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)

Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In the present study, expression of NR2A and its phosphorylation status were investigated in adult rat cerebral cortex and cerebellum, using an experimental paradigm of in vivo chronic ethanol exposure. In addition, PKC activity was measured in both cytosol and membrane fraction of cerebral cortex and cerebellum using Histone III S as substrate. Western blot analysis using NR2A antibody showed an increased immunoreactivity in cerebral cortex and no immunoreactivity in cerebellum of alcohol-treated rats. Furthermore, PKC activity was increased in both membrane and cytosolic fraction of alcohol-treated rat cerebellum, whereas PKC activity in cerebral cortex was found to be decreased in membrane fraction with no appreciable change in cytosolic fraction. In vitro phosphorylation study showed hypophosphorylation in ethanol-treated cerebral cortex and cerebellum. Our current findings imply that the truncation of NR2A subunit upon alcohol administration in cerebellum probably contributes to altered NMDA receptor function and cerebellar atrophy and motor incoordination in alcoholic rats.
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PMID:Ethanol-induced alteration in N-methyl-D-aspartate receptor 2A C-terminus and protein kinase C activity in rat brain. 1294 83

Mechanisms of alcoholic pancreatitis remain unknown. Previously, we showed that ethanol feeding sensitizes rats to pancreatitis caused by CCK-8, at least in part, by augmenting activation of the proinflammatory transcription factor NF-kappaB. To elucidate the mechanism of sensitization, here we investigate the effect of ethanol on Ca(2+)- and PKC-mediated pathways of CCK-induced NF-kappaB activation using an in vitro system of rat pancreatic acini incubated with ethanol. Ethanol augmented CCK-8-induced activation of NF-kappaB, similar to our in vivo findings with ethanol-fed rats. In contrast, ethanol prevented NF-kappaB activation caused by thapsigargin, an agent that mobilizes intracellular Ca(2+) bypassing the receptor. Pharmacological analysis showed that NF-kappaB activation by thapsigargin but not by CCK-8 is mediated through the calcineurin pathway and that the inhibitory effect of ethanol on the thapsigargin-induced NF-kappaB activation could be through inhibiting this pathway. Ethanol augmented NF-kappaB activation induced by the phorbol ester PMA, a direct activator of PKC. Inhibitory analysis demonstrated that Ca(2+)-independent (novel and/or atypical) PKC isoforms are involved in NF-kappaB activation induced by both CCK-8 and PMA in cells treated and not treated with ethanol. The results indicate that ethanol differentially affects the Ca(2+)/calcineurin- and PKC-mediated pathways of NF-kappaB activation in pancreatic acinar cells. These effects may play a role in the ability of ethanol to sensitize pancreas to the inflammatory response and pancreatitis.
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PMID:Ethanol differentially regulates NF-kappaB activation in pancreatic acinar cells through calcium and protein kinase C pathways. 1295 18

The aim of this study was to determine the pathway(s) by which ethanol activates mitogen-activated protein kinase (MAPK) signaling and to determine the role of Ca2+ in the signaling process. MAPK signaling was determined by assessing MAPK activity, measuring phosphorylated extracellular signaling-regulated kinase (pp 44 ERK-1 and pp 42 ERK-2) expression and ERK activity by measuring ERK-2-dependent phosphorylation of a synthetic peptide as a MAPK substrate in rat vascular smooth muscle cells. Ethanol activated extracellular signal-regulated kinase expression (ERK 1 and 2) could be observed when vascular smooth muscle cells (VSMCs) were stimulated for 5 min or less, but was inhibited when cells are treated for 10 min or more with 1-16 mM of ethanol. Maximum ethanol-induced MAPK activity was observed within 5 min with 4 or 8 mM. Ethanol stimulated MAPK activity was blocked by the protein kinase C (PKC) inhibitor (GF109203X) and epidermal growth factor (EGF) receptor antagonist (PD153035) by 41 +/- 24 and 34 +/- 12.3%, respectively. The calcium channel blocker, diltiazem and the chelating agent, BAPTA, reduced the activation of MAPK activity by ethanol, significantly. The data demonstrate that ethanol-stimulated MAPK expression is mediated partially through both the EGF-receptor and PKC intermediates and that activation through the PKC intermediate is calcium-dependent.
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PMID:Ethanol-induced mitogen activated protein kinase activity mediated through protein kinase C. 1498 9

Cytoplasmic proteins of the hsp70/hsc70 family redistribute in cells that have been exposed to stress. As such, the hsp70 Ssa4p of the budding yeast S. cerevisiae accumulates in nuclei when cells are treated with ethanol, whereas classical nuclear import is inhibited under these conditions. The N-terminal domain of Ssa4p, which is lacking a classical NLS, mediates nuclear accumulation upon ethanol exposure. Concentration of the Ssa4p N-terminal segment in nuclei is reversible, as the protein relocates to the cytoplasm when cells recover. Mutant analysis demonstrates that the small GTPase Gsp1p and GTPase-modulating factors are required to accumulate Ssa4p in nuclei upon ethanol stress. Moreover, we have identified the importin-beta family member Nmd5p as the nuclear carrier for Ssa4p. Ethanol treatment significantly increases the formation of import complexes containing Nmd5p and the N-terminal Ssa4p domain. Likewise, docking of the carrier Nmd5p at the nuclear pore is enhanced by ethanol. Furthermore, we show that the stressed-induced nuclear accumulation of Ssa4p depends on signaling through protein kinase C and requires sensors of the cell integrity pathway.
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PMID:Regulated nuclear accumulation of the yeast hsp70 Ssa4p in ethanol-stressed cells is mediated by the N-terminal domain, requires the nuclear carrier Nmd5p and protein kinase C. 1500 63

The reason why low-to-moderate alcohol drinking is associated with reduced cardiovascular mortality is not elucidated. While data suggested that ethanol drinking may have a protective effect on global cardiac ischemia, the effect of chronic low dose ethanol drinking (CLEthD) on myocardial infarct size has not been evaluated in a model of regional ischemia. Using an isolated rat heart model to exclude the effect of various in vivo confounders, we have studied the effect of CLEthD on infarct size (IS) and left ventricular function after 30 min of regional ischemia and 120 min of reperfusion. The effect of CLEthD was compared with ischemic preconditioning (IPC) and protein kinase C (PKC) isoforms were analysed in the myocardium before the 30-min ischemia. Ethanol-fed rats received 9% (v/v) ethanol in their drinking water for 7 weeks. Four groups of rats were studied: (1) control, (2) ethanol, (3) control + IPC, (4) ethanol + IPC. Compared with controls (59 +/- 10), IS (as percent of risk zone) was smaller in the ethanol (39 +/- 6) and IPC (31 +/- 8) groups (both p < 0.05). Combination of ethanol and IPC in the same rats further decreased IS (-46% vs. ethanol, p < 0.05). PKC analyses did not show sustained isoform translocation in that model. These data indicate that chronic low dose ethanol drinking actually induces in the rat heart a chronic protective state that is independent from an effect on the traditional (lipid and coagulation) risk factors. Further studies are required to elucidate the mechanisms of that protection.
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PMID:Cardioprotective effect of chronic low dose ethanol drinking: insights into the concept of ethanol preconditioning. 1508 15

Moderate alcohol consumption has been shown to reduce the morbidity and mortality from coronary heart disease. Ethanol elicits its protective effects via mechanisms that include activation of protein kinases linked to growth and survival. Our results in isolated neonatal rat cardiomyocytes demonstrate that repeated short-term, low-dose exposure to ethanol is sufficient to activate the growth and/or survival pathways that involve PKC-epsilon, Akt, and AMP-activated kinase. In addition, we are able to induce apoptosis in these cardiomyocytes using the saturated fatty acid palmitate. Pretreatment with multiple low-dose ethanol exposures attenuates the apoptotic response to palmitate. This protection is manifested by a reduction in caspase-3-like activity, decreased mitochondrial loss of cytochrome c, and decreased loss of the mitochondrial lipid cardiolipin. We previously reported that incubation of cardiomyocytes with palmitate results in decreased production of reactive oxygen species compared with cells incubated with the nonapoptotic fatty acid oleate. In the present study, we observed an increase in the production of superoxide and the rates of fatty acid oxidation in cardiomyocytes pretreated with ethanol and then exposed to fatty acids. The level of superoxide production in palmitate-treated cells returns to the levels observed in oleate-treated cells after ethanol exposure. Taken together with our observed increase in AMP-activated kinase activity, we propose that ethanol pretreatments stimulate oxidative metabolism and electron transport within cardiomyocytes. We postulate that stimulation of palmitate metabolism may protect cardiomyocytes by preventing accumulation of unsaturated precursor molecules of cardiolipin synthesis. Maintaining cardiolipin levels may be sufficient to prevent the mitochondrial loss of cytochrome c and the downstream activation of caspases.
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PMID:Attenuation of fatty acid-induced apoptosis by low-dose alcohol in neonatal rat cardiomyocytes. 1521 94

The acute effect of hyperosmotic ethanol on gap junction permeability was examined in astroglial cells in primary culture from five different brain regions. Gap junction permeability was analyzed by measuring dye spreading from cell to cell with the low molecular weight dye Lucifer Yellow. Ethanol concentrations 25-300 mM significantly decreased dye spreading in cultures from the cerebral cortex in a dose-dependent but time-independent manner for up to 60 min. Besides cerebral cortex, exposure to 150 mM ethanol decreased dye spreading in astroglial cultures from the hippocampus and from the brain stem, while cultures from the olfactory bulb and from the hypothalamus were not significantly affected. The ethanol-induced decrease in dye spreading in cultures from the cerebral cortex was not mediated through changes in cell volume, osmolarity, protein kinase C (PKC) phosphorylation, intracellular pH, or intracellular calcium concentration ([Ca(2+)](i)). The decrease in dye spreading was abolished upon incubation in sodium-reduced buffer, and after blockage of the Na(+)/K(+)/2Cl(-) cotransporter with furosemide. The results presented here indicate that ethanol-mediated decrease in dye spreading is directly or indirectly dependent on sodium.
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PMID:Ethanol acutely decreases astroglial gap junction permeability in primary cultures from defined brain regions. 1533 95

Ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the underlying cellular/molecular mechanisms remain unknown. Overexpression and high activity of matrix metalloproteinase-2 (MMP-2) are frequently associated with metastatic breast cancers and serve as a prognostic indicator of clinical outcome. MMP-2 is predominantly expressed in stromal fibroblasts and plays a pivotal role in regulating the invasive behavior of breast tumor cells. We hypothesized that ethanol may enhance the invasion of breast tumor cells by modulating the activity of fibroblastic MMP-2. With in vitro models (HS68 and CCD1056SK human fibroblasts), we showed that ethanol at physiologically relevant concentrations (50-200 mg/dl) activated MMP-2; conversely, at a higher concentration (400 mg/dl), it inhibited the MMP-2 activity. Consistently, conditioned medium collected from ethanol (50-200 mg/dl)-exposed fibroblasts markedly enhanced the invasive potential of breast cancer cells and mammary epithelial cells overexpressing ErbB2/HER2 (BT474, SKBR-3 and HB2(ErbB2) cells) but had little effect on cells with low ErbB2 levels (BT20 and HB2 cells). In contrast, conditioned medium obtained from ethanol (400 mg/dl)-treated fibroblasts inhibited cell invasion. Selective inhibitors of MMP-2 (SB-3CT and OA-Hy) eliminated ethanol-stimulated invasion, indicating that the effect of ethanol was mediated by MMP-2. Ethanol activated conventional PKCs and JNKs in fibroblasts; inhibitors of PKC (Go6850 and Go6976) and JNKs (SP600125) significantly inhibited ethanol-mediated MMP-2 activation as well as cell invasion, indicating that PKCs and JNKs play a role in ethanol-induced MMP-2 activation and cell invasion in vitro. Thus, ethanol-promoted breast cancer cell invasion may be mediated by the modulation of fibroblastic MMP-2.
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PMID:Ethanol-induced in vitro invasion of breast cancer cells: the contribution of MMP-2 by fibroblasts. 1538 67

Ethanol withdrawal (EW) produces substantial neurotoxic effects, whereas estrogen is neuroprotective. Given observations that both human and nonhuman female subjects often show less impairment following EW, it is reasonable to hypothesize that estrogens may protect females from the neurotoxic effects of ethanol. This article is based on the assumption that the behavioral deficits seen following EW are produced in part by neuronal death triggered by oxidative insults produced by EW. The EW leads to activation of protein kinase C, especially PKCepsilon, which subsequently triggers apoptotic downstream events such as phosphorylation of nuclear factor-kappaB (NFkappaB) complex. On phosphorylation, active NFkappaB translocates to the nucleus, binds to DNA, and activates caspases, which trigger DNA fragmentation and apoptosis. In contrast, estrogens are antioxidant, inhibit overexpression of PKCepsilon, and suppress expression of NFkappaB and caspases. Estrogen treatment reduces the behavioral deficits seen during EW and attenuates molecular signals of apoptosis. The effects of ethanol and estrogen on each step in the signaling cascade from ethanol exposure to apoptosis are reviewed, and potential mechanisms by which estrogen could produce neuronal protection against the neurotoxicity produced by EW are identified. These studies serve as a guide for continuing research into the mechanisms of the neuroprotective effects of estrogen during EW and for the development of potential estrogen-based treatments for male and female alcoholics.
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PMID:Estrogen neuroprotection against the neurotoxic effects of ethanol withdrawal: potential mechanisms. 1561 21

Ethanol renders the lung susceptible to acute lung injury in the setting of insults such as sepsis. The mechanisms mediating this effect are unknown, but activation of tissue remodeling is considered key to this process. We found that chronic ethanol ingestion in rats increased the expression of fibronectin, a matrix glycoprotein implicated in acute lung injury. In cultured NIH/3T3 cells and in primary rat and mouse lung fibroblasts, ethanol induced fibronectin mRNA and protein expression in a dose- and time-dependent fashion. The effect of ethanol was prevented by inhibitors of protein kinase C and mitogen-activated protein kinases and was associated with the phosphorylation and increased DNA binding of the transcription factor cAMP response element binding protein, followed by increased transcription of the fibronectin gene. Fibroblasts were found to express alpha(7) nicotinic acetylcholine receptor (nAChR), and ethanol induction of fibronectin was abolished by alpha-bungarotoxin and methyllcaconitine, inhibitors of alpha(7) nAChRs. However, ethanol was able to induce fibronectin mRNA and protein in primary lung fibroblasts isolated from alpha(7) nAChR knockout mice. The ethanol-induced fibronectin response was dependent on ethanol metabolism since 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, abolished the effect and acetaldehyde induced it. These observations suggest that ethanol or ethanol metabolites stimulate lung fibroblasts to produce fibronectin by inducing specific signals transmitted via nAChRs independent of the alpha(7-)subunit, and this might represent a mechanism by which ethanol renders the lung susceptible to acute lung injury.
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PMID:Ethanol stimulates the expression of fibronectin in lung fibroblasts via kinase-dependent signals that activate CREB. 1565 13


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