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 effects of GABA on protein kinase C (PKC) were investigated in rat hippocampal slices at various postnatal ages [postnatal day (P) 1-P60]. At P4, GABA (300 microM) induced a rapid (in 1-2 min) 40-50% increase of PKC activity in the membrane fraction and a decrease in the cytosol. These effects were mediated by GABAB receptors because (a) they were neither blocked by 10 microM bicuculline nor reproduced by 10 microM isoguvacine and (b) they were mimicked by the GABAB agonist baclofen (3-30 microM), an effect fully antagonized by the GABAB antagonist 2-hydroxysaclofen (10 microM). A baclofen-induced increased PKC activity in the membrane fraction was only present during the early postnatal period (P1-P14); it was associated with a translocation from the cytosol to the membrane of the immunoreactivity of some PKC isoforms (alpha-, beta-, and epsilon-PKCs). In contrast, after P21, PKC activity and alpha-, beta-, epsilon-, and gamma-PKC immunoreactivities were decreased by baclofen in the membrane fraction and increased in the cytosol. These results suggest that the stimulation of GABAB receptors differentially modulates PKC activity via distinct second messenger pathways in developing and mature hippocampi.
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PMID:Different GABAB-mediated effects on protein kinase C activity and immunoreactivity in neonatal and adult rat hippocampal slices. 761 47

The pharmacology of memory has been recently studied by the infusion of drugs into the hippocampus (HIP), amygdala (AMY), medial septum (MS), and entorhinal cortex (EC) at various times after training or at the time of retention testing. It was found to be remarkably similar to that of long-term potentiation (LTP). Memory and LTP are blocked early on by antagonists of glutamate N-methyl-D-aspartate (NMDA) or metabotropic receptors (mGLUs), by the antagonist of the presynaptic membrane receptor to PAF, BN 52021, by the inhibitor of heme oxygenase, ZnPP, by the inhibitor of NO synthase, N-nitro-arginine, by GABA type A receptor agonists, or by muscarinic blockers. Both memory and LTP are enhanced, at this early stage, by glutamate, mGLU agonists, GABA-A antagonists, muscarinic agonists, and norepinephrine. In the next 1-3 h, memory and LTP are accompanied by enhanced activity of protein kinases and are blocked by specific inhibitors of calcium/calmodulin dependent protein kinase II and protein kinase C. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors and are accompanied by an enhanced sensitivity of these receptors. Memories that depend on HIP are affected by drugs given into the HIP but not the MS or AMY, memories that depend on the AMY are affected by drugs given into the AMY, and memories that depend on the HIP, AMY, and MS are affected by drugs given into the three structures.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation between the pharmacology of long-term potentiation and the pharmacology of memory. 766 77

1. The intracellular phosphorylation of bicuculline- and baclofen-insensitive GABAC receptors was investigated in rat retinal bipolar cells. The cells were recorded in organotypic slice cultures by using the whole-cell configuration of the patch-clamp technique. 2. Peak GABA responses recorded in the presence of bicuculline decreased with repetitive GABA applications. Intracellular application of the phorbol ester, phorbol 12-myristate, 13-acetate (PMA) increased this run-down, whilst it was prevented by both tamoxifen and phosphatase. 3. Perfusing the cells extracellularly with L-AP4, trans-(+/-)-1-amino-1,3-cyclopentane dicarboxylate (ACPD) or alpha-methyl serotonin accelerated the run-down of GABAC responses. 4. Modulation of GABAC responses could be induced by intracellular application of GTP gamma S, indicating involvement of G-proteins in the transduction cascade. 5. These results suggest that retinal GABAC receptors in bipolar cells are modulated by protein kinase C. Receptors which stimulate phospholipase C, presumably via Gi or Go, such as some of the metabotropic glutamate receptors or the 5-HT2 receptor, appear to be linked to this regulatory pathway.
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PMID:Modulation of GABAC receptors in rat retinal bipolar cells by protein kinase C. 773 28

Recent evidence has cast some doubt on the GABA-activated chloride channel as a primary locus of action of ethanol, but strongly implicates the NMDA-receptor-linked cation channel. NMDA antagonists can prevent the development of tolerance to ethanol in various paradigms. However, explanation of the various time-frames of tolerance, and of the role of associative and instrumental learning in its development, requires consideration of probable interactions among NMDA, arginine vasopressin, serotonin 5-HT2, GABA and acetylcholine receptors. A possible locus of such interaction may be a loop involving medial and lateral septal nuclei and hippocampus. Synthesis of protein kinase C and other proteins may be a cellular mechanism of tolerance, as it appears to be in learning. Further clarification of the roles of these cellular mechanisms in tolerance requires detailed analysis of their interactions with the behavioral and environmental factors that markedly affect tolerance.
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PMID:Problems in the search for mechanisms of tolerance. 774 83

Ethanol has been demonstrated to potentiate GABAergic mechanisms in several different cell types and also appears to be active on GABAA receptors in specific brain regions. By expressing brain mRNA and cloned GABA receptor subunits in Xenopus oocytes, we have investigated the requirements for ethanol modulation of the GABAA receptor. Using hybrid arrest techniques, the GABA receptor subunits alpha 1, beta 1, gamma 1, gamma 2S+ gamma 2L, gamma 2L and gamma 3 were individually prevented from expressing. None of these treatments altered potentiation by pentobarbital, the gamma 2S+ gamma 2L and gamma 2L reduced diazepam potentiation, however only the gamma 2L hybridization reduced ethanol sensitivity. By expression of cloned GABA subunits the effects could be reproduced by comparing ethanol sensitivity of alpha 1 beta 1 gamma 2S and alpha 1 beta 1 gamma 2L. The gamma 2L is an alternatively spliced variant of gamma 2 containing an extra eight amino acids bearing a consensus site for phosphorylation by protein kinase C. By using in vitro mutagenesis techniques, alteration of key residues in the phosphorylation site prevented ethanol modulation of the receptors containing mutant gamma 2 subunits. These results suggest that phosphorylation of a site on the gamma 2L subunit can alter the modulatory effects of ethanol on GABAA receptors containing this subunit.
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PMID:GABAA receptor subunit expression and sensitivity to ethanol. 774 19

The adenosine A2a receptor inhibition of potassium (15 mM)-evoked GABA release from striatal nerve terminals has been examined. High extracellular calcium concentrations (4 mM) reduced the effect of the A2a receptor agonist CGS-21680 (1 nM). CGS-21680 inhibited GABA release in the presence of the L-type calcium channel blocker nifedipine, which itself inhibited evoked GABA release (by 16 +/- 4%). omega-Conotoxin inhibited the evoked release by 45 +/- 4% and prevented the action of CGS-21680. Forskolin and 8-bromo cyclic AMP both stimulated evoked GABA release at low concentrations, but at higher concentrations they abolished the inhibition by CGS-21680 without affecting the evoked release. The nonselective protein kinase inhibitor H-7 inhibited both the evoked release and the inhibition by CGS-21680, whereas the selective protein kinase A and G inhibitor HA-1004 had no effect on either evoked release or the action of CGS-21680. Pretreatment with pertussis toxin did not affect the A2a receptor-mediated inhibition. Therefore, the effect of A2a receptor stimulation was not mediated by protein kinases A or G but was inhibited by elevated cyclic AMP levels and mimicked by inhibitors of the N-type calcium channel and protein kinase C.
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PMID:Inhibition of striatal GABA release by the adenosine A2a receptor is not mediated by increases in cyclic AMP. 776 61

Norepinephrine and GABA inhibit omega-conotoxin GVIA-sensitive (N-type) calcium current in embryonic sensory neurons by separate pathways. We have investigated the mechanisms that limit the modulation of N current by varying the level of activation for a single pathway or simultaneously activating multiple pathways. Calcium currents were measured with tight-seal, whole-cell recording methods. Simultaneous application of the two transmitters at saturating concentrations produced a larger inhibition of the current than either transmitter by itself, but the maximal inhibition was not linearly additive. Maximal, direct activation of GTP-binding proteins by intracellular application of guanosine 5'-(3-O-thio)-triphosphate (GTP gamma S) resulted in a similar limit to the inhibition; furthermore, GTP gamma S did not enhance the maximal inhibition produced by co-application of transmitters. Interventions downstream in the modulatory pathway (e.g. direct activation of protein kinase C or inhibition of protein phosphatases) were also unable to alter the maximal limit for inhibition. These results suggest that transmitter-mediated inhibition is not limited by receptor number, levels of G-protein or protein kinase C activation, or degree of phosphorylation; rather, the extent of inhibition may be limited by the structural properties of the N channels themselves.
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PMID:Interaction of convergent pathways that inhibit N-type calcium currents in sensory neurons. 777 62

Currents elicited by activation of GABAA, glycine (GLY) and glutamate (GLU) receptors (R) in pyramidal neurons of CA1 region from thin slices of rat hippocampus were studied using the tight-seal whole-cell recording techniques. GLU (100 mM) induced a long-lasting depression of GABA- and GLY-activated currents (IGABA and IGLY) when using standard saline in conjunction with depolarization. The long-lasting depression was not observed: (1) in neurons held at -70 mV during GLU application; (2) in neurons depolarized by current injection but not exposed to GLU; (3) when GLU/depolarization protocol was performed in Ca(2+)-free medium; or (4) by using recording patch-pipettes filled with a medium that tightly controlled cytosolic Ca2+ transients. Sphingosine (10 mM), staurosporine (1 mM) and the specific inhibitor of protein kinase C (PKC(19-36) (200 mM in the patch-pipette solution), blocked the long-lasting depression of IGABA. IGABA was depressed even when the treatment with GLU was performed before patch-clamping the neuron. We conclude that the sustained IGABA and IGLY depression is mediated by cytosolic events triggered by the activation of GLUR.
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PMID:Inhibition of GABA and glycine responses by glutamate in rat hippocampal neurons. 790 83

Memory processes and long-term potentiation (LTP) are blocked at the time of their initiation by antagonists of glutamate NMDA or metabotropic receptors, by drugs that hinder the activity of carbon monoxide or the platelet-activating factor, and by GABA type A receptor agonists. In the next 2 h, memory and LTP are accompanied by an enhancement of the activity of calcium/calmodulin-dependent protein kinase II and of protein kinase C, and are blocked by inhibitors of these enzymes. At the time of expression, memory and LTP are blocked by antagonists of glutamate AMPA receptors. The effects of drugs on memory are seen upon their infusion into areas of the brain known to be responsible for the storage and retrieval of declarative memories (hippocampus, amygdala, medial septum, entorhinal cortex) and are both task- and structure-specific. When put together with other pharmacologic findings, with lesion and recording studies, and with data on transgenic animals showing deficits of both memory and LTP, the data reviewed here lend strong support to the hypothesis that LTP in these brain areas underlies memory processes.
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PMID:Pharmacological evidence for a role of long-term potentiation in memory. 795 19

The beta 1 and gamma 2L subunits of the gamma-aminobutyric acid type A receptor (GABAR) contain phosphorylation sites for PKC. To determine the effect of PKC on GABAR function, whole-cell recordings were obtained from mouse fibroblasts expressing recombinant alpha 1 beta 1 gamma 2L receptors, and catalytically active PKC (PKM) was applied via the recording pipette. The first experiment was a population study. Intracellular application of PKM increased GABAR currents, and the enhancement was antagonized by coapplication of the PKC inhibitory peptide. No acceleration or deceleration of GABAR desensitization was observed. The second experiment was a reimpalement study in which paired recordings were made successively from individual cells. Enhancement of GABAR currents by PKM was again obtained. PKM increased GABAR currents at high (> 10 microM) but not at low (< 10 microM) GABA concentrations, resulting in increases in both EC50 and maximal GABAR current. Thus, PKC phosphorylation enhanced recombinant alpha 1 beta 1 gamma 2L GABAR current by increasing maximal current without increasing the affinity of GABA for the GABARs.
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PMID:Protein kinase C enhances recombinant bovine alpha 1 beta 1 gamma 2L GABAA receptor whole-cell currents expressed in L929 fibroblasts. 799 33


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