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)

There is substantial evidence that protein kinases, through the phosphorylation of substrate proteins, play a significant role in information processing in the brain, including processes underlying memory formation. Inhibition of the activity of the cyclic-adenosine monophosphate-dependent protein kinase A by the highly specific inhibitor, halofantrine, resulted in impairment of memory formation in day-old chicks trained on a single-trial passive avoidance task. A dose of 9.6 ng/chick halofantrine induced amnesia at the beginning of a protein synthesis-dependent long-term memory stage, the last of three stages of memory postulated to underly memory formation in the chick following passive avoidance learning. The concentration of halofantrine required for 50% inhibition of chick brain protein kinase A was found to be similar to that observed for bovine heart and rat liver. The amnestic effect of halofantrine is tentatively attributed to interference with de novo protein synthesis necessary for long-term memory consolidation. Neither anthraquinone nor the anthraquinone derivative anthraflavic acid, which have little effect on protein kinase A activity, affected memory retention. On the other hand, two other anthraquinone derivatives, chrysophanic acid and purpurin, which inhibit PKA activity, at doses of 0.25 and 0.5 ng/chick also yielded retention deficits. In these cases, however, retention losses occurred earlier than observed with halofantrine, at about 30 min post-training. The earlier effects of these inhibitors may be due to the additional inhibitory action of these compounds on protein kinase C activity, which has been demonstrated in previous studies to be implicated, possibly through phosphorylation of the GAP43 phosphoprotein, in memory processing in the stage of memory immediately preceding the protein synthesis-dependent long-term stage.
Neurobiol Learn Mem 1995 Sep
PMID:Inhibitors of cAMP-dependent protein kinase impair long-term memory formation in day-old chicks. 758 18

Chronic administration of sodium azide in rats inhibits cytochrome oxidase and produces learning and memory deficits. The present experiment tested the hypothesis that chronic sodium azide treatment might also alter protein kinase C activation. Continuous infusion of sodium azide (400 micrograms/h, sc) in rats for 2 weeks significantly decreases membrane-bound protein kinase C in hippocampus, but not frontal cortex, temporal cortex, or cerebellum. Since protein kinase C activation is correlated with hippocampus-dependent learning, these results suggest a possible biochemical mechanism for azide-induced impairment of learning.
Neurobiol Learn Mem 1995 Sep
PMID:Chronic sodium azide treatment decreases membrane-bound protein kinase C activity in the rat hippocampus. 758 27

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)
Neurobiol Learn Mem 1995 Jan
PMID:Correlation between the pharmacology of long-term potentiation and the pharmacology of memory. 766 77

The enzymatic activity of protein kinase C (PKC) was measured in the cytosol and particulate fraction of parabrachial nucleus, the presumed site of conditioned taste aversion (CTA) engrams. At various time intervals after acquisition of the task (pairing saccharin consumption with subsequent LiCl poisoning) the nucleus was dissected from the frozen coronal sections. An increase (+40%) in the cytosol PKC activity was found 48 h after that pairing in comparison with controls (saline injection instead of LiCl). Particulate enzyme activity virtual did not change (-5%). Thus the total PKC activity increased significantly (21%). Qualitatively similar but less markedly expressed PKC shifts (+18% in cytosol) ere found 24 h following CTA. Twelve hours and 5 days after CTA acquisition the activity and distribution of PKC was similar to that seen in normal rats. The control experiments revealed that 6 h after LiCl injection alone (without previous saccharin consumption) translocation of PKC from the cytosol to the membrane fraction (found previously 1 h after LiCl injection alone) still persisted but did not differ from that found 6 h after its pairing with saccharin drinking (CTA). It is concluded that acquisition of conditioned taste aversion may be followed by synthesis of PKC rather than by its translocation or downregulation.
Neurobiol Learn Mem 1996 Mar
PMID:Conditioned taste aversion and protein kinase C in the parabrachial nucleus of rats. 883 4

Lipid bodies, inducible lipid-rich cytoplasmic inclusions, are characteristically abundant in cells associated with inflammation, including eosinophils. Here we reviewed the formation and function of lipid bodies in human eosinophils. We now have evidence that the formation of lipid bodies is not attributable to adverse mechanisms, but is centrally mediated by specific signal transduction pathways. Arachidonic acid and other cis fatty acids by an NSAID-inhibitable process, diglycerides, and PAF by a 5-lipoxygenase dependent pathway are potent stimulators of lipid body induction. Lipid body formation develops rapidly by processes that involve PKC, PLC, and de novo mRNA and protein synthesis. These structures clearly serve as repositories of arachidonyl-phospholipids and are more than inert depots. Specific enzymes, including cytosolic phospholipase A2, MAP kinases, lipoxygenases and cyclooxygenases, associate with lipid bodies. Lipid bodies appear to be dynamic, organelle-like structures involved in intracellular pathways of lipid mobilization and metabolism. Indeed, increases in lipid body numbers correlated with enhanced production of both lipoxygenase- and cyclooxygenase-derived eicosanoids. We hypothesize that lipid bodies are distinct inducible sites for generating eicosanoids as paracrine mediators with varied activities in inflammation. The capacity of lipid body formation to be specifically and rapidly induced in leukocytes enhances eicosanoid mediator formation, and conversely pharmacologic inhibition of lipid body induction represents a potential novel and specific target for anti-inflammatory therapy.
Mem Inst Oswaldo Cruz 1997
PMID:Mechanisms of formation and function of eosinophil lipid bodies: inducible intracellular sites involved in arachidonic acid metabolism. 969 25

We have found that two distinct forms of long-term depression (LTD), one dependent on the activation of NMDA receptors (NMDARs) and the other dependent on the activation of metabotropic glutamate receptors (mGluRs), coexist in pyramidal cells of the CA1 region of the hippocampus of juvenile rats (11-35 days). Both forms were pathway specific, required membrane depolarization, and were blocked by chelating postsynaptic Ca2+ with BAPTA. The mGluR-LTD, but not the NMDAR-LTD, was blocked by the T-type Ca2+ channel blocker Ni2+ and intracellular administration of a protein kinase C inhibitory peptide. In contrast, the protein phosphatase inhibitor Microcystin LR blocked NMDAR-LTD, but not mGluR-LTD. NMDAR-LTD is associated with a decrease in the size of quantal excitatory postsynaptic currents, whereas for mGluR-LTD there was no change in quantal size, but a large decrease in the frequency of events. While mGluR-LTD did not interact with NMDAR-dependent long term potentiation (LTP), NMDAR-LTD was capable of reversing LTP. Prior saturation of mGluR-LTD had no effect on NMDAR-LTD. NMDAR-LTD and mGluR-LTD thus appear to be mechanistically distinct forms of synaptic plasticity in that they share neither induction nor expression mechanisms.
Neurobiol Learn Mem
PMID:NMDA receptor-dependent and metabotropic glutamate receptor-dependent forms of long-term depression coexist in CA1 hippocampal pyramidal cells. 975 87

The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTP(NMDA)), but normal LTP of the AMPA-receptor-mediated component (LTP(AMPA)). This selective loss of LTP(NMDA) was seen in three different genotypic backgrounds and was apparent at all holding potentials (-70 mV to +20 mV). Furthermore, the LTP(NMDA) deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4beta-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTP(AMPA). Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.
Learn Mem
PMID:Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. 1045 58

The activities of protein kinases and phosphatases are believed to regulate neuronal activity and synaptic plasticity in brain. Numerous in vivo and in vitro studies have shown that synaptic strength appears stable under basal conditions and during long-term potentiation (LTP) expression. This may reflect a balance between protein kinase and phosphatase activities. To provide experimental evidence for this hypothesis, and based on our knowledge that Ca2+/CaM activates protein kinases and phosphatases and that postsynaptic Ca2+/CaM signal pathways play important roles in synaptic plasticity, we examined the contribution of postsynaptic Ca(2+)-dependent protein kinases and calcineurin (CaN) in regulating synaptic strength. We show that inhibiting postsynaptic Ca2+/CaM-dependent protein kinase II (CaM-KII) and Ca2+/phospholipitidyserine-dependent protein kinase (PKC) in hippocampal CA1 neurons attenuates significantly the expression of LTP, but not basal synaptic transmission. On the other hand, the inhibition of postsynaptic CaN enhances synaptic transmission at potentiated and naive synapses, and increases significantly the magnitude of synaptic potentiation during the induction phase of LTP. These results indicate that postsynaptic CaM-KII and PKC activities are essential for maintaining LTP expression, but CaN activity limits synaptic strength at stable levels during both basal and potentiated synaptic transmission; that is, the dynamic balance between protein phosphorylation and dephosphorylation that sets physiological synaptic strength is dominated by CaN activity.
Learn Mem
PMID:The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. 1045 87

Ca2+/phospholipid-dependent protein kinase has long been thought to play an important role in modulating synaptic efficacy. It has been shown previously that mice lacking the brain-specific gamma subtype of PKC display abnormal long-term potentiation (LTP), whereas ordinary synaptic transmission is unaffected by the mutation. We now examine the effects of phorbol esters, which are nonselective activators of PKC, on synaptic modulation in these mutant mice. In wild-type mice, phorbol esters produce marked enhancement of synaptic transmission that is largely presynaptic in origin, an effect that has been thought to share mechanisms with LTP. In mutant mice, phorbol ester-mediated potentiation is normal despite the absence of the major PKC isoform. As in wild-type mice, this synaptic enhancement is at least partly attributable to presynaptic changes. Our results demonstrate that the gamma isotype of PKC is not essential for phorbol ester-mediated synaptic facilitation, and place limitations on the possible roles of PKC in LTP.
Learn Mem
PMID:Phorbol ester effects at hippocampal synapses act independently of the gamma isoform of PKC. 1045 88

Quantitative in situ hybridization revealed that following the induction of hippocampal long-term potentiation (LTP) in the dentate gyrus of freely moving rats, specific increases in the expression of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor and mGluR1c, a short splice variant of the metabotropic glutamate receptors that are linked intracellularly to phospholipase C (PLC) and protein kinase C (PKC), were seen in the postsynaptic dentate granule cells. There were no changes in the expression of NR2A; NR2C and NR2D NMDA receptor subunits; or mGluR1a, mGluR1b, mGluR5a, and mGluR5b PLC-associated metabotropic receptors. The elevations in NR2B and mGluR1c mRNA were delayed, occurring days after LTP induction. NR2B expression was enhanced significantly by 48 hr after LTP but was starting to decrease toward basal levels by 96 hr. The transient increase in the expression of NR2B mirrored the increase in the expression of PKC-sensitive isoforms of the NR1 subunits of the NMDA receptor we observed previously (Thomas et al. 1994a). The increase in mGluR1c expression was more persistent, showing a significant increase 96 hr after LTP. This study demonstrates that not only are there changes in the expression of individual glutamate receptor subunits but the increases in their expression occur days after the induction of LTP and may reflect so-called late-onset genes that may be important for the maintenance of LTP.
Learn Mem
PMID:Alterations in the expression of specific glutamate receptor subunits following hippocampal LTP in vivo. 1045 90


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