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 arachidonic acid in the regulation of steroidogenesis in rat Leydig cells was studied. A dose- and time-dependent biphasic effect on maximal and submaximal LH- and dibutyryl-cAMP-stimulated testosterone production was found. The locus of the inhibition, which occurred during 3 h incubation, was prior to the side chain cleavage of cholesterol and after cAMP production. The same inhibitory effect was found with the protein kinase C (PKC) activators, phorbol-12-myristate, 13-acetate (PMA) and oleic acid, also with no change in LH-stimulated cAMP production. Arachidonic acid, PMA, and diolein, all stimulated PKC activity in a dose-dependent fashion in partially purified Leydig cell homogenates. When the cells were incubated for 5 h, arachidonic acid potentiated LH- and dibutyryl-cAMP-stimulated testosterone production. Similarly, incubation with PMA for 5 h, potentiated subsequent basal and dibutyryl-cAMP-stimulated testosterone production. PKC was down-regulated over 5 h (but not during 3 h) by pretreating Leydig cells with PMA or arachidonic acid in the presence of LH. Lipoxygenase and cyclooxygenase inhibitors did not alter the stimulatory effects of arachidonic acid. We conclude that the short-term inhibitory effect of arachidonic acid (and PMA) is via activation of PKC, but when protein kinase C (PKC) is down-regulated by these ligands, steroidogenesis is enhanced. These results suggest that steroidogenesis is normally under tonic inhibitory control by PKC.
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PMID:Direct effect of arachidonic acid on protein kinase C and LH-stimulated steroidogenesis in rat Leydig cells; evidence for tonic inhibitory control of steroidogenesis by protein kinase C. 131 Dec 29

Phorbol 12-myristate 13-acetate (PMA) was found to increase both the short-circuit current (Isc) and the efflux of 125I- or 36Cl- in the colonic epithelial cell line HT-29.cl19A. Neither the PMA-provoked rise in Isc nor the stimulation of 125I- efflux was affected by the cyclooxygenase inhibitor indomethacin. The PMA-induced increase in Cl- efflux was not accompanied by a rise in adenosine 3',5'-cyclic monophosphate (cAMP) levels. A prolonged incubation with PMA (3 h), however, inhibited the PMA- and the cAMP-stimulated Isc by greater than 90%, whereas the cAMP-provoked 125I- and 36Cl- efflux was not inhibited. The long-term PMA treatment was found to inhibit the basal and cAMP-provoked 86Rb+ efflux by 65 +/- 9 and 86 +/- 7%, respectively. A 3-h incubation with PMA also strongly inhibited the Ca2+ ionophore A23187-induced increase in 86Rb+ efflux, whereas the A23187-stimulated 125I- efflux was only marginally inhibited. These data suggest that phorbol esters, presumably by activation of protein kinase C, can provoke Cl- secretion in HT-29.cl19A colonocytes independently of a prostaglandin- or cAMP-mediated pathway. Prolonged exposure to PMA, however, causes an inhibition of net electrogenic Cl- secretion by downregulation of the activity of K+ transporters.
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PMID:Phorbol esters stimulate and inhibit Cl- secretion by different mechanisms in a colonic cell line. 131 11

The lipoxygenase metabolites of arachidonic acid have an important role in lymphocyte activation. We used a specific 5-lipoxygenase inhibitor, A-63162, to examine the role of 5-lipoxygenase (5-LO) in equine blood mononuclear cell (BMC) proliferation and leukotriene B4 (LTB4) synthesis after stimulation with mitogen (phytohemagglutinin, PHA) or calcium ionophore (A23187). The A-63162 inhibited PHA-induced equine BMC proliferation and, at the same concentration, also inhibited A23187-induced LTB4 synthesis. The presence of exogenous interleukin 2 (IL-2) or the cyclooxygenase inhibitor indomethacin, failed to reverse the immunosuppression caused by A-63162. Further, we found that A-63162, at the concentration that inhibited BMC proliferation and LTB4 synthesis, had no effect on BMC viability. The addition of the specific protein kinase C inhibitor, H-7, did not inhibit A23187-induced LTB4 synthesis. Results indicate that 5-lipoxygenase metabolites may have an important role in equine lymphocyte activation and that protein kinase C has no role in regulating LTB4 production after A23187 stimulation.
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PMID:Inhibition of equine mononuclear cell proliferation and leukotriene B4 synthesis by a specific 5-lipoxygenase inhibitor, A-63162. 132 Aug 11

Recombinant human interleukin-1 beta (IL-1 beta) and bradykinin (BK) synergistically stimulate prostaglandin E2 (PGE2) formation in human gingival fibroblasts cultured for 24 h. Neither BK or IL-1 beta per se, nor their combinations, caused any acute stimulation of cellular cyclic AMP accumulation. BK, but not IL-1 beta, caused a rapid, transient rise of intracellular Ca2+ concentration ([Ca2+]i), as assessed by recordings of fura-2 fluorescence in monolayers of prelabelled gingival fibroblasts. IL-1 beta did not change the effect of BK on [Ca2+]i. Ionomycin and A23187, two calcium ionophores, synergistically potentiated the stimulatory effect of IL-1 beta on PGE2 formation. Three different phorbol esters known to activate protein kinase C also synergistically potentiated the action of IL-1 beta on PGE2 formation. Exogenously added arachidonic acid significantly enhanced the basal formation of PGE2. In IL-1 beta treated cells, the enhancement of PGE2 formation seen after addition of arachidonic acid, was synergistically upregulated by IL-1 beta. These data show that i) the synergistic interaction between IL-1 beta and BK on PGE2 formation is not due to an effect linked to an upregulation of cyclic AMP or [Ca2+]i; ii) the signal transducing mechanism by which BK interacts with IL-1 beta, however, may be linked to a BK induced stimulation of [Ca2+]i and/or protein kinase C; iii) the mechanism involved in the action of IL-1 beta may, at least partly, be due to enhancement of the biosynthesis of prostanoids mediated by an upregulation of cyclooxygenase activity.
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PMID:On the signal transducing mechanisms involved in the synergistic interaction between interleukin-1 and bradykinin on prostaglandin biosynthesis in human gingival fibroblasts. 133 55

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary arterial hypoxic contraction: signal transduction. 135 5

Platelet activating factor (PAF) is a phospholipid mediator of inflammation and vascular leakage that may be important in the etiology of asthma. We and others have demonstrated that PAF causes vascular leakage in the rat trachea. In the present study, we attempted to determine how PAF mediates this effect. Vascular leakage was quantitated by measuring the amount of intravascular Evans blue dye extravasated into tracheal tissue. Intravenously administered PAF increased vascular leakage, although Lyso-PAF and Enantio-PAF had no effect. PAF-induced vascular leakage was inhibited in a dose-dependent fashion by the PAF receptor blocker WEB 2086. However, PAF-induced vascular leakage was not inhibited by blockade of cyclooxygenase/lipoxygenase, calmodulin, calcium channels, protein kinase C, histamine receptors, or by destruction of peptidergic sensory nerves. We conclude that PAF causes vascular leakage in the rat trachea by a stereospecific receptor-mediated mechanism that does not depend on arachidonic acid metabolites, calcium, protein kinase C, histamine, or peptidergic sensory nerves.
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PMID:Mechanism of platelet activating factor-induced vascular leakage in the rat trachea. 135 25

We have recently shown that glutamate exerts a stimulatory action on somatostatin secretion in cortical neurons essentially through NMDA receptor sites. Here, we investigated whether arachidonic acid release could be modified after NMDA receptor activation in cortical neurons in primary culture. We also studied whether pharmacological manipulation of phospholipase A2 could modify somatostatin release. We found that both glutamate and NMDA (N-methyl-D-aspartate) stimulated [3H]arachidonic acid release. NMDA-evoked arachidonic acid release was inhibited by MK-801 and TCP (two NMDA receptor-type antagonists), or by mepacrine, an inhibitor of phospholipase A2. NMDA-induced somatostatin release was inhibited by MK-801, mepacrine and by another phospholipase A2 inhibitor, p-bromophenacylbromide (pBPB). However, responses to NMDA were unaffected by H7, NDGA (nordihydroguaiaretic acid), indomethacin or by RHC 80267 (inhibitors of protein kinase C, lipooxygenase, cyclooxygenase and diacylglycerol lipase, respectively). Mepacrine (greater than or equal to 100 microM) decreased NMDA-stimulated phosphatidylinositol (PI) hydrolysis and at higher concentrations (250 microM) was also able to inhibit basal release whereas pBPB had no effect in the range of concentrations tested. Neomycin (which inhibits phosphatidylinositol metabolism by binding strongly and selectively to inositol phospholipids) reduced by 30% the NMDA-stimulated somatostatin release, although chronic treatment of neurons with the phorbol ester 12-myristate, 13-acetate (PMA) had no effect on this response. Melittin, an activator of phospholipase A2, was able to stimulate both arachidonic acid release and somatostatin secretion. High-performance liquid chromatography (HPLC) analysis of tritiated metabolites released from cortical neurons under basal or NMDA-stimulated conditions revealed that [3H]arachidonic acid was the only metabolite detectable. Furthermore, external addition of arachidonic acid increased somatostatin secretion. Our results show a correlation between the two parameters studied.
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PMID:NMDA receptor activation stimulates phospholipase A2 and somatostatin release from rat cortical neurons in primary cultures. 135 46

Arachidonic acid is released by phospholipase A2 when activation of N-methyl-D-aspartate (NMDA) receptors by neurotransmitter glutamate raises the calcium concentration in neurons, for example during the initiation of long-term potentiation and during brain anoxia. Here we investigate the effect of arachidonic acid on glutamate-gated ion channels by whole-cell clamping isolated cerebellar granule cells. Arachidonic acid potentiates, and makes more transient, the current through NMDA receptor channels, and slightly reduces the current through non-NMDA receptor channels. Potentiation of the NMDA receptor current results from an increase in channel open probability, with no change in open channel current. We observe potentiation even with saturating levels of agonist at the glutamate- and glycine-binding sites on these channels; it does not result from conversion of arachidonic acid to lipoxygenase or cyclooxygenase derivatives, or from activation of protein kinase C. Arachidonic acid may act by binding to a site on the NMDA receptor, or by modifying the receptor's lipid environment. Our results suggest that arachidonic acid released by activation of NMDA (or other) receptors will potentiate NMDA receptor currents, and thus amplify increases in intracellular calcium concentration caused by glutamate. This may explain why inhibition of phospholipase A2 blocks the induction of long-term potentiation.
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PMID:Potentiation of NMDA receptor currents by arachidonic acid. 137 30

Human interferon-alpha A/D (Bg/II) (IFN-alpha A/D) and mouse interferon-gamma (IFN-gamma) are shown to induce xanthine dehydrogenase (XD) mRNA in L929 fibroblastic cells. XD mRNA accumulation after IFN-alpha A/D treatment is relatively fast, being already evident after 4 h and reaching its maximum after 24 h. IFN-alpha A/D is active in inducing XD mRNA at 0.1 unit/ml and it is maximally active at 10(3) units/ml. The half-life of the XD message is unaffected by IFN-alpha A/D treatment, whereas the transcriptional activity of the XD gene and the concentrations of XD heterogeneous nuclear RNA are increased by 2- and 6-fold respectively. The effect of IFN-alpha A/D on XD mRNA is insensitive to cycloheximide, suggesting that protein synthesis de novo is not required. Experiments conducted with specific inhibitors suggest that protein kinase C, cyclic AMP and arachidonic acid metabolites derived from lipoxygenase or cyclooxygenase do not act as second-messenger molecules in the induction of XD mRNA by IFN-alpha A/D. XD mRNA is also induced in NIH3T3 fibroblastic cells, but not in F9 teratocarcinoma or B16 melanoma cells after treatment with IFN-alpha A/D. NIH3T3 are the only cells so far tested that have detectable XD and xanthine oxidase activities under basal conditions and after IFN-alpha A/D treatment, although their responsiveness to the cytokine is much less than that observed in L929 cells.
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PMID:Interferons induce xanthine dehydrogenase gene expression in L929 cells. 137 96

We examined the role of the platelet product ATP in regulating replication and secretory activity of cultured rat mesangial cells (MCs). Extracellular ATP (25-100 microM) significantly increased [3H]thymidine uptake of growth-arrested MCs 2.1-fold; cell counts increased by 35.1%. Addition of ATP to MCs in combination with other platelet products, such as platelet-derived growth factor, isoform BB (100 ng/ml), and serotonin (1 microM), resulted in strong synergistic mitogenicity (up to 45.6-fold over control). As immediate signaling events following stimulation with ATP, we found increased production of inositol phosphates (3.2-fold increase for inositol bisphosphate and 1.6-fold increase for inositol trisphosphate by 30 s) and release of prostaglandin E2 (PGE2, 9.2-fold increase by 5 min). When we studied the rank order of potency of various ATP analogues for the production of inositol phosphates and PGE2, ATP, UTP, and adenosine 5'-O-(3-thio)triphosphate (ATP gamma S) were the most potent agonists. Although ATP and ATP gamma S were also strong mitogens, UTP was not. Additional inhibitor studies indicated that protein kinase C or cyclooxygenase products were not involved in the mitogenic effects of ATP. In summary, the major platelet product ATP is a potent comitogen for cultured MCs and strongly synergizes with other growth factors. The experiments with ATP analogues point to different receptors mediating mitogenesis, generation of inositol phosphates, and PGE2 production. The precise mechanism of the mitogenic action of ATP on MCs remains to be characterized.
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PMID:Extracellular ATP stimulates proliferation of cultured mesangial cells via P2-purinergic receptors. 141 66


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