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)

The function of the phosphoinositide signal transduction system and the levels of heterotrimeric G-protein alpha-subunits were examined in postmortem prefrontal cortex regions (8/9) and region (10) from suicide victims with major depression and matched control subjects without psychiatric illness. The hydrolysis of [3H]phosphatidylinositol (PI) stimulated by phospholipase C, GTP-gamma-S, NaF, and neurotransmitter receptor agonists was measured in membrane preparations from both groups. Phospholipase C-beta activity was similar in depressed suicide and control subjects in the two regions of prefrontal cortex. In prefrontal cortex (10), but not in (8/9), the GTP-gamma-S concentration-dependent stimulation of [3H]PI hydrolysis was significantly lower (30%) in the depressed suicide group compared to the control group. Receptor-coupled, G-protein-mediated [3H]PI hydrolysis induced with carbachol, histamine, trans-1-aminocyclopentyl-1, 3-dicarboxylic acid (ACPD, a glutamatergic metabotropic receptor agonist), serotonin, or 2-methylthio-adenosine triphosphate (2mATP, a purinergic receptor agonist) in the presence of GTP-gamma-S stimulated equivalent responses in the two groups of subjects in each brain region. In prefrontal cortex (10) there was a 68% increase in the level of the 45 kDa subtype of G alpha s and in prefrontal cortex (8/9) there was a significant decrease (21%) in the level of G alpha i2 in the depressed suicide group compared to the control group. Levels of other heterotrimeric G-protein alpha-subunits (G alpha q/11, G alpha i1, and G alpha o) were not different in depressed suicide and control subjects in either brain region. Moreover, there were no differences in the levels of phospholipase C-beta or protein kinase C-alpha in the two groups of subjects in either brain region examined. These results demonstrate that in the prefrontal cortex of suicide victims with major depression compared to normal control subjects there is a region-specific alteration of G-protein-induced activation of the phosphoinositide signal transduction system and in the levels of G-protein alpha-subunits involved in cyclic AMP synthesis. These findings provide direct evidence in human brain that these two important signal transduction systems are altered in suicide subjects with major depression.
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PMID:Alterations in phosphoinositide signaling and G-protein levels in depressed suicide brain. 881 80

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

The effect of glutamate on c-fos expression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), two competitive non-NMDA ionotropic receptor antagonists, reduced glutamate-induced c-fos expression, whereas the NMDA antagonist MK-801 was ineffective. In addition, the glutamate receptor agonists (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) and kainate strongly induced c-fos. However, the metabotropic receptor agonist trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (trans-(+/-)-ACPD) did not increase c-fos mRNA level and the antagonist L-(+)-2-amino-3-phosphonopropionic acid did not block glutamate-induced c-fos mRNA. These findings indicate that c-fos induction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate-induced c-fos expression. Similarly, the protein kinase C inhibitor 1-(5-isoquinoline-sulphonyl)-2-methylpiperazine dihydrochloride (H7) and down-regulation of protein kinase C by prolonged exposure to phorbol-12-myristate 13-acetate blocked c-fos induction. These results suggest that induction of c-fos through AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester-sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but not trans-(+/-)-ACPD, caused a dose-dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results suggest that glutamate may modulate the growth and differentiation of oligodendrocytes in the central nervous system.
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PMID:Glutamate induces c-fos proto-oncogene expression and inhibits proliferation in oligodendrocyte progenitors: receptor characterization. 884 39

We previously reported (Staak, S., Behnisch, T. and Angenstein, F., Hippocampal long-term potentiation: transient increase but no persistent translocation of protein kinase C (PKC) isoenzymes alpha and beta, Brain Res., 682 (1995) 55-62) that Ca(2+)-dependent PKC isoenzymes alpha/beta and gamma are not translocated between subcellular compartments after stimulation of glutamate receptor subtypes in hippocampal slices. Extending our previous work in this study in situ phosphorylation of endogenous PKC substrates and the translocation of novel PKC isoenzymes delta and epsilon was analysed to detect PKC activation. Two proteins of approximately 94 kDa and 18 kDa were first characterised to be specific PKC substrates. As control of the technique carbachol was shown to increase in situ phosphorylation of the two substrates without any measurable translocation of PKC protein. Activation of metabotropic glutamate receptors by 50 microM DHPG also increased the situ-phosphorylation by 43.9% (94 kDa) and 32.8% (18 kDa) compared to controls but did not induce a measurable subcellular redistribution of conventional and novel PKC isoenzymes. Stimulation by 50 microM trans-ACPD or 0.1 mM quisqualate enhanced the situ phosphorylation in the same range, whereas 0.1 mM NMDA was ineffective. To our knowledge this is the first report showing a direct link between metabotropic glutamate receptor activation and increased endogenous PKC substrate phosphorylation in adult hippocampal slices. This PKC activation was not detectable by a redistribution of enzyme protein between subcellular compartments. We, therefore, conclude, that the failure to detect PKC translocation in physiological experiments is not an indicator for unchanged enzyme activity.
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PMID:Activation of metabotropic glutamate receptors increases endogenous protein kinase C substrate phosphorylation in adult hippocampal slices. 903 93

The parallel fibers (PFs) of the dorsal cochlear nucleus (DCN) molecular layer use glutamate as a neurotransmitter. Although metabotropic glutamate receptors (mGluRs) have been identified on cells postsynaptic to the PFs, little is known about the effects of mGluR activation in PF synaptic transmission in the DCN. To investigate these effects, PF-evoked field potentials were recorded from the DCN in guinea pig brain stem slice preparations. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated components of the field response were reversibly depressed by bathing the slice in the mGluR agonists (+/-)-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. A similar depression was produced by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine, but not by the mGluR2/3 agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine or by the mGluR4/6/7/8 agonist L(+)-2-amino-4-phosphonobutyric acid. In addition to the AMPA component, an N-methyl-D-aspartate (NMDA) receptor-dependent component of the field potentials could be identified when the slices were bathed in a low magnesium solution. Under these conditions, the ACPD-induced depression of the AMPA component did not completely recover, whereas the depression of the NMDA component usually recovered and potentiated in some slices. Intracellular recordings of PF-evoked responses were obtained to ascertain which neuronal populations were affected by mGluR activation. Activation of mGluRs produced a reversible depression of PF-evoked responses in cartwheel cells that was not accompanied by any changes in paired-pulse facilitation. The PF-evoked responses recorded from pyramidal cells were unaffected by mGluR activation. Both cell types exhibited a reversible depolarization during (1S,3R)-ACPD application. Subsequent experiments explored the involvement of protein kinases in mediating the effects of mGluRs. The protein kinase C (PKC) activator phorbol-12,13-diacetate partially inhibited the mGluR-mediated depression of the field response; however, the PKC inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide or the protein kinase A inhibitor N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide had little effect on the actions of (1S,3R)-ACPD. These results demonstrate that functional mGluRs are present at PF synapses and are capable of modulating PF synaptic transmission in the DCN.
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PMID:Evidence for functional metabotropic glutamate receptors in the dorsal cochlear nucleus. 911 43

The efficacy and mechanisms of 1-amino-cyclopentyl-1S,3R-dicarboxylate (1S,3R-ACPD)-induced neuroprotection were investigated in rat hippocampal slices subjected to 10 min of oxygen and glucose deprivation. Neuronal viability was assessed by measuring both the amplitude of evoked population spike in the CA1 pyramidale and by imaging CA1 neurons using a live/dead fluorescence assay with confocal microscopy. CA1 pyramidal neurons in oxygen-glucose deprived slices remained viable for up to 120 min following the insult but were dead by 240 min. Pretreatment with 1S,3R-ACPD significantly protected the oxygen-glucose deprived slices in a concentration-dependent fashion. Oxygen-glucose deprived slices pretreated for the same period with the protein kinase C (PKC) activation phorbol 12-myristate 13-acetate (PMA; 1 microM) were significantly protected whereas oxygen-glucose deprived slices treated with the adenylyl cyclase activator, forskolin (30 microM) were not. Oxygen-glucose deprivation induced a rapid and persistent decrease (approximately 50%) in PKC activity and a > 6 fold increase in cyclic adenosine monophosphate (cAMP) levels in whole hippocampal slices. While 1S,3R-ACPD did not stimulate PKC activity and had no effect on basal cAMP in whole slices, it significantly enhanced the rate of return of cAMP to basal levels following reperfusion. Consistent with this observation, the 1S,3R-ACPD-induced neuroprotection was inhibited by forskolin (30 microM). These results suggest that in vitro neuroprotection of CA1 neurons by 1S,3R-ACPD involves metabotropic glutamate receptors negatively linked to cAMP and possibly those which increase PKC activity.
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PMID:Mechanisms of 1S,3R-ACPD-induced neuroprotection in rat hippocampal slices subjected to oxygen and glucose deprivation. 912 6

1. The interactions between N-methyl-D-aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) were investigated in striatal slices, by utilizing intracellular recordings, both in current- and voltage-clamp mode. 2. Bath-application (50 microM) or focal application of NMDA induced a transient membrane depolarization, while in the voltage-clamp mode, NMDA (50 microM) caused a transient inward current. Following bath-application of the non-selective mGluR agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 10 microM), NMDA responses were reversibly potentiated both in current (197 +/- 15% of control) and voltage-clamp experiments (200 +/- 18% of control). 3. Bath-application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (3,5-DHPG, 10-300 microM) resulted in a dose-dependent potentiation of NMDA-induced membrane depolarization (up to 400 +/- 33% of control). This potentiation was either prevented by preincubation with (RS)-alpha-methyl-4-carboxyphenylglycine (RS-alpha-MCPG, 300 microM), or blocked when applied immediately after 3,5-DHPG wash-out. 4. Neither (2S,1'S,2'S)2-(2'-carboxycyclopropyl)glycine (L-CCG I, up to 100 microM) nor (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-IV, 1 microM), agonists for group II mGluRs caused any change in NMDA responses. Likewise, L-serine-O-phosphate (L-SOP, 30 microM), agonist for group III mGluRs, did not affect the NMDA-induced depolarization. 5. The enhancement of the NMDA responses was mimicked by phorbol-12,13-diacetate (PDAc, 1 microM) which activates protein kinase C (PKC). The 3,5-DHPG-mediated potentiation of the NMDA-induced depolarization was prevented by preincubation with staurosporine (100 nM) or calphostin C (1 microM), antagonists of PKC. 6. Electrophysiological responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor activation were not affected by agonists for the three-classes of mGluRs. 7. The present data suggest that group I mGluRs exert a positive modulatory action on NMDA responses, probably through activation of PKC. This functional interaction in the striatum appears of crucial importance in the understanding of physiological and pathological events, such as synaptic plasticity and neuronal death, respectively.
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PMID:Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. 913 10

1. Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of different subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory effects of a selective adenosine A1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12-14 days old) rats. Stimulation was delivered to the Schaffer collateral/commissural fibres, and evoked field excitatory postsynaptic potentials (fe. p.s.p.) recorded extracellularly from the stratum radiatum in the CAI area. 2. The concentration-response curve for the inhibitory effects of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA; 2-50 nM), on the fe.p.s.p. slope (EC50 = 12.5 (9.2-17.3; 95% confidence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5-dihydroxyphenylglycine (DPHG; 10 microM) (EC50 = 27.2 (21.4-34.5) nM, n = 4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 microM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM). DHPG (10 microM) itself had an inhibitory effect of 20.1 +/- 1.9% (n = 4) on the fe.p.s.p. slope. 3. The concentration-response curves for the inhibitory effects of CPA (2-20 nM) on the fe.p.s.p. slope were not modified either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I; 1 microM), or in the presence of the non-selective mGluR agonist (which activates both group I and II mGluR), (IS,3R)-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; 100 microM). L-CCG-I had no consistent effects and ACPD (100 microM) decreased by 19.4 +/- 1.8% (n = 4) the fe.p.s.p. slope. 4. The concentration-response curve for the inhibitory effects of CPA (2-100 nM) on the fe.p.s.p. slope (EC50 = 8.2 (6.9-9.6) nM) was displaced to the right by the group III mGluR selective agonist, L-2-amino-4-phosphonobutyrate (L-AP4; 25 microM) (EC50 = 17.7 (13.1-21.9) nM, n = 4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by L-AP4 (25 microM) was blocked in the presence of the mGluR antagonist (selective for the group III mGluR), (R,S)-alpha-methyl-4-phosphonophenylglycine (MPPG; 200 microM). 5. Both the direct effect of DHPG on synaptic transmission and the attenuation of the inhibitory effect of CPA (10 nM) were prevented in the presence of the protein kinase C selective inhibitors, staurosporine (1 microM) or chelerythrine (5 microM), and thus attributed to activation of protein kinase C. 6. The attenuation by L-AP4 (25 microM) of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope was also prevented by the protein kinase C selective inhibitors, staurosporine (1 microM) or chelerythrine (5 microM), and thus attributed to activation of protein kinase C. But this effect seemed to be distinct from the direct effect of L-AP4 (25 microM) on synaptic transmission, which was not modified by the protein kinase C selective inhibitors. 7. We conclude that agonists of metabotropic glutamate receptors (Groups I and III) are able to attenuate the inhibitory effects of adenosine A1 receptor activation in the hippocampus. This interaction may have pathophysiological relevance in hypoxia, in which there is marked release of both excitatory amino acids and the important endogenous neuroprotective substance, adenosine.
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PMID:Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1 receptor activation in the rat hippocampus. 928 86

Application of the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and the Group I selective mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) potentiated NMDA- and AMPA-induced potential changes recorded from ventral roots of the isolated hemisected baby rat spinal cord. Potentiation produced by 1S,3R-ACPD was completely abolished by the Group I selective mGluR antagonists (S)-4-carboxyphenylglycine (4CPG) or (+)-alpha-methyl-4-carboxyphenylglycine (MCPG). In addition, the protein kinase C (PKC) blockers staurosporine or chelerythrine chloride were able to antagonize the 1S,3R-ACPD-induced potentiation of both NMDA and AMPA response, suggesting that the enhancing effect induced by Group I mGluRs is modulated by a PKC-mediated mechanism. The mGluRs-induced potentiation of NMDA and AMPA responses may be important in modulating various forms of synaptic plasticity and nociceptive processes.
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PMID:Potentiation of NMDA and AMPA responses by group I mGluR in spinal cord motoneurons. 929 69

The metabotropic glutamate receptor mGluR5, but not the closely related mGluR1, is expressed in cultured astrocytes, and this expression is up-regulated by specific growth factors. We investigated the capability and underlying mechanisms of mGluR5 to induce oscillatory responses of intracellular calcium concentration ([Ca2+]i) in cultured rat astrocytes. Single-cell [Ca2+]i recordings indicated that an mGluR-selective agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD), elicits [Ca2+]i oscillations in good agreement with the growth factor-induced up-regulation of mGluR5 in cultured astrocytes. A protein kinase C (PKC) inhibitor, bisindolylmaleimide I, converted a 1S,3R-ACPD-mediated oscillatory response into a nonoscillatory response. In addition, the PKC activator phorbol 12-myristate 13-acetate completely abolished the [Ca2+]i increase. These and other pharmacological properties of 1S,3R-ACPD-induced [Ca2+]i oscillations correlate well with those of the cloned mGluR5 characterized in heterologous expression systems. Furthermore, the potential involvement of protein phosphatases in [Ca2+]i oscillations is suggested. The present study demonstrates that mGluR5 is capable of inducing [Ca2+]i oscillations in cultured astrocytes and that phosphorylation/dephosphorylation of mGluR5 is critical in [Ca2+]i oscillations, analogous to the cloned mGluR5 expressed in heterologous cell lines.
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PMID:The metabotropic glutamate receptor mGluR5 induces calcium oscillations in cultured astrocytes via protein kinase C phosphorylation. 932 75


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