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 correlation between regional phorbol ester binding and cerebral blood flow (CBF) was evaluated in the gerbil brain after 2-hour unilateral common carotid artery occlusion. [3H]phorbol 12,13-dibutyrate (PDBu) was used as a specific ligand for estimating the translocation of protein kinase C (PKC), and CBF was determined by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted concurrent measurement of these two parameters in the same brain. In the ischemia group of the animals, statistically significant, inverse correlations were noted between the CBF and PDBu binding in the hippocampus (CA1 and CA3 regions and dentate gyrus), the caudate-putamen and lateral nuclei of the thalamus. In these regions, the PDBu binding increased progressively as CBF fell below 35-40 ml/100 g/min. On the other hand, the PDBu binding in the cerebral cortices did not show any significant changes even when CBF was decreased to below 35 ml/100 g/min. The above data suggest that (1) the translocation of PKC to the cell membrane may be regionally specific in response to ischemia, and may remain in the regions particularly vulnerable to ischemia such as the hippocampus, caudate-putamen and lateral nuclei of the thalamus in the early ischemic phase; (2) the threshold of CBF below which PKC begins to translocate to the cell membrane in the above regions, may be 35-40 ml/100 g/min in 2-hour ischemia.
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PMID:Flow threshold for enhanced phorbol ester binding in the ischemic gerbil brain. 857 3

1. Intracellular recordings were used to study the role of metabotropic glutamate receptors (mGluRs) in modulating GABA-mediated giant depolarizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glutamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In the presence of kynurenic acid, both tetanic stimulation of the hilus or bath application of quisqualic acid (1 microM) and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 microM) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 microM). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (IBMX, 200 microM) or forskolin (30 microM) mimicked the effects of mGluR agonists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 microM), which does not activate adenylate cyclase, was ineffective. 5. Incubation of slices in the presence of the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 microM) or superfusion of Rp-cAMPS (20 microM) prevented the effects of forskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the protein kinase C activator, phorbol 12,13-diacetate (2 microM) induced the appearance of GDPs. This effect was prevented by staurosporine (1 microM). However, staurosporine (1-3 microM) did not modify the effects of t-ACPD on GDPs. 6. It is suggested that, during development, mGluRs enhance the synchronous release of GABA, responsible for GDPs, through cAMP-dependent protein kinase.
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PMID:Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus. 858 96

This study describes changes in the immunoreactivity for muscarinic acetylcholine receptors (mAChRs) in the hippocampus of mice in relation to spatial discrimination behavior, employing the monoclonal antibody M35 raised against purified bovine mAChR protein. Performance in a hole board in which the animals learned the pattern of 4 baited holes out of 16 holes served as the measure of spatial discrimination learning and memory. Twenty-six adult male house mice were used, divided into four groups. Three groups served as various controls: group N (naive; blank controls); group H (habituated; animals were introduced to the hole board with all holes baited for 5 consecutive days), and group P (pseudo-trained; the animals were admitted to the hole board for 13 consecutive days with all holes baited). The T group (trained) was subjected to the hole board for 5 consecutive habituation days with all holes baited (similar to the H and P groups), followed by 8 successive training days with only four holes baited in a fixed pattern. During the 8 training days, the T group gradually acquired a pattern to visit the baited holes, whereas the P group continued visiting holes in a random fashion. The mice were killed 24 h after the last behavioral session. All principal cells in teh cornu ammonis (CA) and dentate gyrus (DG) of the habituated animals revealed increased levels of mAChR immunoreactivity (mAChR-ir) over the naive mice. A minor increase in mAChR-ir was found in the apical dendrites of the CA1 pyramidal cells. Pseudotraining resulted in a CA1-CA2 region with a low level of mAChR-ir, resembling naive animals, whereas the trained mice showed a further increase in mAChR-ir in the CA1-CA2 pyramidal cell bodies and apical dendrites. Optical density measures of the mAChR-ir in the CA1 region revealed a significant (P < 0.05) increase in the pyramidal cell bodies of the H and T group over the N and P group, and a significant (P < 0.05) increase in the apical dendrites of the T group over all other groups. In contrast to the CA1-CA2 region, both pseudotrained and trained mice revealed high mAChR staining in the CA3-CA4 region and the DG. These results indicate that prolonged exposure to the hole board is sufficient for an enhanced mAChR-ir in the CA3-CA4 and DG, whereas the increase in CA1-CA2 pyramidal cells is a training-specific feature related to spatial orientation. Nonpyramidal neurons within the CA1-CA2 region with enhanced mAChR-ir in the pyramidal cells, however, revealed a decreased level of mAChR-ir. The opposing effect of pyramidal and nonpyramidal cells suggests a shift in the excitability of the hippocampal microcircuitry. Previously we demonstrated an increase and redistribution of hippocampal protein kinase C gamma-immunoreactivity (PKC gamma-ir) induced by hole board learning in mice (Van der Zee et al., 1992, J Neurosci 12:4808-4815). Immunofluorescence double-labeling experiments conducted in the present study in naive and trained animals revealed that the principal cells and DG interneurons co-express mAChRs and PKC gamma, and that the immunoreactivity for both markers increased in relation to spatial orientation within these neurons. The mAChR-positive nonpyramidal cells of the CA1-CA2 region were devoid of PKC gamma and revealed an opposite training-induced effect. These results suggest that the postsynaptic changes in mAChR- and PKC gamma-ir reflect functional alterations of the hippocampal formation induced by spatial learning.
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PMID:Alterations in the immunoreactivity for muscarinic acetylcholine receptors and colocalized PKC gamma in mouse hippocampus induced by spatial discrimination learning. 858 98

Hippocampal sympathetic ingrowth (HSI), a form of neuronal plasticity, is induced by medial septal lesions and consists of the sprouting of peripheral sympathetic fibers, arising from the superior cervical ganglion, into the dentate gyrus and CA3 region of the hippocampus. HSI has been previously shown to alter learned and spontaneous behaviors, phosphatidyl inositide hydrolysis, and the antagonist binding kinetics of both muscarinic cholinergic receptors and phorbol ester receptors. We now report that sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C (PKC) following septohippocampal denervation of the rat hippocampus. Further, no changes were found in alpha, beta or gamma PKC isoenzymes among experimental groups, suggesting that the group A PKC isoforms do not mediate the observed changes in activity and phorbol ester binding.
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PMID:Sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C following septohippocampal denervation of the rat hippocampus. 872 Aug 81

The involvement of protein kinase C in long-term potentiation was investigated in the mossy fiber-CA3 pathway in an in vitro slice preparation of rat hippocampus. Tetanic stimulation induced stable long-term potentiation in the mossy fiber-CA3 pathway which was not affected by N-methyl-D-aspartate receptor antagonists. Long-term potentiation was not induced in the presence of a protein kinase C inhibitor, sphingosine. Application of 1 microM phorbol-12, 13-diacetate, an activator of protein kinase C, potentiated the synaptic response by about 400% and this potentiation was completely reversible upon washing. Sphingosine blocked the potentiation when it was applied before protein kinase C activation by phorbol-12, 13-diacetate. However, sphingosine had no effect on the potentiation when it was applied after the synaptic response was potentiated to a plateau following phorbol-12,13-diacetate perfusion. Long-term potentiation and phorbol ester-induced potentiation were not additive when phorbol-12,13-diacetate was applied after induction of long-term potentiation, suggesting that long-term potentiation and phorbol-12, 13-diacetate activate the same protein kinase C pool. The enhanced response caused by phorbol-12,13-diacetate returned to the long-term potentiation level after wash-out of phorbol-12,13-diacetate. Thus the cellular changes underlying long-term potentiation are long-lasting or permanent, while those caused by phorbol-12,13-diacetate are not. However, if tetanic stimulation was induced during prolonged phorbol-12,13-diacetate application (1 h), a potentiation similar in amplitude to long-term potentiation was induced but the population response returned to the control pre-long-term potentiation level after 2 h of washing. The potentiation following tetanic stimulation during prolonged application of phorbol-12,13-diacetate was blocked in the presence of D-2-amino-5-phosphonovaleric acid, a N-methyl-D-aspartate receptor antagonist. Thus, in the presence of phorbol esters the N-methyl-D-aspartate-independent long-term potentiation is occluded but a transient potentiation appears, presumably due to hyperexcitability and activation of N-methyl-D-aspartate receptors in recurrent pathways of area CA3. Normal N-methyl-D-aspartate-independent long-term potentiation could be induced after the 2 h washout period and now was maintained. In conclusion, protein kinase C activation is essential but not sufficient for long-term potentiation in the mossy fiber-CA3 pathway and when stimulated by application of phorbol esters produces a large and reversible synaptic potentiation. These investigations show that long-term potentiation in CA3 is a complex event involving several steps, and that activation of protein kinase C is only one of them.
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PMID:Protein kinase C activation is necessary but not sufficient for induction of long-term potentiation at the synapse of mossy fiber-CA3 in the rat hippocampus. 873 Jul 1

Three days after long-term potentiation (LTP) there is a decrease in the gene expression of protein F1 (GAP-43) and gamma-PKC in CA3 pyramidal cells that is correlated with the magnitude of LTP. We predicted these decreases would be preceded by an increment in gene expression. At 1 h, but not at 2 h after LTP, F1/GAP-43 and gamma-PKC mRNA hybridization were increased, but increases were also observed after control stimulation. At both 1 and 2 h after LTP, changes in F1/GAP-43 hybridization were positively correlated with gamma-PKC hybridization and negatively correlated with LTP magnitude. These data indicate that correlated alterations in F1/GAP-43 gene expression and synaptic efficacy can occur as early as 1 h after LTP and persist for days.
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PMID:Protein F1/GAP-43 and PKC gene expression patterns in hippocampus are altered 1-2 h after LTP. 875 Aug 40

Age-related alterations in bindings of major second messengers in the brain were studied in 3-week- and 6-, 12-, 18- and 24-month-old Fisher 344 rats using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu) and [3H]forskolin were used to label protein kinase C (PKC) and adenylate cyclase, respectively. In immature rats (3-week-old), [3H]PDBu binding showed a significant decrease only in the cerebellum as compared to adult rats (6-month-old), whereas [3H]forskolin binding exhibited a significant reduction in the neocortex, nucleus accumbens, thalamus and substantia nigra. In aged rats, [3H]PDBu binding showed no significant change in all brain areas. In contrast, [3H]forskolin binding showed a conspicuous reduction in various brain areas in 18-month-old rats as compared to adult animals. The age-related reduction was especially observed in the cerebral cortex, hippocampal CA3 pyramidal cell layer, dentate gyrus, thalamus and molecular layer of cerebellum of 24-month-old rats. The results indicate that adenylate cyclase system in the rat brain is more susceptible to aging processes than phosphoinositide cycle system. Furthermore, our data demonstrate that the change in the adenylate cyclase system is more pronounced than that in the phosphoinositide cycle system in immature rat brain. These findings suggest that the adenylate cyclase system is primarily affected in aging processes and this may lead to age-related neurological deficits.
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PMID:Age-related changes in bindings of second messengers in the rat brain. 878 18

The transcript levels of the protein kinase C (PKC) isoform genes during the development of a kindled epileptogenic focus, elicited by stimulation of Schaffer collateral/commissural fibres in the CA1 area of the rat hippocampus, were compared with the expression levels in control animals using a semi-quantitative in situ hybridization approach. In the hippocampus of control animals, the levels of PKC-alpha-zeta transcripts showed a gene-specific expression pattern and significant differences in expression level were observed between the neurons of CA1, CA3 and fascia dentata. In the early stages of kindling epileptogenesis, i.e. following 6 and 14 afterdischarges, specific changes in the expression levels of PKC-beta, -epsilon, and -zeta but not of PKC-alpha, -gamma, and -delta were found. PKC-beta expression was decreased in CA1, while the PKC-epsilon and -zeta specific hybridization signals were increased in CA1, CA3 and fascia dentata. In fully kindled animals, that had experienced 10 generalized seizures, most expression levels tended to return to control values. One month after the last seizure no significant alterations were encountered. These results indicate an involvement of specific PKC-isoform gene expression in the induction of an epileptogenic focus, but not in the maintenance of the long-lasting kindled state.
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PMID:Isozyme specific changes in the expression of protein kinase C isozyme (alpha-zeta) genes in the hippocampus of rats induced by kindling epileptogenesis. 884 1

Long-term potentiation (LTP) observed at the synapses of mossy fiber-CA3 (MF-CA3) pathway differs from that observed at the Schaffer collateral-CA1 pathway (SC-CA1), in being independent of N-methyl-D-aspartate (NMDA) receptors. The induction and expression mechanisms of MF-CA3 LTP remain to be determined. We have compared the occurrence and magnitude of LTP with that of two other indicators of presynaptic plasticity, post-tetanic potentiation (PTP) and paired-pulse facilitation in control brain slices from young rats and in slices treated with phorbol-12, 13-diacetate (PDAc), a protein kinase C activator. Paired-pulse facilitation is a potentiation of the second of two responses at intervals of tens of milliseconds and is due to a presynaptic calcium increase. Tetanic stimulation of mossy fibers induced LTP is area CA3 in only 64% of slices. In those slices that showed LTP, the size of the PTP was significantly greater than in those slices that did not, and the degree of correlation between LTP and PTP amplitude overall was r = 0.7. The degree of paired-pulse facilitation before tetanic stimulation was also positively correlated to the occurrence and magnitude of LTP and PTP after tetanic stimulation. The correlation coefficient between PTP and PPF was 0.749 for all slices studied, while that between LTP and PPF was 0.835 overall. Application of PDAc potentiated synaptic transmission and abolished paired-pulse facilitation (control ratio of second to first response, 2.1; after PDAc ratio 0.8) and LTP. PTP was absent at the control stimulus intensity in PDAc, but was apparent if the stimulus intensity was reduced to give a response of the same amplitude as before administration of PDAc. Stable LTP was also accompanied by a marked decrease in paired-pulse facilitation. These data suggest that MF-CA3 LTP, PTP and paired-pulse facilitation share common mechanisms and are all at least primarily of presynaptic origin. The occurrence of large paired-pulse facilitation or PTP is a predictor of a preparation which will show LTP. It is likely that presynaptic [Ca2+]i is an essential factor in LTP, PTP and paired-pulse facilitation, as well as the potentiation induced by application of PDAc, but the factors which determine whether or not [Ca2+]i rises following these various stimuli are not clear from the techniques used in these investigations.
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PMID:Interactions among paired-pulse facilitation and post-tetanic and long-term potentiation in the mossy fiber-CA3 pathway in rat hippocampus. 885 15

The detailed mechanisms underlying long-term potentiation (LTP) are not known. In hippocampal CA1, translocation of protein kinase C (PKC) activity from cytosol to membrane and subsequent phosphorylation of growth associated protein (GAP)-43 have been demonstrated to be critical events for the maintenance phase of LTP. LTP in mossy fiber (MF)-CA3 pathway and the Schaffer collateral/commissural (SC)-CA1 pathway differ in a number of ways: SC-CA1 LTP depends on NMDA receptors while MF-CA3 LTP does not, and SC-CA1 LTP is primarily postsynaptic while MF-CA3 LTP is primarily presynaptic. The role of PKC in MF-CA3 LTP has not been studied. We investigated the role of PKC in CA3 and show that PKC inhibitors prevent LTP, but that PKC activators produce a reversible synaptic potentiation, indicating that PKC activation is an essential but not sufficient component of LTP in CA3. Then using antibodies against specific PKC isozymes we have determined the membrane vs. cytosolic distribution of various PKC isozymes in slices subjected to low or tetanic stimulation, or perfused with phorbol esters (PDAc). Compared with control, LTP and PDAc slices show greater PKC-alpha and -epsilon immunoreactivity in the membrane fraction, indicating that both LTP and phorbol ester treatment induce translocation of PKC-alpha and -epsilon from cytosol to membrane. However, with PKC-beta and PKC-gamma the only detectable translocation from cytosol to membrane was in the phorbol ester-treated slices. Thus, while phorbol ester treatment causes translocation of PKC-alpha, -beta, -gamma and -epsilon, the only detectable translocation associated with CA3 LTP is that of PKC-alpha and -epsilon.
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PMID:The translocation and involvement of protein kinase C in mossy fiber-CA3 long-term potentiation in hippocampus of the rat brain. 895 49


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