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)

Long-term potentiation (LTP) is an example of a persistent change in synaptic function in the mammalian brain, thought to be essential for learning and memory. At the synapse between hippocampal CA3 and CA1 neurons LTP is induced by a Ca2+ influx through glutamate receptors of the NMDA (N-methyl-D-aspartate) type (see Collingridge et al 1992, this volume). How does a rise in [Ca2+]i lead to enhancement of synaptic function? We have tested the popular hypothesis that Ca2+ acts via a Ca(2+)-dependent protein kinase. We found that long-lasting synaptic enhancement was prevented by prior intracellular injection of potent and selective inhibitory peptide blockers of either protein kinase C (PKC) or Ca2+/calmodulin-dependent protein kinase II (CaMKII), such as PKC(19-31) or CaMKII(273-302), but not by control peptides. Evidently, activity of both PKC and CaMKII is somehow necessary for the postsynaptic induction of LTP. To determine if these kinases are also involved in the expression of LTP, we impaled cells with microelectrodes containing protein kinase inhibitors after LTP had already been induced. Strikingly, established LTP was not suppressed by a combination of PKC and CaMKII blocking peptides, or by intracellular postsynaptic H-7. However, established LTP remained sensitive to bath application of H-7. Thus, the persistent signal may be a persistent kinase, but if so, the kinase cannot be accessed within the postsynaptic cell. Evidence for a presynaptic locus of expression comes from our studies of quantal synaptic transmission under whole-cell voltage clamp. We find changes in synaptic variability expected to result from enhanced presynaptic transmitter release, but little or no increase in quantal size. Furthermore, miniature synaptic currents in hippocampal cultures are increased in frequency but not amplitude as a result of a glutamate-driven postsynaptic induction. The combination of postsynaptic induction and presynaptic expression necessitates a retrograde signal from the postsynaptic cell to the presynaptic terminal.
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PMID:Persistent signalling and changes in presynaptic function in long-term potentiation. 132 79

1. Intracellular microelectrode recordings were used to study the cellular location, pharmacology, and mechanism of action of gamma-aminobutyric acidB (GABAB) receptors on pyramidal cells and presynaptic axonal endings in area CA3 of organotypic hippocampal slice cultures. 2. Baclofen (bath applied at 10 microM) caused a 10-15 mV hyperpolarization of CA3 cells and a 75-100% decrease in the amplitude of excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Baclofen reduced the amplitude of monosynaptic IPSPs elicited in the presence of excitatory amino acid receptor antagonists, as well as the amplitude of EPSPs elicited after blocking GABAA receptors and reducing subsequent epileptic bursts with excitatory amino acid receptor antagonists. These data indicate that GABAB receptors are located on both excitatory and inhibitory presynaptic elements. 3. The GABAB receptor antagonist CGP 35 348 blocked the postsynaptic action of baclofen, the late IPSP, and the reduction of EPSPs and monosynaptic IPSPs by baclofen. 3-Aminopropylphosphinic acid (3-APA) mimicked all the pre- and postsynaptic actions of baclofen, and its effects were fully antagonized by CGP 35 348. 4. Incubation of cultures with pertussis toxin (500 ng/ml for 48 h) prevented both the postsynaptic hyperpolarization and the block of monosynaptic IPSPs induced by baclofen. The action of baclofen on isolated EPSPs, however, was not affected by pertussis toxin treatment. Stimulation of protein kinase C with phorbol ester (phorbol 12, 13 dibutyrate, 1 microM for 10 min) reduced all pre- and postsynaptic effects of GABAB receptor activation. 5. Barium (bath applied at 1 mM) prevented both the baclofen-induced hyperpolarization of pyramidal cells and the block of monosynaptic IPSPs by baclofen. In the presence of barium, however, baclofen was fully capable of blocking EPSPs. 6. We conclude that pre- and postsynaptic GABAB receptors are pharmacologically indistinguishable, at present, and that all actions of GABAB receptors are inhibited by stimulation of protein kinase C. Both the postsynaptic action of baclofen and the block of GABA release from interneurons are mediated by pertussis toxin-sensitive G proteins which can be inactivated by stimulation of protein kinase C. Baclofen acts at postsynaptic sites and on the axon terminals of inhibitory interneurons by activating the same barium-sensitive K+ conductance. GABAB receptors on excitatory axons must, however, work through some other mechanism.
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PMID:Comparison of the actions of baclofen at pre- and postsynaptic receptors in the rat hippocampus in vitro. 132 19

The Mongolian gerbil was used as a model of aging because of its relatively short lifespan, genetic homogeneity and the fact that data had been collected previously. Furthermore, gerbils have been widely used in biomedical investigations of stroke and epilepsy. Age-related differences in signal transmission and transduction systems were investigated in brains of three-, 11- and 21-month-old gerbils by morphological and in vitro receptor autoradiographic studies. Morphometric analysis revealed a decreased number of neurons in layer III of the occipital cortex and also a decrease in cerebellar Purkinje cells in 21-month-old animals. However, no statistical differences were observed in the hippocampal formation, the dorsolateral striatum and layer III of the frontal cortex. Autoradiography was used to map muscarinic cholinergic (labeled with [3H]quinuclidinyl benzilate), serotonin2 ([3H]spiperone), dopamine D2 ([3H]spiperone), adenosine A1 ([3H]cyclohexyladenosine), GABAA ([3H]muscimol), naloxone ([3H]naloxone), protein kinase C ([3H]phorbol 12,13-dibutyrate), adenylate cyclase ([3H]forskolin), cyclic AMP ([3H]cyclic AMP) and L-type Ca2+ channels ([3H]PN200-110). Muscarinic cholinergic receptor and protein kinase C, cyclic AMP and L-type Ca2+ channels were significantly decreased in the cerebral cortex and/or in the CA1 subfield of the hippocampus in the 21-month-old group. Muscarinic cholinergic receptor and L-type Ca2+ channel binding sites were significantly reduced in the dentate gyrus. In contrast, protein kinase C was increased in this area in the 21-month-old group. Also, naloxone binding sites were increased in the CA3 subfield, hilus, dentate gyrus and molecular layer of the cerebellum in the 11- and 21-month-old groups. Muscarinic cholinergic, serotonin2 and dopamine D2 receptors and adenylate cyclase were significantly decreased in the striatum. On the other hand, adenosine A1 and GABAA receptors remained unchanged in the 21-month-old group. Although age-related histopathological abnormalities were only observed in the occipital cortex and in the cerebellum, alterations of signal transmission and transduction systems were noticed in all areas examined (e.g. cerebral cortex, CA1 subfield, dentate gyrus and striatum). These data indicate that changes in these receptors and binding sites may be related to dysfunction of learning and memory and to the loss of motor function. The aged gerbil model is a good system for studying aging and is of value for simulating aging after epilepsy and stroke.
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PMID:Effects of aging on signal transmission and transduction systems in the gerbil brain: morphological and autoradiographic study. 134 8

We have shown that bifemelane augments long-term potentiation in the mossy fiber-CA3 system, but not in the Schaffer collateral-CA1 system. To elucidate the mechanism of action of bifemelane in relation to pathway-specific augmentation of long-term potentiation, we prepared a mossy fiber terminal-rich synaptosomal fraction (P3) from guinea-pig hippocampus and investigated the effect of bifemelane on the release of glutamate from these synaptosomes, using an in vitro superfusion technique. Bifemelane (0.01-1 microM) dose dependently increased the 30 mM K(+)-evoked release of glutamate from the P3 fraction, without affecting glutamate release from a conventional synaptosomal P2 fraction. This stimulatory effect of 1 microM bifemelane was abolished by 100 microM H-7, which also suppressed the increase in K(+)-evoked glutamate release by phorbol 12,13-dibutyrate (1 microM). Bifemelane (1 microM) induced the translocation of protein kinase C activity from cytosol to membrane in the P3 fraction (which contains large and irregular-shaped synaptosomes probably derived from mossy fiber terminals), but not in the P2 fraction. These findings suggest that bifemelane directly acts on mossy fiber terminals to potentiate depolarization-induced glutamate release, which may be at least partly mediated by the translocation (activation) of protein kinase C.
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PMID:Bifemelane enhances high K(+)-evoked release of glutamate from mossy fiber synaptosomes of guinea-pig hippocampus. 135 42

The alterations of second-messenger ligand binding and cerebral blood flow (CBF) were evaluated in the gerbil brain after 2-h unilateral common carotid artery occlusion. [3H]Forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu) were used as specific ligands for adenylate cyclase (AC) and protein kinase C (PKC) activity estimation, respectively. CBF was determined at the end of the experiment by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted simultaneous measurement of the three parameters in the same brain. The levels in the caudate-putamen, globus pallidus, and hippocampus were analyzed. The animals were divided into three groups: Group 1 with severe ischemia (CBF in the lateral nuclei of the thalamus (CBFt) less than 50 ml/100 g/min), Group 2 with mild ischemia (CBFt greater than or equal to 50 ml/100 g/min), and the Sham Group. The PDBu binding revealed a statistically significant increase in the caudate-putamen, lateral nuclei of the thalamus and hippocampus (CA1 and CA3 regions and dentate gyrus) on the ischemic side in Group 1 as compared to that in Group 2 and the Sham Group. In contrast, the FK binding did not show any significant changes in any of the regions. These data and our previous findings for 6-h ischemia suggest that (1) PKC translocation to the cell membrane may occur at the early ischemic phase in particular regions including the caudate-putamen, lateral nuclei of the thalamus and hippocampus, with the translocated PKC gradually diminishing during the subsequent ischemic period; and (2) the suppression of the AC system observed in 6-h ischemia may not appear in the early ischemic phase.
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PMID:Alteration of second-messenger ligand binding following 2-hr hemispheric ischemia in the gerbil brain. 139 61

1. Intracellular microelectrode recordings were used to study the cellular location, the receptor pharmacology, and the mechanism of action of adenosine on pyramidal cells and presynaptic axonal endings in area CA3 of organotypic hippocampal slice cultures. 2. Adenosine (bath applied at 50 microM) caused a 10-15 mV hyperpolarization of CA3 cells, as well as a 75-100% decrease in the amplitude of excitatory and polysynaptic inhibitory postsynaptic potentials (EPSPs and IPSPs). Adenosine had no effect on the amplitude of monosynaptic IPSPs elicited in the presence of excitatory amino acid receptor antagonists, but did reduce the amplitude of isolated EPSPs, elicited after blocking GABAA receptors and reducing subsequent epileptic bursts with excitatory amino acid receptor antagonists. These data indicate that adenosine receptors are located on excitatory, but not inhibitory, presynaptic elements. 3. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, bath applied at 200 nM) blocked the pre- and postsynaptic actions of adenosine. DPCPX had no effect on the amplitude of control synaptic responses, suggesting that there is no tonic activation of adenosine receptors in hippocampal slice cultures under control conditions. The A1 receptor agonists R-N6-phenylisopropyladenosine (R-PIA) mimicked all pre- and postsynaptic actions of adenosine. 4. Pertussis toxin pretreatment (500 ng/ml for 48 h) prevented adenosine from activating postsynaptic K+ conductance, but not from inhibiting EPSPs. In contrast, stimulation of protein kinase C with phorbol ester (phorbol 12, 13-dibutyrate, 1 microM for 10 min) reduced the presynaptic, but not the postsynaptic, actions of adenosine. 5. Barium (bath applied at 1 mM) blocked the adenosine-activated K+ conductance, but not the inhibition of isolated EPSPs by adenosine. 6. Adenosine at 0.03-1 microM reduced the frequency of, or blocked, spontaneous epileptiform bursting produced by bicuculline. DPCPX (200 nM) increased the rate of spontaneous bursting, consistent with a tonic activation of adenosine receptors during hyperactivity, and led to the development of prolonged ictal-like bursts, suggesting that the endogenous release of adenosine may contribute to the termination of epileptic bursts. 7. We conclude that adenosine acts at pre- and postsynaptic receptors which are pharmacologically indistinguishable. Postsynaptically, adenosine increases a barium-sensitive K+ conductance via a pertussis toxin-sensitive GTP-binding protein. The presynaptic action of adenosine must, however, be mediated by some other mechanism.
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PMID:Comparison of the actions of adenosine at pre- and postsynaptic receptors in the rat hippocampus in vitro. 140 15

We used monoclonal antibodies to examine the immunohistochemical distribution of the three major Ca(2+)-dependent protein kinase C (PKC) isozymes (I, II, and III) in ischemic gerbil hippocampus. Groups of four animals were sacrificed at 15 min, 4 h, 1 day, 2 days, 3 days, and 7 days after a 10-min episode of global forebrain ischemia. In control animals, PKC-I immunoreactivity was greater in CA1 neurons than in CA3-4. Terminal-like staining was not evident. PKC-II immunoreactivity was observed in all CA fields and in the outer molecular layer of the dentate gyrus. PKC-III staining was present in the CA fields, the inner molecular layer of the dentate gyrus and the subiculum. Dentate granule cells and mossy fibers were not stained with any of the PKC antibodies. Fifteen minutes and 4 h after ischemia, PCK-I, -II and -III immunoreactivity were all increased in CA1 neurons and PKC-III immunoreactivity alone was visualized in granule cells and mossy fibers. Staining patterns returned to baseline one day after ischemia. PKC-II and -III terminal-like staining were preserved in the stratum lacunosum-moleculare for 3 days and 2 days after ischemia respectively and then disappeared. The altered patterns of PKC staining in the hippocampus may reflect activation and/or down-regulation of PKC isozymes. Ca(2+)-dependent PKC isozymes may, therefore, potentially play a role in the pathogenesis of delayed ischemic neuronal death.
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PMID:Immunohistochemical distribution of protein kinase C isozymes is differentially altered in ischemic gerbil hippocampus. 152 42

Changes in second messenger and neurotransmitter system receptor ligand binding induced by transient forebrain ischemia were studied in the gerbil hippocampus. The animals were allowed variable periods of recovery ranging from 2 h to 7 days after 5-min bilateral carotid artery occlusion. The binding of second messenger systems ([3H]inositol 1,4,5-trisphosphate ([3H]IP3)to inositol 1,4,5-triphosphate, [3H]forskolin to adenylate cyclase and [3H]phorbol 12,13-dibutylate to protein kinase C) and neurotransmitter receptor systems ([3H]PN200-110 to L-type calcium channels. [3H]N6-cyclohexyl-adenosine to adenosine A1 and [3H]quinuclidinyl benzilate to muscarinic cholinergic receptor) were assayed using quantitative autoradiography. In the CA1 subfield, 2 h after ischemia, [3H]IP3, [3H]forskolin, and [3H]quinuclidinyl benzilate binding activities significantly decreased by 25, 17 and 13%, respectively, though no morphological abnormalities were obvious. Six hours after ischemia, the [3H]phorbol 12,13-dibutylate binding activity in the stratum oriens of the CA1 subfield increased by 15%. One day after ischemia, [3H]PN200-110 binding activity in this subfield decreased by 26%, and 7 days after ischemia, [3H]phorbol 12,13-dibutylate and [3H]N6-cyclohexyl-adenosine receptor binding activities decreased in this subfield. In particular, at 7 days after ischemia, [3H]IP3 binding activity in the CA1 subfield showed a complete decline. In the CA3 subfield, [3H]PN200-110 binding activity decreased 2 days after ischemia, and [3H]IP3 and [3H]N6-cyclohexyl-adenosine binding activities decreased 7 days after ischemia. In the dentate gyrus, the structure of which remained histologically intact after ischemic insult, [3H]IP3 and [3H]forskolin binding activities decreased 7 days after ischemia. In contrast, the [3H]phorbol 12,13-dibutylate binding activity increased in the molecular layer of the dentate gyrus 7 days after ischemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 subfield and that the histologically intact CA3 and dentate gyrus also shows modulated neuronal transmission after ischemia.
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PMID:Autoradiographic analysis of second messenger and neurotransmitter system receptors in the gerbil hippocampus following transient forebrain ischemia. 165 Feb 82

This study compares the distribution of protein kinase C (PKC) alpha and beta with the distribution of PKC epsilon in the hippocampal formation of rats by immunocytochemistry and in situ hybridization histochemistry. Alpha and PKC beta are members of the group A PKC genes that were first described; PKC epsilon is a member of the group B PKC genes that were more recently identified by molecular cloning. A combination of all three gene products and their mRNAs overlapped in their distributions in dentate granule cells and pyramidal and nonpyramidal neurons. However, each subspecies predominated in one of the major cell types. PKC alpha-immunoreactivity and mRNA were most intense in CA2-3 pyramidal cells and dendrites, whereas PKC beta-immunoreactivity and mRNA were most intense in CA1 pyramidal cells and dendrites. PKC epsilon-immunoreactivity and mRNA were concentrated in dentate granule cells and CA3 pyramidal cells. Furthermore, PKC epsilon-immunoreactivity was detectable in mossy fibers. Each subspecies labeled different kinds of interneurons that were particularly numerous in, but not restricted to, the hilus. These data support the contention that different subtypes of hippocampal neurons are distinguished by the expression of different combinations of PKC subspecies under resting conditions.
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PMID:Protein kinase C subspecies distinguish major cell types in rat hippocampus: an immunocytochemical and in situ hybridization histochemical study. 166 11

In-vitro quantitative receptor autoradiography with [3H]phorbol 12,13-dibutyrate (PDBu) was used to determine the affinity constant (Kd) and the maximum number of receptor sites (Bmax) for protein kinase C (PKC) in subregions of the gerbil hippocampus, and to compare the distribution of [3H]PDBu binding sites in the gerbil hippocampus with that in the rat hippocampus. The Kd and Bmax values in the subregions of the gerbil hippocampus were estimated at 2.6-3.8 nM and 2.38-2.54 pmol (mg tissue)-1, respectively. The distribution of hippocampus [3H]PDBu binding sites was uniform in the gerbil but not in the rat. The [3H]PDBu binding activities in the strata oriens of the CA1 and CA3 subfields and the molecular layer of the dentate gyrus in the rat hippocampus were significantly higher than in the gerbil hippocampus. However, binding activity in the stratum lacunosum-moleculare of the rat CA1 subfield was statistically lower. These data demonstrate a difference in the distribution of [3H]PDBu binding activity in the hippocampus between the gerbil and rat.
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PMID:Distribution of protein kinase C in the hippocampus of the gerbil and rat: autoradiographic analysis by [3H]phorbol 12,13-dibutyrate. 168 2


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