Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells have the capacity to metabolize several important lipids; this includes the ability to store and then metabolize arachidonate, as well as the capacity to synthesize platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine). Arachidonate is predominantly metabolized via cyclooxygenase to PGI2 although the spectrum of prostaglandins may vary depending upon the source of the endothelial cell. Biosynthesis of eicosanoids and PAF are likely to be an important physiologic function of the endothelial cell as these potent lipids appear to have a role in maintaining vascular tone and mediating interactions of the endothelium with circulating inflammatory cells. In addition to production of eicosanoids and PAF, endothelial cells metabolize exogenous arachidonate and arachidonate metabolites and other fatty acids such as linoleate to bioactive compounds (HODEs). There is also evidence that small amounts of arachidonate are metabolized via a lipoxygenase. The physiologic significance of these minor lipid pathways is not known at this time. Production of eicosanoids and PAF is not a constitutive function of the endothelial cell. Lipid biosynthesis by endothelial cells is one component of the early activation response that occurs in response to stimulation with pro-inflammatory and vasoactive hormones or to pathologic agents such as oxidants and bacterial toxins. A central mechanism for activation of the relevant pathways is a rise in cellular calcium concentrations that can be mediated by hormone-receptor-binding or by direct permeabilization of the cell membrane to calcium (Fig. 3). Regulatory mechanisms distal to the calcium signal are unknown, but current evidence suggests that calcium directly or indirectly activates phospholipases that release arachidonate from phospholipids and hydrolyze a specific phospholipid to the immediate precursor of PAF. There is evidence that protein kinase C may, in part, regulate this process, but the role of other potential regulatory components, such as other protein kinases or G-proteins is not known. As noted above, the most direct mechanism for initiation of PAF biosynthesis and arachidonate release would be activation of a phospholipase A2 as shown in Fig. 3. Activation of other phospholipases (e.g. phospholipase C) may contribute to the total amount of arachidonate released, although the magnitude of that contribution is not yet known. In addition to generation of PAF and eicosanoids, activation of endothelial cell phospholipases generates second messengers that are important in intracellular signaling (Fig. 4). Activation of phospholipase C, in response to hormonal stimulation, generates diacylglycerol and inositol phosphates from phosphatidylinositol. Each of these is a potent intracellular second messenger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lipid metabolism and signal transduction in endothelial cells. 212 4

Inhibition of diacylglycerol (DAG) kinase, an alternative way to increase the cellular DAG level, was shown to reproduce, in renal proximal tubular cells, the inhibitory effect of protein kinase C (PKC) activators on Na-Pi and Na-alpha-methyl-D-glucopyranoside (MGP) cotransport. To evaluate whether 12S-hydroxyeicosatetraenoic acid (12S-HETE) or 12R-HETE, a DAG kinase inhibitor in endothelial cells, has a similar effect in proximal tubular cells, we studied the influence of this lipoxygenase product on Na-dependent uptake of Pi, MGP, and alanine, as well as on [14C]arachidonate-DAG content and [32P]phosphatidic acid (PA) content in rabbit proximal tubular cells grown as a primary culture. 12-HETE (1-10 microM) decreased [32P]PA content and stimulated [14C]DAG accumulation in a concentration-dependent manner. The labeled phosphatidylcholine, lysophosphatidylcholine, and sphingomyelin contents were not modified. 12-HETE also decreased DAG kinase activity of cell membranes. 12-HETE (10 microM) decreased the maximum velocity of Pi uptake by 36% and that of MGP uptake by 44% but did not affect alanine uptake. The effect of 12-HETE on transport was potentiated by calcium ionophore A23187 and was blunted by PKC downregulation. The effects of 12-HETE on lipid composition and transport were mimicked by R 59022, a pharmacological DAG kinase inhibitor. Neither arachidonic acid nor prostaglandin E2 reproduced the effects of 12-HETE. We conclude that in the proximal tubule, 12-HETE affected Na-dependent Pi and MGP cotransport through stimulation of PKC and that 12-HETE-induced activation of PKC is mediated by the inhibition of DAG kinase.
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PMID:12-HETE modulates Na-coupled uptakes in proximal tubular cells: role of diacylglycerol kinase inhibition. 217 22

Multiple (at least seven) steps are involved in GnRH-induced gonadotropin secretion and gonadotropin gene expression. After binding to specific receptors located exclusively on pituitary gonadotrophs, GnRH stimulates a rapid phosphodiesteric hydrolysis of phosphoinositides for which no rise in [Ca2+]i is required. Activation of PLC is most likely mediated by a pertussis toxin-insensitive GTP-binding protein (Gp). In its activated state (Gp-GTP) the binding affinity of GnRH to is receptor is reduced. Rapid formation of IP3 will enhance Ca2+ release from intracellular sources most likely via a specific IP3 receptor. The transient Ca2+ rise might be responsible for a burst phase of LH release lasting for about 100 sec, which is not dependent on extracellular Ca2+. The backbone moiety of the phosphoinositides, DG, and the elevated [Ca2+]i are most likely responsible for translocation of PKC subspecies from the cytosol to the membrane. The most likely candidates are alpha- and beta II-PKC. The activated PKC subspecies phosphorylate substrate proteins which activate secretory reactions and participate in gonadotropin gene expression. In parallel Ca2(+)-influx via nifedipine-sensitive and insensitive channels further elevates [Ca2+]i, which participates in the sustained phase of gonadotropin secretion in concert with the activated PKCs. GnRH also triggers the release of AA and the formation of lipoxygenase and/or epoxygenase products of the fatty acid which are also involved in the process of the exocytosis. We predict that the continuous supply of DG and AA needed for GnRH action is also provided via activated PLD which will also supply phosphatidic acid, the role of which is as yet unclear. The interaction of the various second messengers involved in GnRH action (IP3, Ca2+, DG, AA) and their relative roles in gonadotropin secretion and gonadotropin gene expression await further investigation. In several aspects GnRH action on gonadotropin secretion is unique when compared to other Ca2(+)-mobilizing ligands: 1) At physiological concentrations GnRH up-regulates its own receptors whereas most ligands down-regulate the respective receptor; 2) PKC up-regulates GnRH receptors whereas in most cases PKC down-regulates the ligand receptor; 3) GnRH stimulation of PLC activity is most likely mediated by Gp whereas some Ca2(+)-mobilizing ligands operate via Gi; 4) Activated PKC does not exert negative feedback upon GnRH-induced inositol phosphate production as is the case with several other peptides; 5) Activated PKC might be responsible for Ca2+ influx whereas in several other systems PKC is inhibitory to Ca2+ influx.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Signal transduction mechanisms of Ca2+ mobilizing hormones: the case of gonadotropin-releasing hormone. 219 85

We present published data along with our own results concerning the role of second messengers and their intracellular receptors in molecular mechanisms associated with the plasticity of neurons during learning. The participation of cyclic 3',5'-adenosine monophosphate, cyclic 3',5'-guanosine monophosphate, calcium, calmodulin, and also the metabolic products of inositol phospholipids, inositol-1,4,5-triphosphate, diacylglycerol and the protein kinase C activated by it, arachidonic acid, and the products of its lipoxygenase oxidation during the regulation of neuronal plasticity over the course of prolonged potentiation, sensitization, habituation, and classical associative training are discussed.
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PMID:Molecular mechanisms of neuronal plasticity during learning: the role of secondary messengers. 219 76

The possible involvement of protein kinase C and/or a lipoxygenase product in the mechanism by which adenosine inhibits release of [3H]acetylcholine evoked by electrical pulses from [3H]choline-labelled hippocampal slices was examined. For comparison, the muscarinic autoreceptors were examined using carbachol. The order of potency of adenosine analogues (CHA = R-PIA greater than NECA much greater than CGS 21680, CV 1808) indicates that the adenosine receptor responsible is of the A1 subtype. Adenosine (10 microM) and R-PIA (0.1 microM) were virtually equiactive as inhibitors and were antagonized to an equal extent by 8-CPT with a potency (IC50 approximately 25 nM) which is also compatible with A1-receptor mediation. The effects of carbachol and of R-PIA were not antagonized by the lipoxygenase inhibitor NDGA (10 or 50 microM). Stimulation of protein kinase C by the phorbol ester 4 beta-phorbol 12,13-dibutyrate caused a concentration-dependent increase in stimulation-evoked 3H overflow, but did not antagonize the presynaptic inhibitory effect of R-PIA or carbachol (0.01-1 microM). Staurosporine (0.1 microM), which inhibited the stimulating effect of phorbol dibutyrate, did not alter the effects of carbachol or R-PIA. The presynaptic effects of phorbol dibutyrate, R-PIA and adenosine were reduced by pretreatment with N-ethylmaleimide (100 microM for 10 min), which inactivates G-proteins. The evoked transmitter release was unaffected by nifedipine (1 microM) in the presence and in the absence of phorbol dibutyrate. These results indicate that adenosine, by acting at presynaptic A1-receptors, reduces transmitter release by a mechanism that involves neither an NDGA-sensitive lipoxygenase nor protein kinase C. The results also indicate that the enhancement of transmitter release by phorbol esters is due to protein kinase C activation and that a G-protein may be involved in the effect but a dihydropyridine-sensitive L-type Ca2+ channel probably is not.
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PMID:Adenosine A1-receptor-mediated inhibition of evoked acetylcholine release in the rat hippocampus does not depend on protein kinase C. 226 53

The mechanisms that enable epinephrine (EPI) and lipoxygenase inhibitors to impede insulin secretion are unknown. We examined the possibility that EPI inhibits Ca2+ fluxes as its major mechanism by studying 45Ca efflux from prelabeled, intact rat islets. EPI (2.5 x 10(-7) to 1 x 10(-5) M) inhibited insulin release induced by the influx of extracellular Ca2+ (46 mM K+) or the mobilization of intracellular Ca2+ stores (2 mM Ba2+), but it did not reduce the 45Ca efflux stimulated by either agonist. EPI also nullified insulin release induced by isobutylmethylxanthine or dibutyryl cAMP, with minimal or no effects on 45Ca efflux, and blocked the insulinotropic effects of 12-O-tetradecanoylphorbol-13-acetate (a direct activator of protein kinase C), which is believed primarily to sensitize the exocytotic apparatus to Ca2+ without mobilizing additional Ca2+. Previously we reported that similar effects were induced by inhibitors of pancreatic islet lipoxygenase. In this study, however, pretreatment with either the alpha 2-adrenergic antagonist yohimbine or pertussis toxin did not block the effects of lipoxygenase inhibitors, although either agent did block the effects of EPI. Thus, EPI, via an alpha 2-receptor mechanism, is able to reduce exocytosis largely distal to, or independent of, changes in Ca2+ flux, cAMP formation or its Ca2+-mobilizing action, or generation of protein kinase C activators. Therefore, EPI may reduce the sensitivity of the exocytotic apparatus to Ca2+. Inhibition of islet lipoxygenase may have a similar effect; however, in this case, the effect would have to be unrelated, or distal, to stimulation of alpha 2-receptors.
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PMID:Epinephrine impairs insulin release by a mechanism distal to calcium mobilization. Similarity to lipoxygenase inhibitors. 244 39

By using human neutrophils we studied the on-off phenomenon for leukotriene B4 (LTB4) -induced functional responses compared with fMetLeuPhe (fMLP). LTB4 induced rapidly appearing and disappearing neutrophil chemiluminescent (CL), superoxide anion formation, aggregatory and membrane depolarizing responses, whereas fMLP responses were slower both in onset and termination. Increases of intracellular calcium concentrations (as reflected by quin2 and fura-2 fluorescence) were of similar magnitude for both stimuli; however, LTB4 responses were more rapidly terminated and fMLP responses were biphasic. When intracellular calcium fluxes, calmodulin or protein kinase C activities were inhibited by quin2, trifluoperazine, verapamil or 3,4,5-trimethoxybenzoic acid 8-diethylamino)octyl ester (TMB-8), profound changes were noted for chemiluminescent and aggregation kinetics induced by fMLP, whereas kinetics of LTB4 responses were less affected. When drugs were used to modulate cAMP levels, or to inhibit cyclo- and lipoxygenase metabolites of arachidonic acid, no effects on response kinetics were observed. Cytochalasin B both amplified and delayed responses although chemiluminescent responses to fMLP were amplified more than those to LTB4. Despite those effects cytochalasin B did not enhance peak fura-2 or quin2 responses to either fMLP or LTB4. Thus, LTB4 rapidly initiates functional responses in neutrophils, and stimulus-specific response patterns are already discernable during the mobilization of calcium, and can be modulated by interference with calcium-dependent reactions.
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PMID:Leukotriene B4 triggers highly characteristic and specific functional responses in neutrophils: studies of stimulus specific mechanisms. 245 94

The gamma-subspecies of protein kinase C (PKC) apparently is expressed only in central nervous tissues, and at a high level in the cerebellum and hippocampus. gamma-PKC from bovine cerebellum, but not the alpha- or beta I/beta II-subspecies, is activated by micromolar concentrations of arachidonic acid (AA), in the absence of both phospholipid and diacylglycerol. A significant component of this activation is also calcium independent. Other unsaturated fatty acids are much less active in this respect. Among the AA metabolites tested, lipoxin A (5(S),6(R),15(S)-11-cis-isomer) was a potent, selective activator of the gamma-subspecies, and also, to a lesser extent, 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid could support activation. These results raise the possibility that AA and some of its lipoxygenase metabolites may function as messenger molecules in neurones to activate the gamma-subspecies of PKC.
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PMID:Selective activation of the gamma-subspecies of protein kinase C from bovine cerebellum by arachidonic acid and its lipoxygenase metabolites. 249 51

The role of several lipoxygenase metabolites of arachidonic acid in the action of luteinizing hormone-releasing hormone (LHRH) on ovarian hormone production was investigated. Like LHRH, treatment of rat granulosa cells with 5-HETE, 5-HPETE, 12-HETE, 15-HETE or 15-HPETE stimulated progesterone (P) and prostaglandin E2 (PGE2) production. 12-HEPE was most potent and stimulated P and PGE2 equally well. By contrast, 5-HETE stimulated P better than PGE2, while 15-HETE was a potent stimulator of PGE2 but not of P. Stimulation of P and PGE2 by LHRH or 12-O-tetradecanoylphorbol 13-acetate (TPA) was further augmented by several HETEs and HPETEs. Like protein kinase C, arachidonic acid metabolites appear to mediate the multiple actions of LHRH in the ovary.
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PMID:Stimulation of progesterone and prostaglandin E2 production by lipoxygenase metabolites of arachidonic acid. 249 61

12-O-Tetradecanoylphorbol-13-acetate (TPA) has been used as a potent tumor promoter in mouse skin. The mechanisms of TPA actions were studied by using several types of inhibitors. TPA-caused responses in mouse skin such as skin tumor promotion, epidermal ornithine decarboxylase (ODC) induction and skin inflammation were inhibited by various lipoxygenase inhibitors of the arachidonic acid cascade. Lipoxygenase inhibitors also inhibited TPA-caused ODC induction in isolated epidermal cells or cultured epidermal cells. Therefore, it is possible that these drugs inhibit TPA-caused ODC induction in mouse skin by directly acting on epidermal cells. TPA actions were also inhibited by either protein kinase C inhibitors, calmodulin antagonists or calcium blockers. These results suggest that arachidonic acid/lipoxygenase, protein kinase C and calcium-calmodulin systems play essential roles in the mechanism of tumor promotion by TPA.
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PMID:The mechanism of skin tumor promotion caused by phorbol esters: possible involvement of arachidonic acid cascade/lipoxygenase, protein kinase C and calcium/calmodulin systems. 249 58


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