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)

We investigated, to examine the involvement of lipid peroxidation and inhibitory mechanisms, a novel lipid peroxidation inhibitor (KB-5666) and a GABAA receptor-effector (pentobarbital) on ischemic neuronal damage and the alterations in the second messenger and neurotransmitter systems in Mongolian gerbils by means of morphology and in vitro receptor autoradiography. Quantitative receptor autoradiography visualized binding sites for [3H]inositol 1,4,5-trisphosphate, [3H]forskolin, [3H]phorbol 12,13-dibutyrate, [3H]isradipine (PN200-110), [3H]N6-cyclohexyl-adenosine, and [3H]quinuclidinyl benzilate indicating binding sites for inositol 1,4,5-trisphosphate, forskolin, protein kinase C, L-type calcium channels (or dihydropyridine binding sites), adenosine A1, and muscarinic cholinergic receptors, respectively. In the morphological study, KB-5666, 10 and 50 mg/kg, i.v., 5 min before ischemia, protected against ischemic neuronal damage to the hippocampal CA1 subfield following 5 min of bilateral carotid artery occlusion in a dose-dependent manner. Pentobarbital, 30 mg/kg, i.v., 5 min before ischemia, also had a protective effect. In receptor autoradiographic studies, all receptor bindings decreased significantly in the CA1 subfield seven days after ischemia. In particular, [3H]inositol 1,4,5-trisphosphate binding in the CA1 subfield was completely lost after ischemia. [3H]Inositol 1,4,5-trisphosphate and [3H]forskolin binding decreased as early as 6 h after ischemia. In the CA3 subfield, [3H]inositol 1,4,5-trisphosphate, [3H]PN200-110, and [3H]N6-cyclohexyladenosine bindings decreased seven days after ischemia. In the dentate gyrus, [3H]inositol 1,4,5-trisphosphate binding decreased seven days after ischemia. KB-5666 and pentobarbital prevented reductions in these receptor bindings in the CA1 subfield at 6 h and seven days after ischemia. These results indicate that KB-5666 and pentobarbital protect the brain from both structural and functional damage after ischemia, and that lipid peroxidation and inhibitory mechanisms may play a pivotal role in the neuronal damage of the hippocampal CA1 subfield after ischemia.
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PMID:Involvement of lipid peroxidation and inhibitory mechanisms on ischemic neuronal damage in gerbil hippocampus: quantitative autoradiographic studies on second messenger and neurotransmitter systems. 171 54

Bifemelane has an anti-amnesic effect, produces the translocation of protein kinase C in the hippocampal CA3 region but not in CA1 and enhances long-term potentiation in the mossy fibre-CA3 system but not in the Schaffer collateral-CA1 system. The present study examined the specific binding of [3H]bifemelane in membrane preparations of guinea pig hippocampus and regional differences in such a binding. The binding of [3H]bifemelane was reversible and greater when incubated at 4 degrees C than at 25 or 37 degrees C. The binding of [3H]bifemelane appeared to be composed of at least 2 different affinity components. Imipramine significantly suppressed the binding of [3H]bifemelane at 1 microM and, in the presence of 1 microM imipramine, the low-affinity component of the binding of [3H]bifemelane was eliminated. The density of specific binding sites for 1 nM [3H]bifemelane was significantly higher in the hippocampal CA3 region than in the CA1. The specific binding of 1 nM [3H]bifemelane was not inhibited by other nootropic drugs, such as idebenone, calcium hopantenate, vinpocetine, indeloxazine and piracetam. The present results suggest that there are specific binding sites for bifemelane in hippocampus, which are different from those for other nootropic drugs tested and that the regional differences in the pharmacological susceptibilities to bifemelane are at least, in part, attributed to those in the density of binding sites for bifemelane.
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PMID:Specific binding sites for bifemelane in the hippocampus of the guinea pig, relevant to its pharmacological actions. 178 82

Ependymin, a glycoprotein of the brain ECF, has been implicated in the neurochemistry of memory and neuronal regeneration. Three behavioral experiments (swimming with a float, avoidance conditioning, and classical conditioning) in the goldfish and one in the mouse (T-maze learning) indicate that ependymin has a role in the synaptic changes that take place in the consolidation step of memory formation and the activity-dependent phase of sharpening of goldfish retinotectal connections during neuronal regeneration. The ECF concentration of the protein was found to decrease after the goldfish learned to associate a light stimulus (CS) with the subsequent arrival of a shock (US): paired CS-US gave changes whereas an unpaired presentation of CS-US gave no changes relative to the unstimulated controls. Ependymin is present in ECF as a mixture of three disulfide-linked dimers of two acidic (alpha and beta) polypeptide chains (37 kDa and 31 kDa). Upon removal of its N-linked glycan fragment by N-glycosidase F, the beta chain yields gamma-ependymin (26 kDa). Determinations of the amino acid sequence of gamma-ependymin indicate that it is a unique protein with no long sequence homologies to any known polypeptide. There are, however, small segments (5-7 amino acids long) with homologies to fibronectin, laminin, and tubulin. Ependymin has the capacity to polymerize into FIP (after activation by phosphorylation) in response to events that deplete ECF calcium. FIP is insoluble in 2% SDS in 6 M urea, 10 mM Ca2+Ac2, 100% acetic acid, chloroform/methanol (2/1), saturated KCNS, and even 100% trifluoroacetic acid. FIP was found to be present in goldfish brain and to be formed as a labeled product in vivo. Ependymin's FIP-forming property was used to propose a molecular hypothesis for generating synaptic changes in response to local extracellular depletions of calcium at sites of "associating inputs." The model assumes that, following NMDA receptor stimulation, the translocated PKC that is generated activates extracellular ependymin by converting it to its phosphorylated form using presynaptically released ATP. The hypothesis was tested in studies of LTP of rat hippocampal slices at CA1. After LTP, new sites that stained with antisera to ependymin, visible at 100x, were obtained in its potentiated radiatum in the CA1 region but not in the unpotentiated CA3. Electron microscopic studies showed that the horseradish peroxidase reaction product obtained was localized at synaptic clefts and postsynaptic regions. The results suggest that FIP may be formed at extracellular and postsynaptic loci where multiple associating inputs interact at CA1.
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PMID:Ependymin, a brain extracellular glycoprotein, and CNS plasticity. 183 64

This manuscript describes experiments designed to investigate protein kinase C redistribution occurring during acquisition of the rabbit nictitating membrane (NM) conditioned response (CR). The first experiment defined the acquisition phase of the NM response for our laboratory. A group of rabbits (n = 6) was given 2 days of paired NM training; a second group (n = 6) was given 2 days of unpaired NM training. The data document a variable level of responding on day 1 for rabbits given paired training (mean +/- SEM, 21 +/- 11% CRs) but show that on day 2 most rabbits reached the behavioral asymptote (five of six rabbits responding with greater than 85% CRs). Rabbits responding at the behavioral asymptote were defined as having acquired the NM conditioned response. These data were interpreted to indicate that 1 day of training initiated processes necessary for behavioral acquisition (i.e., responding at the behavioral asymptote). A quantitative film autoradiographic study of [3H]phorbol 12,13-dibutyrate binding was then used to determine the distribution of hippocampal protein kinase C in rabbits sacrificed after receiving either 1 day of paired stimuli (n = 10), 1 day of unpaired stimuli (n = 6), or no stimuli (n = 6). Autoradiograms were analyzed by measuring binding in strictly defined regions of interest and from transept profiles. A significant increase in binding of the phorbol ester was found in the CA3 stratum oriens in the paired group relative to unpaired and naive controls. No other significant differences were found.
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PMID:Protein kinase C redistribution within CA3 stratum oriens during acquisition of nictitating membrane conditioning in the rabbit. 186 86

The effect of transient cerebral ischemia and intraventricular injection of kainic acid on adenylate cyclase and protein kinase C as labeled by [3H]forskolin ([3H]FOR) and [3H]phorboldibutyrate ester ([3H]PDBU) in several rat brain microregions was investigated in a quantitative autoradiographic study. Four days after transient four vessel occlusion a 80% loss of [3H]FOR and a 35% loss of [3H]PDBU binding could be measured in the CA1 stratum radiatum of operated Wistar rats as compared to control rats. Four days after intraventricular injection of kainic acid only a marginal loss of [3H]FOR and a 30% increase of [3H]PDBU binding was seen in the CA1 stratum radiatum while in the CA3 stratum lucidum and radiatum respectively a 30% loss of [3H]FOR and no significant change in [3H]PDBU binding was observed. As transient cerebral ischemia and intraventricular kainic acid injection are depleting the hippocampal CA1 region of CA1 pyramidal cells and axons of CA3 pyramidal cells respectively in rat brain, these findings strongly suggest that both adenylate cyclase and protein kinase C are localized in CA1 pyramidal cells of rat hippocampus.
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PMID:Post- and presynaptic lesions in the CA1 region of hippocampus: effect on [3H]forskolin and [3H]phorboldibutyrate ester binding. 203 10

The subcellular distributions of the gamma- and beta II-subspecies of protein kinase C (gamma- and beta II-PKC) were studied in the rat hippocampus by light and electron microscopic immunocytochemistry. Both subspecies were abundant in the hippocampus with distinct subcellular distributions. The immunoreactivity of gamma-PKC was observed throughout the Ammon's horn, while intense beta II-PKC immunoreactivity was observed predominantly in the CA1 region. gamma-PKC was distributed diffusely through the cytoplasm of pyramidal cells from the perikarya to the dendritic spines. In contrast, beta II-PKC was concentrated around the Golgi complex and present diffusely in distal dendrites, except for the dendritic spines. Neither PKC subspecies could be detected in the presynaptic terminal. The postsynaptic localization of gamma- and beta II-PKC in CA1 suggests that both PKC subspecies may correlate to long-term potentiation in the CA1 region contributing to the postsynaptic side. gamma-PKC may have a specific function not only in CA1 but also in the mossy fiber-CA3 pathway at the postsynaptic side. beta II-PKC may have another function concerning the Golgi complex in CA1.
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PMID:Electron microscopic localization of gamma- and beta II-subspecies of protein kinase C in rat hippocampus. 220 88

We made use of the [3H]phorbol 12,13-dibutyrate binding assay to investigate the effects of bifemelane on the subcellular distribution of protein kinase C in the CA3 and CA1 regions of guinea-pig hippocampal slices. Bifemelane, a drug that augments the long-term potentiation in the CA3 region, significantly induced the translocation of [3H]phorbol 12,13-dibutyrate binding activity from the cytosol to the membrane in a dose-dependent manner (10(-8) to 10(-6) M) and with no effects on total binding activity in the CA3 region. Bifemelane, at a concentration of 10(-6) M, was without effect on the subcellular distribution of [3H]phorbol 12,13-dibutyrate binding activity in the CA1 region. These observations suggest that bifemelane acts directly on the hippocampus to induce translocation of protein kinase C in the CA3 region. Such an effect may be associated with the bifemelane-induced augmentation of the long-term potentiation in this region of the brain.
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PMID:Bifemelane induces translocation of protein kinase C in the CA3, but not the CA1, region of guinea-pig hippocampus. 232 98

Decreased levels of protein kinase C (PKC) and a reduction in the in vitro phosphorylation of a Mr 86,000 protein (P86), the major PKC substrate, are biochemical characteristics of brain tissue from patients with Alzheimer's disease (AD) (Cole et al., 1988). In the current study, we utilized antibodies against individual isozymes of PKC to assess the degree of involvement of different PKC isoforms in AD. The concentration of PKC(beta II) was lower in particulate fractions prepared from AD hippocampal and cortical tissue than in controls and higher in AD cytosol fractions from the cortex than in controls. Immunohistochemical studies in AD neocortex revealed reduced numbers of anti-PKC(beta II)-immunopositive neurons and diminished staining intensity. In contrast, AD hippocampal neurons in CA3-CA4 were more intensely stained with anti-PKC(beta II) antiserum than were controls. The concentration of PKC(beta I) was lower in particulate fractions prepared from AD hippocampus than in controls and was higher in soluble fractions prepared from AD cortex than in controls. The concentration of PKC(alpha) was lower in AD particulate fractions than in controls in the hippocampus. Immunohistochemistry with PKC(alpha) antiserum revealed moderately intense neuron staining and an intense staining of glial cells in AD neocortex. The concentrations and histochemical distributions of PKC(gamma) were not altered in the disease. PKC immunoreactivity was also found in neuritic plaques. The staining patterns of neuritic plaques with different isoform antibodies varied considerably. Anti-PKC(alpha) faintly stained entire plaques and surrounding glial cells; anti-PKC(beta I) stained dystrophic plaque neurites; and anti-PKC(beta II) stained the amyloid-containing portions of plaques.
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PMID:Differential involvement of protein kinase C isozymes in Alzheimer's disease. 237 71

We examined the role of phosphoinositide turnover in muscarinic rhythmic slow activity (RSA; also called theta) in rat CA3 pyramidal neurons. Pre-incubation of hippocampal slices in pertussis toxin (which inhibits some GTP-binding proteins) or in Li+ (which blocks inositol phosphate degradation, and thereby decreases the resynthesis of phosphoinositides), prevented the induction of RSA by carbachol. Phorbol esters, which can activate protein kinase C (PKC) directly, did not induce RSA but inhibited muscarinic RSA. We infer that muscarinic RSA involves a GTP-binding protein linked increase in phosphoinositide turnover, while the activation of PKC may have a negative feedback role.
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PMID:Phosphoinositides and GTP binding proteins involved in muscarinic generation of hippocampal rhythmic slow activity. 255 Aug 54

In experiments on the hippocampus in situ (in rats under urethane), neither cyclic GMP nor H-8 (an antagonist of cyclic nucleotide-dependent kinases) had much effect on CA1/CA3 population spikes or on the excitatory action of ACh. This is further evidence against the idea that cyclic nucleotides play a major role as cholinergic second messengers. On the other hand, the results of tests with a PKC antagonist sphinganine are in keeping with some involvement of PKC in cholinergic actions. (Another PKC antagonist, H-7, proved to be a very powerful excitant, probably via disinhibition). Preliminary experiments on CA1 neurons in hippocampal slices (by single electrode voltage clamp), confirmed previous reports that carbachol depresses A- and C-type K currents, as well as inward Ca2+ currents; though the latter effect was sometimes mainly due to frequency-dependent inactivation of Ca currents. It is suggested that a single, primary muscarinic action, the acceleration of phosphinositide turnover, may account for a variety of secondary effects: on the one hand, via activation of PKC, a number of possible PKC-mediated actions, such as block of the slow AHP; on the other, via IP3 formation, a block of IM and a rise in cycloplasmic free Ca2+ that may cause inactivation of both Ca2(+)-inward currents, and Ca2(+)-dependent GKs.
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PMID:Mediation of acetylcholine's excitatory actions in central neurons. 255 9


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