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)

The physiological characteristics and significance of long-term potentiation in the hippocampus were summarized. In particular, it was pointed out that different mechanisms are involved in the production of hippocampal LTP between the mossy fiber-CA3 system and other systems such as Schaffer collateral-CA1, fimbrial fiber-CA3 and commissural/associational fiber-CA3. Furthermore, the epsilon-subspecies of protein kinase C (PKC) was demonstrated to be exclusively located at the presynaptic terminals in the hippocampus and activated by arachidonic acid, and this enzyme is suggested to be involved in the production of LTP through a phosphorylation of GAP-43, while the gamma-subspecies of PKC may be postsynaptically involved in LTP through an activation of NMDAR1. The production of LTP in the hippocampus is facilitated by many factors such as epidermal growth factor, fibroblast growth factors, somatostatin, M1 receptor agonists and many drugs like anirasetam, bifemelane, idebenone, indeloxazine and vinpocetine, but inhibited by M2-receptor agonists, scopolamine and midazolam. In addition to electrophysiological methods, LTP-like phenomena in 2-deoxyglucose uptake and leucine incorporation can be detected. These LTP phenomena in several animal models will be useful as indices for evaluating facilitatory actions of various compounds on learning/memory functions.
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PMID:[Pharmacology of long-term potentiation]. 810 51

We used oligonucleotide in situ hybridization and film autoradiography to quantitate the distributions of protein kinase C (PKC) alpha, beta, gamma, and epsilon mRNAs in subregions of rabbit hippocampus. Levels of each of the hippocampal PKC isozyme mRNAs and patterns of their regional distributions were remarkably invariant between individuals. Within stratum pyramidale, the highest levels of PKC alpha mRNA were in the CA2 region, while PKC beta mRNA was maximally expressed in CA1, and PKC epsilon mRNA in CA3; PKC gamma mRNA was abundantly expressed throughout Ammon's horn. Previous experiments employing quantitative autoradiography for [3H]PDBU (Olds et al., Science, 245 (1989) 866-869) revealed an increase in membrane-bound PKC in the CA1 region of rabbit hippocampus up to 3 days following classical conditioning of the nictitating membrane response. We report here that there were no differences in levels of PKC alpha, beta, gamma, or epsilon mRNA between conditioned and control rabbits in any hippocampal region one day after training. These data are consistent with the hypothesis that PKC is post-translationally activated and translocated to the membrane during memory storage.
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PMID:Quantitative distribution of protein kinase C alpha, beta, gamma, and epsilon mRNAs in the hippocampus of control and nictitating membrane conditioned rabbits. 823 30

The mRNA levels of protein F1 (also known as GAP-43), and protein kinase C (PKC) subtypes were measured 3 days after the induction of long-term enhancement (also known as long-term potentiation) in the hippocampus of chronically prepared conscious rats by quantitative in situ hybridization. Altered mRNA levels correlated significantly with alternations in synaptic efficacy; such correlations have not been reported previously. Rats with greater synaptic enhancement had lower gene expression in the CA3 subfield of F1/GAP-43 and both beta-PKC and gamma-PKC, but not alpha-PKC. For microtubule-associated protein 2 (MAP-2), neurogranin, and the glutamate receptor subtype B-flip, no correlation was observed in any cell field between synaptic enhancement and hybridization to the mRNA. To our surprise, alterations in mRNA levels of F1/GAP-43 and gamma-PKC were highly correlated (r = +0.928, P < 0.001), suggesting coordinate regulation. Since F1/GAP-43 is associated with neurite growth, its lowered expression at 3 days would reduce potential growth, leading to synaptic stabilization. We propose that long-term synaptic change is mediated by gene expression of the very same proteins initially modified posttranslationally.
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PMID:Protein kinase C and F1/GAP-43 gene expression in hippocampus inversely related to synaptic enhancement lasting 3 days. 826 69

1. The electrophysiological action of the mu-opioid receptor-preferring agonist D-Ala2, MePhe4, Met(O)5-ol-enkephalin (FK 33-824) on synaptic transmission has been studied in area CA3 of organotypic rat hippocampal slice cultures. 2. FK 33-824 (1 microM) had no effect on the amplitude of pharmacologically isolated N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated EPSPs. 3. FK 33-824 (10 nM to 10 microM) reduced the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) that were elicited in pyramidal cells with local stimulation after pharmacological blockade of excitatory amino acid receptors. This effect was reversible, dose-dependent, and sensitive to naloxone and the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP). FK 33-824 at 1 microM caused a mean reduction in the amplitude of the monosynaptic IPSP of 70%. 4. Neither delta- nor kappa-receptor-preferring agonists had any effect on excitatory or inhibitory synaptic potentials. 5. The disinhibitory action of FK 33-824 was blocked by incubating the cultures with pertussis toxin (500 ng/ml for 48 h) or by stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu, 0.5 microM). 6. The depression of monosynaptic IPSPs by FK 33-824 was unaffected by extracellular application of the K+ channel blockers Ba2+ or Cs+ (1 mM each). 7. FK 33-824 produced a decrease in the frequency of miniature, action potential-independent, spontaneous inhibitory synaptic currents (mIPSCs) recorded with whole-cell voltage-clamp techniques, but did not change their mean amplitude. Application of the Ca2+ channel blocker Cd2+ (100 microM) or of nominally Ca(2+)-free solutions did not alter either the frequency and amplitude of mIPSCs or the reduction of mIPSC frequency induced by FK 33-824. 8. The effect of FK 33-824 on spontaneous mIPSCs was prevented by naloxone, and by incubation of cultures with pertussis toxin. 9. These results indicate that mu-opioid receptors decrease GABA release presynaptically by a G protein-mediated inhibition of the vesicular GABA release process, and not by changes in axon terminal K+ or Ca2+ conductances that are sensitive to extracellular Ba2+, Cs+ or Cd2+.
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PMID:Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. 830 42

Fast synaptic transmission in the central nervous system can be modulated by neurotransmitters and second-messenger pathways. For example, transmission at glutamatergic synapses can be depressed by the metabotropic glutamate receptor, providing autoreceptor-mediated negative feedback. Metabotropic glutamate receptor inhibition of Ca2+ channels may contribute to this pathway. In contrast, stimulation of protein kinase C can enhance excitatory synaptic transmission, whereas both depression and enhancement of Ca2+ current have been reported. Here we show that in hippocampal CA3 and cortical pyramidal neurons, activation of protein kinase C enhances current through N-type Ca2+ channels and, in addition, dramatically reduces G protein-dependent inhibition of these same channels by the metabotropic glutamate receptor. In parallel experiments on fast excitatory transmission at corticostriatal synapses, kinase C activators were similarly found to reduce the inhibitory effect produced by stimulation of the metabotropic glutamate receptor. The results show that second-to-second control of Ca2+ channels by the metabotropic glutamate receptor can itself be modulated on a slower timescale by protein kinase C. These mechanisms may be used in the control of fast excitatory synaptic transmission.
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PMID:Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission. 838 Jun 26

The transient activation of the N-methyl-D-aspartate (NMDA) receptor system by high frequency (tetanic) stimulation results in a rapidly developing and long-lasting potentiation of synaptic transmission in the CA1 region of the hippocampus. This potentiation can be divided into an early decremental component, known as short-term potentiation (STP), and a more slowly developing persistent phase, termed long-term potentiation (LTP). Here we describe how activation of metabotropic glutamate receptors (mGluRs), by aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD), can induce the same stable form of LTP, but without the STP component. 1S,3R-ACPD-induced LTP does not require electrical stimulation during its induction, but is dependent on an intact connection between the CA3 and CA1 regions of the hippocampus. 1S,3R-ACPD-induced LTP circumvents the need for the activation of NMDA receptors and is likely to involve both the stimulation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores.
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PMID:Characterisation of LTP induced by the activation of glutamate metabotropic receptors in area CA1 of the hippocampus. 838 24

The effects of immobilization stress on the cerebral second messenger (adenylate cyclase and phosphoinositide) were investigated autoradiographically in mongolian gerbils. After 10 min (10-min stress group, n = 7), or after 6 h (6-h stress group, n = 7) of fixation on a flat board while supine, in vitro autoradiography was performed using [3H]forskolin (3H-FK) and [3H]phorbol-12,13-dibutyrate (3H-PDBu) as specific ligands to identify the distribution of adenylate cyclase and protein kinase C, respectively. In another group of 7 gerbils (control group), the same autoradiographic procedure was performed immediately after the animals were removed from the cage. In the 10-min stress group, FK binding was significantly decreased in the hypothalamus and amygdala, but significantly increased in the basal ganglia including the caudate-putamen and globus pallidus. FK binding in the 6-h stress group tended to increase throughout the brain, rising significantly in the basal ganglia. PDBu binding in either stress group did not change significantly compared to the control group in any region except the hippocampal CA3 region of the 6-h stress group. Under immobilization stress, the adenylate cyclase system may undergo time-dependent and regionally specific changes, while the phosphoinositide system remains relatively stable.
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PMID:Immobilization stress induces alterations of second-messenger systems in the gerbil brain. 841 15

GAP-43 (B-50,F1, pp46) is a calmodulin binding protein which is specific to the nervous system and also a substrate for the protein kinase C. Furthermore an enrichment of this protein in the growth cone and developmental brain indicate that this protein is related to nerve development, regeneration, and outgrowth. While its level dramatically decreases after the completion of synaptogenesis, the protein is still to some extent continuously expressed in certain regions of the mature brain. In order to clarify GAP-43 localization in mature normal rats, we investigated the distribution of GAP-43 mRNA in the rat central nervous system by using a non-radioisotopic in situ hybridization histochemistry. This method demonstrated GAP-43 mRNA expressing cells with high resolution. GAP-43 mRNA was more abundant in the forebrain than in the lower brainstem. Intense hybridization signal was observed in the mitral cells of olfactory bulb, cerebral cortex, CA3 region of hippocampus, diagonal band, substantia nigra, raphe nuclei, locus coeruleus, and dorsal motor nucleus of vagus. Weak to moderate hybridization signals were also widely expressed in thalamus, hypothalamus, and midbrain. Moreover, most noradrenergic, adrenergic, serotonergic, histaminergic, and caudal part of dopaminergic cells exhibited an intense GAP-43 mRNA signal. Thus, GAP-43 mRNA is abundantly expressed under normal conditions in the brain and may play an important physiological role particularly in the forebrain and in monoaminergic neurons supporting the findings that GAP-43 could be implicated in plasticity and monoamine release.
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PMID:Distribution of GAP-43 (B50/F1) mRNA in the adult rat brain by in situ hybridization using an alkaline phosphatase labeled probe. 847 78

The cellular and intracellular localization of the epsilon-subspecies of protein kinase C (PKC) in the rat brain was demonstrated by immunocytochemistry using specific antibodies against epsilon-PKC. The epsilon-PKC-specific immunoreactivity was most abundant in the hippocampal formation, olfactory tubercle and Calleja's islands, was moderate in the cerebral cortex, anterior olfactory nuclei, accumbens nucleus, lateral septal nuclei and caudate-putamen and low in the thalamus and medulla. The epsilon-PKC-immunoreactivity was scanty in the perikarya, except for the pyramidal cells of CA3 region of the hippocampus and the immunoreactivity was mainly present in neuropils and nerve fibers. The distribution of epsilon-PKC immunoreactive neurons was consistent with that obtained by in situ hybridization histochemistry. Electron microscopic observations of the hippocampus revealed that the epsilon-PKC is predominantly present in the cytoplasm of axon and nerve terminals and that this enzyme is associated with mitochondrial membrane and vesicles. These results suggested that epsilon-PKC is probably involved in presynaptic functions in CNS, perhaps even neurotransmitter release.
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PMID:Cellular and intracellular localization of epsilon-subspecies of protein kinase C in the rat brain; presynaptic localization of the epsilon-subspecies. 848

There is strong evidence that ATP acts as an excitatory neurotransmitter in the periphery, yet little is known about fast central ATP-mediated transmission. We report here the molecular cloning of a novel neuronal ionotropic ATP receptor of the P2x subtype (P2x3) isolated from rat brain. This central P2x channel subunit has significant amino acid homology with two recently cloned ATP-gated channels from rat smooth muscle (47%) and pheochromocytoma PC12 cells (37%). P2x3 receptor contains the characteristic 10 conserved cysteines of ATP-gated channels, a putative extracellular region homologous to the Walker type A motif found in various nucleotide-binding proteins, and two potential sites for phosphorylation by protein kinase C. Homomeric receptor P2x3 channels expressed in Xenopus oocytes produce rapid cation-selective purinergic currents that are potentiated by zinc ions and reversibly blocked by the P2x antagonists suramin, Reactive Blue 2, and pyridoxalphosphate-6-axophenyl-2U,4U-disulfonic acid. P2x3-receptor subunit mRNA is found in the Purkinje cells and the granule cells of the cerebellum as well as in CA3 pyramidal cells of the hippocampus that are innervated by zinc-rich axon terminals of mossy fibers. Our results suggest that fast excitatory synaptic transmission mediated by zinc-sensitive ATP-gated channels is widespread in mammalian brain.
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PMID:A novel neuronal P2x ATP receptor ion channel with widespread distribution in the brain. 855 29


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