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 (1-200 mM), a potent depressor of respiration and motor activity, potentiated the inhibitory Cl- current activated by glycine in 80% of the cultured mouse spinal (n = 236) neurons studied. Ethanol (100 mM) had no effect on the gamma-aminobutyric acidA current and slightly inhibited the N-methyl-D-aspartate current in these neurons. Ethanol increased the affinity of the receptors to glycine without changing the maximal amplitude of the glycine current. The EC50 was reduced from 54 +/- 3 microM in the absence of ethanol to 38 +/- 5 microM in the presence of ethanol. Activation of GTP binding proteins in the neurons with intracellular guanosine-5'-0-(2-thiotriiphosphate) (0.5 mM) enhanced the effect of ethanol, and application of a similar concentration of guanosine 5'-0-(2-thiodiphosphate had an inhibitory effect upon the current potentiation. The potentiating effect of ethanol persisted after culturing the neurons with pertussis toxin, but not with cholera toxin, an irreversible activator of Gs. Activation of cyclic AMP-dependent protein kinase by cyclic AMP and Sp-adenosine-3',5'-cyclic monophosphothioate triethylamine salt, but not of protein kinase C and protein kinase G, potentiated the glycine current. The effect of Sp-adenosine-3',5'-cyclic monophosphothioate triethylamine salt, but not of ethanol, was inhibited completely by the protein kinase A peptide inhibitor. These results suggest that ethanol potentiates the glycine activated Cl- current by modifying a signal transduction step other than protein kinase A.
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PMID:Potentiation of the glycine-activated Cl- current by ethanol in cultured mouse spinal neurons. 896 32

Ethanol inhibits the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal systems, but the mechanism of the inhibition has not been elucidated. Previous work, using primary cultures of rat cerebellar granule cells, showed that both exposure to alcohol and activation of protein kinase C (PKC) by the phorbol ester PMA reduced the potency of the co-agonist, glycine, to enhance NMDA receptor function (measured as an increase in intracellular Ca2+), resulting in inhibition of the NMDA response at low glycine concentrations. Inhibition of NMDA receptor function by PMA and ethanol could also be overcome by PKC antagonists, implicating PKC in the inhibitory effect of ethanol. We have now compared the effects of ethanol and PKC activation of NMDA receptor function in primary cultures of rat cerebral cortical cells. The receptor in these cells was much less sensitive to ethanol inhibition, and the inhibition was not overcome by high concentrations of glycine. Furthermore, PMA treatment resulted in an increased response to NMDA at low glycine concentrations. The results indicate that PKC does not mediate ethanol inhibition of NMDA receptor function in cerebral cortical cells, and that the mechanism of ethanol inhibition can vary among brain regions and/or cell types. Possible determinants of the differing mechanisms of ethanol's actions include the subunit composition of the NMDA receptor and/or the isoforms of PKC present in the different cells.
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PMID:Ethanol inhibition of NMDA receptor function in primary cultures of rat cerebellar granule cells and cerebral cortical cells. 897 36

Phospholipase C (PLC)-mediated signal transduction processes in rat hepatocytes are subject to modulation by protein phosphatases (PPases) and protein kinases, including protein kinase A (PKA) and protein kinase C. Ethanol (EtOH) stimulates PLC activity in liver cells in the absence of hormones, and EtOH pretreatment inhibits the subsequent stimulation of PLC by hormonal stimuli. There is evidence that protein kinase activities are involved in these actions of EtOH. We investigated the effects of okadaic acid (OKA), a PPase inhibitor, and 8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate (cpt-cAMP), a cell permeant cAMP analog that activates PKA, on EtOH-induced PLC activation. In addition, we studied the combined effects of cpt-cAMP and EtOH/OKA on vasopressin-induced PLC activation. PLC activation (cytosolic Ca2+ mobilization and inositol trisphosphate accumulation) induced by EtOH and vasopressin was inhibited by treatment with OKA, and was potentiated by cpt-cAMP. OKA treatment prevented the effect of cpt-cAMP. Pretreatment with EtOH caused inhibition of vasopressin-induced PLC activation. EtOH also decreased the enhancing effect of cpt-cAMP on the responses to vasopressin. The susceptibility to enhancement by cpt-cAMP plotted as a function of the initial rate of vasopressin-induced Ca2+ mobilization in EtOH-treated cells was similar to the pattern observed in OKA-treated cells. These data suggest that interactions of OKA and PKA on EtOH-induced PLC activation occurred at the level of G-protein, and indicate that EtOH may act as an inhibitory agent of PPase.
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PMID:Interaction of protein phosphatases and ethanol on phospholipase C-mediated intracellular signal transduction processes in rat hepatocytes: role of protein kinase A. 898 30

We have studied nerve growth factor (NGF)-induced differentiation of PC12 cells to identify PKC isozymes important for neuronal differentiation. Previous work showed that tumor-promoting phorbol esters and ethanol enhance NGF-induced mitogen-activated protein (MAP) kinase activation and neurite outgrowth by a PKC-dependent mechanism. Ethanol also increases expression of PKCdelta and PKCepsilon, suggesting that one these isozymes regulates responses to NGF. To examine this possibility, we established PC12 cell lines that express a fragment encoding the first variable domain of PKCepsilon (amino acids 2-144), which acts as an isozyme-specific inhibitor of PKCepsilon in cardiac myocytes. Phorbol ester-stimulated translocation of PKCepsilon was markedly reduced in these PC12 cell lines. In addition, phorbol ester and ethanol did not enhance NGF-induced MAP kinase activation or neurite outgrowth in these cells. In contrast, phorbol ester and ethanol increased neurite outgrowth and MAP kinase phosphorylation in cells expressing a fragment derived from the first variable domain of PKCdelta. These results demonstrate that PKCepsilon mediates enhancement of NGF-induced signaling and neurite outgrowth by phorbol esters and ethanol in PC12 cells.
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PMID:An inhibitory fragment derived from protein kinase Cepsilon prevents enhancement of nerve growth factor responses by ethanol and phorbol esters. 916 79

The mechanism of action of ethanol on voltage-activated Ca2+ currents in neurons of the mollusk, Helix pomatia, was studied focusing on intracellular signaling. Ethanol suppressed inward Ca2+ currents in a time- and voltage-dependent manner. Buffering of intracellular Ca2+ with bis(o-aminophenoxy)ethane-N,N,N',N-tetraacetic acid (BAPTA) abolished the ethanol effects on Ca2+ currents. Intracellular GTP-gamma-S injection decreased Ca2+ currents whereas GDP-beta-S injection was ineffective. Ethanol had no further blocking effect on Ca2+ currents in GTP-gamma-S injected cells. In the presence of dopamine, which is known to suppress Ca2+ currents by G0-protein activation, ethanol application was ineffective. The protein kinase C (PKC) blockers, staurosporine and chelerythrine, prevented the ethanol effects on Ca2+ currents. The PKC activators, 1,2-oleoylacetylglycerol (OAG) and beta-phorbol-12,13-dibutyrate (PdBu), both, after maximum stimulation, also occluded the effect of ethanol on Ca2+ currents, whereas in the presence of 4-alpha-phorbol-12,13-didecanoate (4-alpha-PDD), an ineffective phorbol ester, ethanol suppressed Ca2+ currents. Ethanol increased the threshold of Ca2+-dependent action potentials and decreased their duration. Our results indicate that the suppression of voltage-activated Ca2+ currents by ethanol and its effects on action potentials involve activation of a G-protein/protein kinase transduction pathway.
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PMID:Ethanol suppresses neuronal Ca2+ currents by effects on intracellular signal transduction. 931 Mar 91

Ethanol inhibits L-type Ca++ channels, but little is known about its effect on other voltage-gated Ca++ channels. To examine non-L-type channels we used nerve growth factor-differentiated PC12 cells treated with the L channel blocker nifedipine. Using selective Ca++ channel antagonists, we found that N-type and P/Q-type channels mediate most of the remaining depolarization-evoked Ca++ rise. Ethanol (10-150 mM) inhibited depolarization-induced rises in intracellular Ca++ with maximal inhibition of 46% achieved using 50 mM ethanol. Inhibition was time dependent, requiring at least 8 min to develop fully. Ethanol did not alter Ca++ mobilization, sequestration, extrusion or capacitative entry. Sp-adenosine cyclic 3',5'-phosphorothioate, a specific activator of protein kinase A (PKA), blocked inhibition by ethanol, whereas the protein kinase C activator phorbol 12-myristate, 13-acetate did not. Okadaic acid, an inhibitor of protein phosphatases type-1 and type-2A, also blocked inhibition by ethanol with an IC50 of 3 nM. This was prevented by inhibiting PKA, indicating that the action of okadaic acid was due to increased PKA-mediated phosphorylation. These results indicate that ethanol can inhibit N-type and P/Q-type channels and this is antagonized by activating PKA. The findings suggest the sensitivity of these channels to ethanol is regulated by a phosphoprotein that is a substrate for PKA and protein phosphatase type-2A.
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PMID:Protein kinase A regulates regulates inhibition of N- and P/Q-type calcium channels by ethanol in PC12 cells. 931 63

The effects of increasing concentrations of ethanol (25-200 mM) on the enhancement of [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding produced by different glutamate receptor agonists, indicative of a translocation of the intracellular enzyme protein kinase C (PKC), were studied in rat cerebellar granule cells at 2, 4, 8, and 12 days in vitro (DIV). Glutamate-produced stimulation of [3H]PDBu binding was inhibited by 50 mM ethanol at 2 DIV, whereas higher ethanol concentrations (> 100 mM) were needed to reduce the increase of [3H]PDBu binding in cells grown for 4, 8, and 12 DIV. Ethanol significantly inhibited NMDA-stimulated [3H]PDBu binding in a concentration-dependent fashion in cells maintained in culture for 4 and 8 days, respectively, with a slightly less pronounced inhibition by ethanol (50 mM) seen in cells kept for 2 and 12 DIV. Application of higher ethanol concentrations (> 100 mM), inhibited the NMDA-induced stimulation in all cell preparations. Following kainic acid-induced enhancement of [3H]PDBu binding, ethanol (100 mM) reduced the binding only in cells maintained for 2 DIV. Even higher ethanol concentrations (200 mM) inhibited the effects of kainic acid only in cells maintained for 2 and 4 DIV, respectively. Our data suggest that various subclasses of glutamate receptors display a developmentally determined differential sensitivity to ethanol at least in cerebellar granule cells in vitro.
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PMID:Developmental changes in the inhibitory actions of ethanol on glutamate-induced translocation of protein kinase C in cerebellar granule neurons. 940 73

CNS glutamatergic transmission is altered by chronic ethanol intake and may underlie the behavioral hyperactivity associated with ethanol withdrawal. Because astrocytes regulate extracellular glutamate levels, the aim of this investigation was to characterize the effects of in vitro ethanol exposure on Na+-dependent glutamate uptake parameters in astrocytes. Ethanol exposure elicited a time and concentration-dependent increase in the maximal uptake capacity, Vmax, for [3H] glutamate, which was reversed upon withdrawal of ethanol from the media. None of the ethanol exposures had any effect on the Km for this process. In addition, the ethanol-induced increase in Vmax for glutamate was reversed by the protein kinase C inhibitors, calphostin C and bisindolylmaleimide, and was not associated with an increase in the expression of either of the major glutamate transporter proteins, GLT-1 or GLAST.
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PMID:Regulation of glutamate uptake in astrocytes continuously exposed to ethanol. 941 69

Ethanol suppression of astrocyte mitogenesis is well recognized but ethanol, under some conditions, has also been shown to stimulate astrocyte proliferation. This study addressed the role of protein kinase C and other mitogenic factors as mechanisms responsible for the bidirectional effects of ethanol on astrocyte DNA synthesis. Ethanol treatment inhibited astrocyte DNA synthesis both at 4 hr (short term) and 24 hr (long term) in serum free medium. In contrast, when the medium contained serum, ethanol was less effective in inhibiting DNA synthesis at 4 hr and treatment with ethanol for 24 hr increased DNA synthesis. Protein kinase C activity was increased in cells treated with ethanol for either 4 or 24 hr. Ethanol inhibition of DNA synthesis in serum free medium was not reversed by down regulating protein kinase C. In contrast, downregulating protein kinase C activity by continuous treatment with phorbol myristic acetate partially reversed the effect ethanol had on DNA synthesis. Also, directly inhibiting protein kinase C with H-7 in cells maintained and treated in the presence of serum abolished the stimulatory effect ethanol had on DNA synthesis. It appears that the negative regulation of astrocyte DNA synthesis by ethanol occurs by protein kinase C and serum independent mechanisms whereas adaptive or stimulatory effects of ethanol on astrocyte DNA synthesis requires the interaction of protein kinase C with other factors present in serum.
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PMID:Negative and positive regulation of astrocyte DNA synthesis by ethanol. 945 15

The effect of polychlorinated biphenyls (PCBs) on the activation of respiratory burst measured as luminol-amplified chemoluminescence in human granulocytes is elucidated here. Chemoluminescence was stimulated in a concentration-dependent manner (ED50 approximately 10 microM) by ortho-substituted PCB congeners, while meta- and para-substituted congeners had no significant effect. Two ortho-substituted PCB congeners were chosen for the mechanistic studies, namely 2,2',4,4'-TeCB and 2,2'-DCB, since they have been used in previous studies by others. In the absence of extracellular calcium, the respiratory burst in response to 2,2'-DCB and 2,2',4,4'-TeCB was reduced by 63% and 82%, respectively. Bisindolylmaleimide, which inhibits protein kinase C, reduced activated chemoluminescence by 2,2'-DCB, 2,2',4,4'-TeCB, N-formyl-methionyl-leucyl-phenylalanine, and phorbol 12-myristate 13-acetate. Neomycin, which inhibits phospholipase C, had a slight, but significant, effect on the 2,2',4,4'-TeCB-activated chemoluminescence but had a more pronounced effect on the 2,2'-DCB-activated chemoluminescence. 2,2'-DCB and 2,2',4,4'-TeCB significantly increased phospholipase D (PLD) activity measured as the amount of 14C-phosphatidylbutanol formed. Ethanol (1%), a phospholipase D modulator, reduced the response to 2,2'-DCB and 2,2',4,4'-TeCB by 72% and 75%, respectively. Furthermore, wortmannin (25 nM), a phosphatidylinositol 3-kinase, and genistein, a more unspecific tyrosine kinase inhibitor, reduced chemoluminescence in response to PCB. In conclusion, our results indicate that PCB-activated chemoluminescence is dependent on the Ca(2+)-dependent phospholipase D or phospholipase C, phosphatidylinositol 3-kinase, and protein kinase C activation prior to activation of the NADPH oxidase. Defects in neutrophhil functions upon exposure to PCB may render a greater susceptibility in the host to invading microorganisms or evoke inappropriate inflammatory responses leading to tissue injury.
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PMID:Ortho-substituted polychlorinated biphenyls activate respiratory burst measured as luminol-amplified chemoluminescence in human granulocytes. 965 68


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