices incubated at 37 degrees C in a buffered and oxygenated physiological saline solution, 0.1-10 microM-melittin produced a concentration-dependent stimulation of both prostaglandin E2 (PGE2) synthesis and renin secretion. However, melittin-stimulated renin secretion is independent of melittin-stimulated phospholipase A2 activity, arachidonic acid release, and PG synthesis, since 20 microM-quinacrine (a phospholipase A2 antagonist) and 50 microM-meclofenamate (a cyclooxygenase antagonist) antagonized basal and melittin-stimulated PGE2 synthesis but had no effects on basal or melittin-stimulated renin secretion. 3. Furthermore, melittin-stimulated renin secretion is not produced by inhibition of protein kinase C, since an activator of protein kinase C (12-O-tetradecanoylphorbol 13-acetate, TPA), enhanced rather than antagonized melittin-stimulated renin secretion. Ouabain partially antagonized, but did not completely block, melittin-stimulated renin secretion. 4. Thus, melittin-stimulated phospholipase A2 activity probably accounts for stimulated PGE2 production, but not for stimulated renin secretion. The mechanism of melittin-stimulated renin secretion is unclear; an effect on protein kinase C does not appear to be involved, and in contrast to the stimulatory effects of a variety of other substances, melittin-stimulated renin secretion is only partially antagonized by ouabain.
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PMID:Effect of melittin on renin and prostaglandin E2 release from rat renal cortical slices. 223 11

Excessive production of tumor necrosis factor (TNF) after stimulation by lipopolysaccharide (LPS) may result in fever, intravascular coagulation, and lethal shock. An efficient way of preventing the excessive TNF production is desensitization of monocytes/macrophages to LPS. We have analyzed the molecular mechanisms involved in the induction of desensitization and the mechanisms operative in the desensitized, LPS-refractory cells by employing the human monocytic cell line Mono-Mac-6. Similar to human blood monocytes, treatment of Mono-Mac-6 cells with LPS (1 microgram/ml) results in a rapid and transient expression of TNF. When Mono-Mac-6 cells are precultured in medium containing low levels of LPS, they become refractory to subsequent LPS stimulation and show no or little secretion of TNF protein. Desensitization can be blocked by the inhibition of cyclooxygenase and protein kinase C; both prostaglandin E2 (together with a second signal) and phorbol 12-myristate 13-acetate can mimic desensitization. By employing prostaglandin E2 and low concentrations of phorbol 12-myristate 13-acetate, a synergism in the induction of desensitization can be demonstrated. Hence, our studies show that two distinct pathways are involved in the induction of hyporesponsiveness. In both LPS-responsive and LPS-desensitized Mono-Mac-6 cells, LPS was able to induce the transcription factor NF-kappa B in the nucleus. Still, the prevalence of TNF-specific mRNA was dramatically reduced in the desensitized cells. These data indicate that LPS-desensitized Mono-Mac-6 cells are able to activate initial steps of signal transduction up to the level of the NF-kappa B transcription factor. The absence of TNF transcripts, however, indicates that additional nuclear factors may be missing or that silencers may be active such that transcription of the TNF gene is prevented.
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PMID:Molecular mechanisms in down-regulation of tumor necrosis factor expression. 226 11

In isolated rat aorta and urinary bladder, indomethacin inhibited the synthesis of the prostaglandins (PG) PGI2, PGE2, PGF2 alpha and TXA2 equipotently when PG synthesis was stimulated with excitatory receptor agonists (noradrenaline and carbachol), fluoride (a G protein activator), phorbol ester (a protein kinase C (PKC) activator) and calcium ionophore A23187 (a creator of artificial calcium channels). However, there was a marked right shift (30 fold) in the indomethacin concentration-inhibition curves when PG synthesis was stimulated by arachidonate (PG substrate) and trauma (freeze fracturing and sonication). Although less potent than indomethacin, the NSAIDs tiaprofenic acid and ibuprofen showed a similar disparity between the IC50s with the same PG stimulators. Since PG synthesis stimulated by receptor agonists, fluoride, phorbol ester and A23187 is dependent on calcium channel activation whereas trauma and arachidonate-stimulated PG synthesis bypass calcium channel activation, these data indicate that NSAIDs inhibit not only cyclooxygenase but also (and more potently) the mobilisation of Ca2+ linked to PG synthesis in these tissues.
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PMID:Differential inhibitory potencies of non-steroidal antiinflammatory drugs on smooth muscle prostanoid synthesis. 240 14

Incubation of cultured bovine pulmonary artery endothelial cells with 200 microM of 3-isobutyl-1-methylxanthine (IBMX) for 24 hr produced a five- to tenfold increase in cellular angiotensin converting enzyme activity (ACE) above that of untreated control cells. A lesser increase was observed in medium ACE. Other methylxanthines produced a similar, but less marked, effect. The elevation of ACE seemed to require de novo protein synthesis since it was reduced by 0.1 microgram/ml cycloheximide. Elevation of cellular cAMP was detected at 30 min after introduction of IBMX, then rapidly returned to control levels at 1 hour, while elevation in cellular ACE at 24 hr required contact with IBMX for at least 2 hr. Hence, the transient elevation in cAMP is unlikely to be the cause of the elevation of ACE. Phorbol ester and synthetic diacyl glycerol OAG, activators of protein kinase C, did not elevate ACE. Indomethacin, at a concentration known to inhibit cyclooxygenase activity, had no effect on the elevation of ACE. The elevation of ACE by IBMX was not affected by the calcium channel blocker verapamil or the calcium chelator EGTA. In contrast, the effect of IBMX was totally abolished by the calmodulin inhibitors trifluoperazine and calmidazolium. The data show that IBMX elevates endothelial cell ACE and suggest that the elevation is mediated by a calcium-calmodulin complex. The studies demonstrate a novel effect of methylxanthines on endothelial cells in culture.
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PMID:Elevation of angiotensin converting enzyme by 3-isobutyl-1-methylxanthine in cultured endothelial cells: a possible role for calmodulin. 245 40

We have recently shown that the synthesis of cyclooxygenase [also called prostaglandin (PG) synthase or PG endoperoxide synthase; 8,11,14-icosatrienoate, hydrogen-donor:oxygen oxidoreductase, EC 1.14.99.1] in human dermal fibroblasts is markedly stimulated by the cytokine interleukin 1 (IL-1). We now show that the temporal sequence of the induced synthesis of PG synthase can be separated into an early transcriptional (i.e., actinomycin D inhibitable) phase and a subsequent translational (cycloheximide but not actinomycin D inhibitable) phase and that IL-1 exerts its effect during the transcriptional phase. Phorbol 12-myristate 13-acetate also stimulates synthesis of PG synthase and, together with IL-1, produces a synergistic stimulatory effect. Inhibitors of protein kinase C activation abolished the stimulatory effect of IL-1, suggesting that protein kinase C activation is a critical event in the signal-transduction sequence of the IL-1-induced increase of PG synthase synthesis. The antiinflammatory glucocorticosteroids dexamethasone and triamcinolone, but not progesterone or testosterone, were potent inhibitors of PG synthase synthesis (complete inhibition at 20 nM; IC50, 1 nM) when added during the translational phase of the synthesis sequence. The glucocorticosteroid effect was blocked by RNA and protein synthesis inhibitors. This report suggests that glucocorticosteroids exert their effect via a newly synthesized protein, causing a profound translational control of PG synthase synthesis. This novel mechanism of suppression of arachidonate metabolism is distinct from any influence of steroids on phospholipase A2 activity.
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PMID:Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. 249 47

The treatment of human HL-60 promyelocytic leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of tumor necrosis factor (TNF) transcript. The study reported here has examined TPA-induced signaling mechanisms responsible for the regulation of TNF gene expression in these cells. Run-on assays demonstrated that TPA increases TNF mRNA levels by transcriptional activation of this gene. The induction of TNF transcripts by TPA was inhibited by the isoquinolinesulfonamide derivative H7 but not by HA1004, suggesting that this effect of TPA is mediated by activation of protein kinase C. TPA treatment also resulted in increased arachidonic acid release. Moreover, inhibitors of phospholipase A2 blocked both the increase in arachidonic acid release and the induction of TNF transcripts. These findings suggest that TPA induces TNF gene expression through the formation of arachidonic acid metabolites. Although indomethacin had no detectable effect on this induction of TNF transcripts, ketoconazole, an inhibitor of 5-lipoxygenase, blocked TPA-induced increases in TNF mRNA levels. Moreover, TNF mRNA levels were increased by the 5-lipoxygenase metabolite leukotriene B4. In contrast, the cyclooxygenase metabolite prostaglandin E2 inhibited the induction of TNF transcripts by TPA. Taken together, these results suggest that TPA induces TNF gene expression through the arachidonic acid cascade and that the level of TNF transcripts is regulated by metabolites of the pathway, leukotriene B4 and prostaglandin E2.
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PMID:Role of arachidonic acid metabolism in transcriptional induction of tumor necrosis factor gene expression by phorbol ester. 249 31

We demonstrated a unique myoelectric response to phorbol esters and a diacylglycerol, 1-oleoyl-2-acetyl-snglycerol, in rabbit ileal loops. This retrograde activity, the orad migrating complex (OMC), was devoid of slow-wave distortion or alterations in slow-wave frequency. The OMC was not inhibited by the cyclooxygenase inhibitor indomethacin or enhanced by addition of the calcium ionophore A23187. The OMC occurred after 4 beta-phorbol 12-myristate 13-acetate, a phorbol ester known to activate protein kinase C, and after 4 alpha-phorbol 12,13-didecanoate, one that does not. Therefore, these studies provide initial evidence that the myoelectric activity induced by phorbol esters and a diacylglycerol is most likely in addition to the activation of protein kinase C.
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PMID:Phorbol esters induce retrograde myoelectric activity in rabbit ileum in vivo. 250 85

This study was undertaken to examine the role of phospholipase A2 and protein kinase C in the potentiation of beta-adrenoceptor-mediated cyclic AMP formation by alpha-adrenoceptors in rat cerebral cortical slices. Inhibition of arachidonic acid metabolism by a range of cyclooxygenase and lipoxygenase inhibitors had no effect on the potentiation of isoprenaline-stimulated cyclic AMP. Conversely, stimulation of leukotriene formation had no effect on the response to isoprenaline. The phospholipase A2 activator, melittin, stimulated cyclic AMP and potentiated the effect of isoprenaline, but these responses were not influenced by cyclooxygenase or lipoxygenase inhibitors. Indomethacin was also ineffective against the potentiation of vasoactive intestinal peptide-stimulated cyclic AMP by noradrenaline. Phorbol ester potentiated the cyclic AMP response to isoprenaline, and this potentiation was antagonized by three different putative protein kinase C inhibitors. However, the same inhibitors did not affect the alpha-adrenoceptor-stimulated enhancement of the response to isoprenaline. We have found no evidence, therefore, to support the suggestion that arachidonic acid and its metabolites and/or protein kinase C mediate the alpha-adrenoceptor modulation of beta-adrenoceptor function.
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PMID:No role for phospholipase A2 and protein kinase C in the potentiation by alpha-adrenoceptors of beta-adrenoceptor-mediated cyclic AMP formation in rat brain. 196 88

The stimulation of cultured guinea pig alveolar macrophages by the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine, or by the phospholipid inflammatory mediator platelet activating factor (PAF) induced an increase in arachidonic acid release and its cyclooxygenase products. This release, which was mimicked by the association of threshold concentrations of the calcium ionophore A 23187 and of the protein kinase C activator tetradecanoyl phorbol acetate arose mainly from diacyl- and alkyl-acyl-phosphatidylcholine and phosphatidylinositol. Using [1-14C]arachidonic acid-labeled membranes as an endogenous substrate as well as dioleoyl-phosphatidyl [14C]ethanolamine as an exogenous substrate, we showed that phospholipase A2 activity of stimulated macrophages increases upon stimulation. Treatment of macrophages by prostaglandin E2 decreased the arachidonic acid release elicited by the chemotactic peptide and PAF. Furthermore, prostaglandin E2 increased and PAF decreased the cellular content in cyclic AMP. From these results we suggest that an initial stimulation of alveolar macrophages by a bacterial signal initiates the sequential activation of a phospholipase C and of phospholipase A2, leading to the release of PAF and eicosanoids. These mediators may in turn modulate the cell response by increasing or decreasing cyclic AMP, Ca2+, or diacyglycerol macrophage content.
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PMID:Phospholipase A2-mediated release of arachidonic acid in stimulated guinea pig alveolar macrophages: interaction with lipid mediators and cyclic AMP. 254 80

In experiments on human platelets, inhibition of Na+/H+ exchange was caused either by equimolar substitution of external Na+ with choline or N-methyl-D-glucamine, by decreasing the pHo to 6.8, or by an inhibitor of the antiport 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In all these cases a considerable inhibition of PAF-induced platelet aggregation and as a rule a more or less marked decrease in the cytoplasmic Ca2+ signal (quin-2-loaded platelets) occurred. Stimulation by 10(-7) M PAF caused biphasic pHi changes in human platelets loaded with the pH-sensitive fluorescent probe BCECF: a small transient decrease, followed by a sustained increase of 0.02 +/- 0.006 pH units, resulted from stimulation of the Na+/H+ exchange. Thrombin (0.1 U/ml) also caused biphasic pHi changes, but the alkalinization step was more pronounced (0.15 +/- 0.03 U). Every means of Na+/H+ exchange inhibition prevented a rise in pHi in stimulated platelets. Activation of the adenylate cyclase system by carbacyclin suppressed the agonist-induced pHi increase. The inhibition of neither cyclooxygenase by 10(-5) M indomethacin nor calmodulin-dependent enzymes by 10(-5) M calmidazolium affected the agonist-induced pHi signals. A decrease in temperature from 37 to 24 degrees C caused a considerable increase in the lag phase of the pHi signal induced by tetradecanoyl phorbol acetate (TPA), but did not affect the kinetics of the pHi signal induced by PAF. An inhibitor of protein kinase C (PKC), compound H-7 (60 microM), completely abolished the TPA-induced increase in pHi but caused only a partial inhibition of the pHi signal in about 50% of the experiments with PAF. On the basis of these results the conclusion is drawn that the activation of PKC is not the only pathway for the PAF-induced stimulation of Na+/H+ exchange. The PAF-induced pHi rise depended both on the presence of extracellular Ca2+ and on the [Ca2+]i increase. On the other hand, inhibition of Na+/H+ exchange decreased the magnitude of the Ca2+i signal in PAF-induced platelets loaded with quin-2, but did not influence the Ca2+ mobilization from intracellular stores as measured by quin-2 or chlortetracycline in experiments with thrombin-stimulated platelets. We conclude that in PAF-activated platelets some initial increase of [Ca2+]i is essential for Na+/H+ exchange activation while activated antiport potentiates a full-scale Ca2+ influx into the cells.
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PMID:Na+/H+ exchange in PAF-stimulated platelets. 256 35


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