EC:2.7.11.13 - FACTA Search

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)

Ethanol increases human and animal susceptibility to opportunistic lung infections in part by suppression of endotoxin (LPS) and bacteria-mediated upregulation of inducible nitric oxide synthase (iNOS) in alveolar macrophages (AM). LPS and cytokine-induced NOS mRNA are dependent on NF-kappaB/Rel (NFkappaB) and Activator Protein-1 (AP-1), which are regulated in turn by protein kinase C and tyrosine kinase-dependent phosphorylation. ETOH does not directly inhibit NFkappaB or AP-1, in vivo, but rather inhibits LPS-induced activation of the MEKK/MAP kinase system and inhibition of inhibitory protein IkappaBalpha required for formation of AP-1 and NFkappaB, respectively. in AM. Both transcription factors are involved iNOS mRNA transcription. LPS-induced upregulation of MEKK/MAP tyrosine kinase upregulates NADPH oxidase activity and oxygen free radical formation required for activation of NFkappaB and AP-1 and phosphorylation of IkappaBalpha. LPS downregulates endogenous calcium-sensitive PKC isozymes (PKCdelta), which repress iNOS mRNA expression. ETOH inhibits LPS-induced upregulation of iNOS mRNA by preventing its ability to decrease PKCdelta and upregulate tyrosine kinase-mediated phosphorylation. This effect of ETOH is prevented by inhibitors of PKC and tyrosine kinase. The data support the hypothesis that ETOH inhibits LPS-induced upregulation of iNOS mRNA by interfering with the phosphorylation processes involved in activation of the nuclear transcription factors NFkappaB and AP-1.
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PMID:Role of PKC and tyrosine kinase in ethanol-mediated inhibition of LPS-inducible nitric oxide synthase. 966 19

Previous studies in this laboratory have shown that the ethanol inhibition of recombinant NMDA receptors expressed in Xenopus oocytes is subunit-dependent, with the NR1/2A receptor being more sensitive than NR1/2C receptors. The ethanol sensitivity of NR1/2A receptors is reduced by substitution of the wild-type NR1-1a (NR1(011)) subunit with the calcium-impermeable NR1 (N616R) subunit. In the present study, the ethanol inhibition of NMDA receptors was determined under different conditions to examine the role that calcium plays in determining the ethanol sensitivity of recombinant NMDA receptors. The ethanol sensitivity of NR1/2B or NR1/2C receptors was not affected by alterations in extracellular calcium levels or by coexpression with calcium-impermeable NR1 mutants. In contrast, the inhibition of NR1/2A receptors by 100 mM ethanol was reduced in divalent-free recording medium and was significantly increased when 10 mM calcium was used as the only charge carrier. The increase in the ethanol sensitivity of NR1/2A receptors under high-calcium conditions was prevented by preinjection of oocytes with the calcium chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) but not by inhibitors of calmodulin or protein kinase C. Ethanol did not alter the channel blocking activity of divalent cations on NMDA-induced currents. The enhanced ethanol sensitivity of NR1/2A receptors in 10 mM calcium persisted when the NR1 subunit was replaced by the alternative splice variant NR1-4a (NR1(000)), which lacks the C1 and C2 cassettes. However, expression of a mutant NR1 subunit that lacked the C0, C1, and C2 domains abolished the calcium-dependent enhancement of ethanol's inhibition of NR1/2A receptors. Finally, the ethanol sensitivity of wild-type NR1/2A receptors measured in transfected HEK 293 cells by whole cell patch-clamp electrophysiology was significantly reduced by expression of the C-terminal truncated NR1 subunit. These results demonstrate that the ethanol sensitivity of certain NMDA receptors is modulated by an intracellular, calcium-dependent process that requires the C0 domain of the NR1 subunit.
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PMID:Intracellular calcium enhances the ethanol sensitivity of NMDA receptors through an interaction with the C0 domain of the NR1 subunit. 972 34

The effect of ethanol on the current activated by 2.5 to 40 microM gamma-aminobutyric acid (GABA) was studied in freshly isolated rat dorsal root ganglion (DRG) neurons under voltage clamp in the whole-cell and perforated-patch recording configurations. Our results confirmed that GABAA-activated current in these neurons was insensitive to ethanol at concentrations from 2.5 to 100 mM [G. White, D.M. Lovinger, F.F. Weight, Ethanol inhibits NMDA-activated current but does not alter GABA-activated current in an isolated adult mammalian neuron, Brain Res. 507 (1990) 332-336.]. In addition, the ethanol sensitivity of GABA receptors was studied under conditions that promote phosphorylation of the PKC site on the gamma2L subunit. The presence of the gamma2L and other subunit mRNAs was detected by reverse transcription (RT) of total RNA purified from adult DRG followed by polymerase chain reaction (PCR) using subunit specific primer sets. We found that the GABA response remained insensitive to 2.5-100 mM ethanol despite: (i) the extracellular preapplication of 5, 20 or 500 nM phorbol 12-myristate 13-acetate (PMA); (ii) raising free intracellular Ca2+ ([Ca2+]i) from 7 to 100 or 600 nM by altering the intracellular Ca2+/EGTA ratio; (iii) intracellular application of PKC (0.247 U ml-1 ); and (iv) combining the intracellular application of 1 microM okadaic acid and 30 microM peptide 3 with the extracellular application of 20 nM PMA. These results suggest that phosphorylation of the gamma2L subunit is not the only requirement for ethanol sensitivity of GABAA receptors.
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PMID:Phosphorylation of the GABAA receptor gamma2L subunit in rat sensory neurons may not be necessary for ethanol sensitivity. 973 42

Activation of phospholipase D (PLD) and phosphoinositide-specific phospholipase C (PI-PLC) by fluoride, to stimulate heterotrimeric G-proteins, and by phorbol esters, to stimulate protein kinase C (PKC), was studied in rat atria. Fluoride and 4beta-phorbol-12beta,13alpha-dibutyrate (PDB), in contrast to 4beta-phorbol-13alpha-acetate (PAc), activated PLD, catalyzing the formation of [3H]-phosphatidylethanol ([3H]-PETH), [3H]-phosphatidic acid ([3H]-PA), choline and sn-1,2-diacylglycerol (DAG). Basal PLD activity was resistant to drastic changes in Ca2+ and to Ro 31-8220, a PKC inhibitor, but was decreased by genistein, an inhibitor of tyrosine kinase, and increased by vanadate, a tyrosine phosphatase inhibitor; both effects were, however, very small. Fluoride-evoked PLD activity was resistant to Ro 31-8220 and to genistein, but was Ca2+-dependent. The rate of fluoride-induced PLD activation was maintained for at least 60 min. In contrast, PDB-mediated PLD activity was blocked by Ro 31-8220 and was resistant to extracellular Ca2+-depletion and desensitized within ca. 15 min. PDB markedly potentiated the fluoride-evoked generation of [3H]-phosphatidylethanol and of choline, but inhibited the formation of [3H]-inositol phosphates ([3H]-IP(1-3)). Ethanol (2%) blocked the PDB-evoked generation of both [3H]-phosphatidic acid and of sn-1,2-diacylglycerol, whereas fluoride-evoked responses were reduced only to approximately 50%. In conclusion, the trimeric G-protein-PLD pathway in heart tissue did not enclose PKC activation and was long-lasting and Ca2+-dependent; there was no evidence for an involvement of tyrosine phosphorylation. However, PKC activation modulated G-protein-coupled PLD and PI-PLC activities in opposite directions. PLD activity significantly contributed to the mass production of sn-1,2-diacylglycerol in the heart. The evidence for a pathophysiological role of PLD activation in cardiac hypertrophy and in ischemic preconditioning is discussed.
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PMID:Phospholipase D in rat myocardium: formation of lipid messengers and synergistic activation by G-protein and protein kinase C. 977 41

Ethanol is known to enhance the activity of adenylyl cyclase (AC) in a number of cells and tissues. Recent work has suggested that the various isoforms of AC show differential sensitivity to ethanol, with Type VII AC being most sensitive. However, the mechanism of action of ethanol is unclear. In the present work, we investigated the effect of ethanol on AC activity in the human erythroleukemia (HEL) cell line, platelets, and AC VII-transfected HEK 293 cells. The HEL cells contain abundant amounts of mRNA for Type VII AC. We found that both ethanol and phorbol dibutyrate (PDBu) treatment enhanced agonist (prostaglandin E1; PGE1)-stimulated AC activity in HEL cells, as well as in platelets and HEK 293 cells transfected with AC VII. Inhibitors of protein kinase C (PKC) blocked the stimulatory effects of both ethanol and PDBu. However, the effects of ethanol and PDBu on AC activity were additive, suggesting that the mechanisms of action of ethanol and PDBu were not identical. Furthermore, a 30-min exposure of HEL cells to ethanol attenuated (desensitized) the ability of ethanol, but not PDBu, to enhance agonist-activated AC activity. On the other hand, a 30-min pretreatment with PDBu attenuated the AC response to the phorbol ester, but not to ethanol; but, after a 20 hr preincubation with phorbol ester, the ability of both PDBu and ethanol to enhance prostaglandin E1-stimulated AC activity was completely eliminated. Finally, pretreatment of HEL cells with pertussis toxin blocked the effect of PDBu, but not ethanol, on AC activity. The results support the involvement of phorbol ester-sensitive PKC(s) in ethanol's enhancement of agonist-activated activity of AC in HEL cells, but suggest that the mechanism of ethanol's action is different from that of PDBu. The findings with pertussis toxin suggest that PDBu activation of PKC(s) may affect AC activity through phosphorylation of a G1 protein, whereas ethanol may act by promoting phosphorylation of a different substrate (e.g., AC VII).
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PMID:Role of protein kinase C in ethanol-induced activation of adenylyl cyclase. 1002 6

Ethanol is a potent inhibitor of muscarinic receptor-mediated proliferation in glial cells. Glial proliferation has been suggested as a major target of ethanol neurotoxicity during development, leading to the microencephaly that is a predominant feature of fetal alcohol syndrome. As part of an attempt to understand the mechanism of ethanol's inhibitory effects on muscarinic receptor-mediated proliferation, this study investigated the effects of ethanol on the expression of the immediate-early genes (IEGs), c-fos and c-myc, whose induction is thought to be an essential first step in the initiation of the mitogenic program. Unexpectedly, ethanol had no inhibitory effect on c-fos and c-myc mRNA expression induced in primary rat cortical astrocytes by the mitogens carbachol, histamine, or tetradecanoyl phorbol 13-acetate; rather, a modest potentiation of IEG expression was observed in the presence of 25 to 100 mM ethanol. Control experiments showed that ethanol alone was capable of IEG mRNA induction, with 100 mM ethanol inducing IEG mRNA levels comparable with those induced by 100 ng/ml of tetradecanoyl phorbol 13-acetate; as measured by [3H]thymidine incorporation, however, 25 to 100 mM ethanol had no effect on proliferation. Experiments with the protein kinase C inhibitor bisindolylmaleimide and the Ca2+ chelators BAPTA and EGTA indicated that this IEG induction by ethanol was not mediated by protein kinase C or Ca2+. A possible explanation for this ethanol-induced IEG expression in the absence of a proliferative effect might be found in the increasing number of studies showing IEG involvement (especially that of c-myc) in apoptosis.
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PMID:Effects of alcohol on immediate-early gene expression in primary cultures of rat cortical astrocytes. 1019 17

We investigated the effects of different concentrations of ethanol on contraction of gallbladder isolated from guinea pig. Ethanol at 25 mM significantly inhibited the contraction induced by histamine, but not those by KCl and acetylcholine. A higher concentration (100 mM) of ethanol inhibited both histamine-, acetylcholine- and KCl- induced contractions. The inhibitory effect of the lower concentration (25 mM) of ethanol was not observed in the presence of verapamil, an antagonist of L-type Ca2+ channel or staurosporine, a selective inhibitor of protein kinase C. Verapamil and staurosporine significantly inhibited both histamine- and acetylcholine-induced contractile responses: the inhibitory effect was more potent for the histamine contraction. Our recent study has demonstrated that contraction caused by protein kinase C activation is completely dependent on Ca2+ influx through the L-type Ca2+ channel in gallbladder smooth muscle of guinea pig. Therefore, the difference in 25 mM ethanol effect on histamine- and acetylcholine-induced contractions may be due to different degree of involvement of protein kinase C activation in the agonist-induced contraction. On the other hands, the higher concentration (100 mM) of ethanol inhibits the common pathway of contraction in gallbladder smooth muscle cells.
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PMID:[Mechanism of inhibitory effects of ethanol on gallbladder contraction: differences in cases of histamine- and acetylcholine-induced contraction]. 1020 23

Ethanol alone had no effect on neuronal nitric oxide synthase (nNOS) expression in PC12 cells. However, in the presence of nerve growth factor (NGF), nNOS expression was amplified (threefold, P < 0.05), compared to NGF alone. This increase was eliminated with pretreatment of PC12 cells with staurosporine, suggesting that the effects of ethanol on nNOS expression are mediated by a protein kinase C-dependent pathway.
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PMID:The synergistic action of ethanol and nerve growth factor in the induction of neuronal nitric oxide synthase. 1045 78

Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation. Because ethanol inhibits cell proliferation in vivo and in vitro, we hypothesize that ethanol-induced inhibition results from differential interference with signal transduction pathways activated by PDGF. Cultured cortical astrocytes were used to examine the effects of ethanol on PDGF-mediated signal transduction, on the expression of two PDGF monomers (A- and B-chains), and on the expression of two PDGF receptor subunits (PDGFalphar and PDGFbetar). PDGF-B chain homodimer (PDGF-BB), and to a lesser extent PDGF-A chain homodimer (PDGF-AA), stimulated the proliferation of astrocytes raised in a serum-free medium. Ethanol attenuated these actions in a concentration-dependent manner. Ethanol inhibited both PDGF-AA- and PDGF-BB-mediated phosphorylation of PDGFalphar, but it had little effect on PDGFbetar autophosphorylation. Likewise, ethanol abolished the association of PDGFalphar to Ras GTPase-activating protein (Ras-GAP), but it did not affect the binding of Ras-GAP to PDGFbetar. PDGF stimulated the activities of mitogen-activated protein kinase (MAPK) in protein kinase C (PKC) independent and dependent manners. Ethanol inhibited the PKC-independent, acute activation of MAPK; however, it stimulated the PKC-dependent, sustained activation of MAPK. The expression of neither ligand was altered by exposure to ethanol for 3 d. Moreover, such treatment specifically upregulated PDGFalphar expression in a concentration-dependent manner. It did not, however, affect the binding affinity of either receptor. Thus, the signal transduction pathways initiated by PDGF-AA and PDGF-BB were differentially affected by ethanol. This differential vulnerability resulted from the preferential effects of ethanol on PDGFalphar autophosphorylation. Hence, ethanol-induced alterations are transduced through specific receptors of mitogenic growth factors.
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PMID:Platelet-derived growth factor-mediated signal transduction underlying astrocyte proliferation: site of ethanol action. 1055 9

Prenatal ethanol exposure can cause a number of physiological deficits known as fetal alcohol syndrome (FAS). Because protein kinase C (PKC) regulates the cell cycle and has been linked to growth, we examined the effect of ethanol on PKC isoform expression in a developing chick brain. Ethanol exposure causes decreased head weight in chickens at day 5 in a dose-dependent manner and a decreased brain weight at days 7 and 10 at an ethanol concentration of 1.0 g/kg. Antibodies specific for PKC-alpha, beta, gamma, delta, epsilon, iota, lambda, mu and zeta were used to examine ethanol's effect on PKC expression in the growth-suppressed brain at days 5, 7 and 10 of development. Only four of the PKC isoforms tested are expressed in the chick brain prior to day 10: alpha, gamma, epsilon, and iota. PKC-alpha, gamma, and epsilon are developmentally increased during the time period studied. Ethanol causes a decreased expression of PKC-alpha on days 5, 7 and 10 and a decreased expression of PKC-gamma on days 7 and 10. Ethanol causes a decreased expression of PKC-epsilon only on day 7. PKC-iota expression is unchanged over the developmental times studied and ethanol exposure has no effect on PKC-iota expression. These data suggest that only specific PKC isoforms are developmentally expressed in the embryonic chick brain and that ethanol may inhibit the expression of those PKC isoforms that are developmentally regulated.
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PMID:Ethanol-induced decrease of developmental PKC isoform expression in the embryonic chick brain. 1056 37

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