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)

A front phosphorylation assay followed by two-dimensional gel electrophoresis was used to detect proteins in the tadpole optic tectum, the phosphorylation state of which is regulated by NMDA receptor activation. Five proteins with isoelectric points between 4 and 7 displayed marked increases in their phosphorylation state in response to application of 10 microM glutamate and 50 microM NMDA. This response was inhibited by 60 microM 2-amino-5-phosphopentanoic acid. These proteins are termed NMDA receptor activation-responsive phosphoproteins (NARPPs). Two NARPPs were identified as both in vitro and in vivo substrates for protein kinase C. Of these two NARPPs, one was located in the postsynaptic density (NARPP-50), and one was located in the nuclear fraction (NARPP-21). Phosphorylation of NARPP-21 was also induced by application of the metabotropic glutamate receptor agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) (100 microM). Phosphorylation of all NARPPs was eliminated by dantrolene, which inhibits release of calcium from intracellular stores. In adult tecta, only NARPP-21 and -50 were phosphorylation. Thus the phosphorylation state of most NARPPs is regulated differently when synaptic plasticity is low. Further characterization of NARPPs should lead to identification of second messenger systems involved in NMDA receptor signaling and developmental synaptic plasticity.
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PMID:NMDA receptor activation-responsive phosphoproteins in the developing optic tectum. 877 97

Although classically studied as regulators of cell proliferation and differentiation, mitogen-activated protein kinases (MAPKs) are highly expressed in post-mitotic neurons of the adult nervous system. We have begun investigating the potential role of MAPKs in the regulation of synaptic plasticity in mature neurons. In particular, we have studied the regulation of two MAPK isoforms, p44 and p42 MAPK, in hippocampal long term potentiation (LTP), a system widely studied as a model for the cellular basis of learning and memory. We have found that p42 MAPK, but not p44 MAPK, is activated in area CA1 following direct stimulation of two required components of the LTP induction cascades: protein kinase C and the N-methyl--aspartate (NMDA) subtype of glutamate receptor. Furthermore, we have demonstrated that p42 MAPK, but not p44 MAPK, is activated in area CA1 in response to LTP-inducing high frequency stimulation and that this activation requires NMDA receptor stimulation. These data demonstrate that p42 MAPK can be regulated in an activity-dependent manner in the hippocampus and identify it as a potential component of the LTP induction cascades in area CA1. Such observations suggest that p42 MAPK might be an important regulator of synaptic plasticity in post-mitotic neurons.
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PMID:Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation. 879 83

Developmental changes in glutamate receptor agonist-produced enhancement of 4-beta-[3H]phorbol-12,13-dibutyrate binding ([3H]-PDBu binding), indicative of an intracellular translocation of protein kinase C (PKC), were investigated in cerebellar granule cells. Our observations demonstrate that the magnitude of glutamate-, NMDA-, and kainate-produced enhancement of PKC translocation was dramatically decreased between 2 and 12 DIV, whereas there was only a minor reduction in the corresponding response caused by the non-NMDA receptor agonist, AMPA. The maximally enhanced stimulation of PKC translocation caused by glutamate and NMDA was significantly reduced already at 4 DIV, whereas a significant reduction of the kainate-induced enhancement of [3H]PDBu binding was not observed until 8 DIV. Glutamate- and NMDA-induced responses were effectively blocked by the specific NMDA receptor antagonists MK-801 (1 microM) and APV (100 microM) as well as by the addition of Mg2+ into assay media. In contrast, the non-NMDA receptor antagonist, CNQX (10 microM), effectively blocked the kainate-induced enhancement of [3H]PDBu binding, but had no effect on the NMDA- and glutamate-induced stimulation of PKC translocation. The metabotropic glutamate receptor agonist, ACPD (up to 250 microM), had no effect on the translocation of PKC. Taken together, our data support the working hypothesis that the rapidly occurring changes in the glutamate receptor agonist-produced translocation of PKC are most likely due to a differential maturation of glutamate ionotropic receptor subtypes and/or to development-dependent alterations in mechanisms responsible for the coupling between the glutamate receptor subtypes and the activation of PKC translocation in cerebellar granule neurons.
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PMID:Developmental changes in glutamate receptor-activated translocation of protein kinase C in cerebellar granule neurons. 881 73

Modulation of N-methyl-D-aspartate (NMDA) receptor-mediated ion currents by serotonin was investigated with a two-electrode voltage clamp technique in Xenopus oocytes injected with rat brain RNA. After a 1-min application of 200 nM serotonin a transient potentiation of the NMDA receptor-mediated ion currents was observed. The serotonin-induced enhancement was mimicked by the protein kinase C activators 1-oleoyl-2-acetyl-sn-glycerol (100 microM) and phorbol 12-myristate 13-acetate (10 nM), whereas the inactive phorbol ester 4-alpha-phorbol 12-myristate 13-acetate (10 nM) had no effect. From these observations it was concluded that protein kinase C was involved in the enhancement of NMDA-induced currents. In agreement with this conclusion, it was found that the serotonin effect was inhibited by the protein kinase C inhibitors sphingosine (1 microM) or staurosporine (1 microM) added 20 min before NMDA application and by oocyte injection of protein kinase C (PKC)-inhibitor peptide (500 ng/oocyte) 1 hr prior to recordings. The serotonin receptor involved was identified as a 5-HT2 receptor subtype by the finding that 200 nM of the selective 5-HT2 receptor agonist alpha-methyl-5-hydroxytryptamine mimicked the potentiation of NMDA-induced ion currents by serotonin. Furthermore, the observed potentiation was significantly reduced by co-application of serotonin with 100 microM of the selective 5-HT2 receptor antagonist ketanserin. These results indicate that 5-HT2 receptors enhance NMDA receptor function via phosphoinositol hydrolysis and subsequent stimulation of PKC.
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PMID:Serotonin 5-HT2 receptor activation potentiates N-methyl-D-aspartate receptor-mediated ion currents by a protein kinase C-dependent mechanism. 884 32

Acute ammonia toxicity is mediated by activation of NMDA receptors and is prevented by chronic moderate hyperammonaemia. The aim of this work was to assess whether the protective effect of chronic hyperammonaemia is due to impaired activation of the NMDA receptor. It is shown that chronic hyperammonaemia in rats decreases the binding of [3H]MK-801 to synaptosomal membranes from the hippocampus but not the amount of NMDAR1 receptor protein as determined by immunoblotting. In primary cultures of cerebellar neurons, long-term treatment with 1 mM ammonia also decreased significantly the binding of [3H]MK-801. These results suggest that ammonia impairs NMDA receptor activation. To confirm this possibility we tested the effect of long-term treatment of the cultured neurons with 1 mM ammonia on three well known events evoked by activation of the NMDA receptor: neuronal death induced by glutamate, increase in aspartate aminotransferase activity and increase in free intracellular [Ca2+]. Long-term treatment with ammonia prevented noticeably the effects of glutamate or NMDA on all these parameters. These results indicate that long-term treatment of neurons with 1 mM ammonia leads to impaired function of the NMDA receptor, which cannot be activated by glutamate or NMDA. Activation of protein kinase C by a phorbol ester restored the ability of the NMDA receptor to be activated in neurons treated with ammonia. This suggests that ammonia impairs NMDA receptor function by decreasing protein kinase C-dependent phosphorylation.
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PMID:Ammonia prevents activation of NMDA receptors by glutamate in rat cerebellar neuronal cultures. 884 43

Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptors significantly contribute to the development of kindling. In addition, a lasting enhancement of the NMDA receptor function has been suggested to play a significant role in the chronic hyperexcitability occurring in the hippocampus after kindling epileptogenesis. We have investigated whether hippocampal kindling induces changes in the NMDA receptor at the molecular level by assessing the expression of mRNAs of the different spliced variants at the N-terminal (exon 5) and C-terminal (exon 21) position of the NMDA receptor 1 (NR1) gene by means of the reverse transcription-polymerase chain reaction. Alternative splicing at exon 5 confers different sensitivity of the NMDA receptor to polyamines while exon 21 encodes a 37-amino acid insert containing the major phosphorylation sites for protein kinase C. One week after the acquisition of stage 5 of kindling in rats (generalized tonic-clonic seizures), the relative abundance of the two alternatively spliced forms at the C-terminal domain, respectively containing (+) or lacking (-) exon 21, was reversed compared to controls (implanted with electrodes but not stimulated) in the dorsal hippocampus ipsilateral and contralateral to the electrical stimulation. The exon 21+/exon 21- mRNA ratio for controls was 1.3 +/- 0.04 (mean +/- SE); for ipsilaterally kindled rats it was 0.64 +/- 0.05 (P < 0.05), and for contralaterally kindled rats it was 0.48 +/- 0.07 (P < 0.01). Similar bilateral effects were observed in the ventral hippocampus (temporal pole). No changes were found 4 weeks after stage 5 seizures and 1 week after the induction of a single afterdischarge. No significant alterations were induced by kindling in the relative abundance of the spliced variants containing or lacking exon 5. Our findings show selective changes in alternative splicing of the NR1 gene after repeated application of an epileptogenic stimulus. This may generate receptors with different functional properties, which may contribute to the increased sensitivity for the induction of generalized seizures during kindling.
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PMID:Alternative splicing at the C-terminal but not at the N-terminal domain of the NMDA receptor NR1 is altered in the kindled hippocampus. 884 57

Ethanol is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in various neuronal preparations. In primary cultures of cerebellar granule cells, ethanol was suggested to interact with the glycine co-agonist site of the receptor by a mechanism involving protein kinase C. In the present study, the interaction of ethanol with various sites on the NMDA receptor was examined in primary cultures of cerebral cortical cells from embryonic rats. NMDA receptor function was determined by measuring increases in intracellular Ca2+ with fura-2 fluorescence. Ethanol inhibited the function of the NMDA receptor in cerebral cortical cells, but in contrast to the results in cerebellar granule cells, phorbol ester treatment did not inhibit the NMDA response, and ethanol did not alter the effect of glycine on NMDA receptor function. Ethanol also did not affect inhibition of the NMDA response by Mg2+ or dizocilpine. The results support the hypothesis that the mechanism of ethanol inhibition of NMDA receptor function can vary in neurons from different brain regions.
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PMID:Mechanism of ethanol inhibition of NMDA receptor function in primary cultures of cerebral cortical cells. 886 71

Glutamate-induced neurotoxicity was examined in cultured rat cortical cells. Primary cultures were obtained from the cerebral cortex of fetal rats (17-19 days of gestation). Single cells dissociated from the cerebral cortex were plated on plastic coverslips placed in 35- or 60-mm culture dishes. Cultures were incubated in Eagle's minimal essential medium supplemented with 10% fetal calf serum or 10% horse serum at 37 degrees C in a humidified 5% CO2 atmosphere for 10-14 days. The neurotoxicity induced by glutamate was quantified by trypan blue exclusion. The viability of cultures was markedly reduced by a 10-min exposure to glutamate followed by incubation with glutamate-free medium for 1-24 hr. Glutamate neurotoxicity was prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801, 3-[(+/-)-2-carboxypiperazin-4-yl] propyl-1-phosphoric acid (CPP), ifenprodil and 7-Cl-kinurenate. Glutamate neurotoxicity was augmented by phorbol dibutyrate, that activates protein kinase C (PKC), but reduced by H-7, that inhibits PKC. These results suggest that PKC plays an important role in NMDA receptor-mediated glutamate neurotoxicity in the cerebral cortex.
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PMID:[Experimental techniques for developing new drugs acting on dementia (11)--Experimental methods on glutamate neurotoxicity]. 890 96

The spatiotemporal expression patterns of the NR2C subunit of the NMDA receptor and PKC gamma isoform during cerebellar development suggests that both proteins are involved in the molecular mechanisms of synaptogenesis. However, the topographic distribution of WGA-HRP labeled spinocerebellar mossy fiber terminals in NR2C/PKC gamma double mutants (n = 4) appears similar to controls (n = 3). While the results do not rule out a role for NR2C receptor subunits and the PKC gamma isoform in cerebellar synaptogenesis, they indicate that neither is necessary for the formation or maintenance of normal spinocerebellar mossy fiber afferent maps.
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PMID:Spinocerebellar mossy fiber terminal topography in the NR2C/PKC gamma double mutant cerebellum. 894 62

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


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