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 mechanism of delayed neurotoxicity, triggered by glutamate, was studied in 7-8-day-old primary cultures of rat cerebellar granule cells. Treatment of cultures for 15 min with 50 microM glutamate in Mg2+ -free medium, followed by removal of the excitoxin, resulted in neuronal death, which started to appear 2-3 hr after the termination of glutamate treatment. The number of dead neurons increased gradually in the next few hours and 80-85% of neurons were found dead 24 hr later. Antagonists of N-methyl-D-aspartate-sensitive glutamate receptors (phencyclidine) or 1.2 mM MgCl2, but not the antagonist of N-methyl-D-asparatate-insensitive glutamate receptors (6-cyano-7-nitroquinoxaline-2,3-dione), abolished the neurotoxic effect of kainate. Development of glutamate-induced neuronal death depends strongly on Ca2+. Removal of extracellular Ca2+ (with 1mM ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid) immediately after the termination of glutamate exposure and before the appearance of the early signs of neuronal death (post-glutamate period) dramatically reduced neuronal degeneration. Neurotoxic concentrations of glutamate induced sustained increase of 45Ca2+ uptake in the post-glutamate period. The delayed increase of 45Ca2+ uptake, as well as the delayed neurotoxicity, were not affected by post-glutamate treatment with phencyclidine, dibenzocyclohepteneimine; DL-2-amino-5-phosphonovalerate, or MgCl2 or with voltage-dependent Ca2+ channel blockers (nitrendipine, verapamil, diltiazem). Neurotoxic concentrations of glutamate also induced a delayed sustained increase of [3H]phorbol-12,13-dibutyrate binding, reflecting an increased translocation of protein kinase C (PKC) from cytosol to the cell membrane during the post-glutamate period. Pretreatment of neurons with the ganglioside GT1b (trisialosylgangliotetraglycosylceramide), followed by removal of free GT1b from the incubation medium, prevented PKC translocation, the sustained increase of 45Ca2+ uptake in the post-glutamate period, and the delayed neuronal death. We suggest that the sustained activation and translocation of PKC primed by glutamate receptor stimulation may be the triggering event causing the protracted increase of neuronal Ca2+ influx. This influx is insensitive to voltage-dependent Ca2+ channel blockers and glutamate receptor antagonists. It appears that this delayed increase of Ca2+ influx may be important in causing neuronal death.
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PMID:Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. 256 79

Spinal cord slice preparation and intracellular recording techniques were used to examine the effects of phorbol esters on the sodium- and calcium-dependent action potentials, the excitatory synaptic transmission, the basal (resting) and the dorsal root stimulation-evoked release of 9 endogenous amino acids, including glutamate and aspartate, and the responsiveness of the rat dorsal horn neurons to excitatory amino acids (glutamic, kainic, quisqualic, and N-methyl-D-aspartic). 4-beta-Phorbol-12, 13-dibutyrate and 4-beta-phorbol-12, 13-diacetate produced minor alterations in membrane potential and resistance, but they broadened the sodium-dependent action potential and reduced the duration of the calcium-dependent action potential. In addition, phorbol esters caused a marked and long-lasting increase in the amplitude and the duration of excitatory postsynaptic potentials (EPSPs) evoked in dorsal horn neurons by orthodromic stimulation of a lumbar dorsal root. Phorbol esters produced a brief increase in the basal and electrically evoked release of endogenous excitatory (glutamic, aspartic) and inhibitory amino acids (glycine, GABA). In addition, the rates of release of alanine, serine, and threonine were also elevated. In the presence of TTX, phorbol esters selectively enhanced, in a reversible manner, the depolarizing responses of dorsal horn neurons to N-methyl-D-aspartic acid and L-glutamate but not the responses to kainic or quisqualic acids. The potentiation of the NMDA response was blocked by APV, a specific NMDA receptor antagonist. Thus, phorbol esters appear to enhance excitatory synaptic transmission in the rat spinal dorsal horn slice preparation by acting both at pre- and postsynaptic sites. Phorbol esters could potentiate excitatory synaptic transmission by acting predominantly at a postsynaptic site (NMDA receptor), since the duration of the increased responsiveness of dorsal horn neurons to glutamate and NMDA correlates better with the enhancement of EPSPs than with the increased release of the stimulation-evoked glutamate and aspartate. The increased release of endogenous amino acids is consistent with a presynaptic (terminal) site of action, but it could also be explained by enhanced interneuronal activity. Although our results suggest that in the rat spinal dorsal horn protein kinase C may have a role in controlling the release of putative excitatory and inhibitory neurotransmitters and may also be involved in the regulation of postsynaptic NMDA receptors, the identity of endogenous substance(s) participating in these effects is presently unknown.
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PMID:Multiple effects of phorbol esters in the rat spinal dorsal horn. 257 84

LTD has now been established as a synaptic plasticity specific to the cerebellum. Cellular and molecular mechanisms of LTD have been elucidated to some extent, but still a number of questions are left open. The most crucial question may concern its time course, as to how long the LTD lasts beyond the limit of the present maximum observation time of 3 hr, and whether and how it is eventually transformed to a permanent memory. Molecular mechanisms underlying LTD should be investigated further in respect to Ca2+ binding and storage, protein kinase C, phosphorylation of glutamate receptors, GTP proteins, etc. The ineffectiveness of mass field potentials in representing LTD makes such studies relatively difficult, and a hope for future development may be placed in reproduction of LTD in tissue cultured Purkinje cells or even in isolated glutamate receptors in a simplified form. The cerebellar neuronal network incorporating LTD as a memory element has been conceived as a simple perceptron-like (Albus 1971) or adaptive filter-like (Fujita 1982a) parallel processing computer. Such a neuronal computer incorporated in a reflex or a more complex movement system would endow the system with subtle capabilities of adaptation and learning. The scheme of the floccular control of the VOR closely resembles that of a self-tuning regulator, a type of adaptive control system. For cerebellar control of voluntary movements, however, another version of the adaptive control system, the model reference control system, seems to be more applicable (Ito 1986). This system continuously readjusts its dynamics by referring to errors derived through comparison of its performance with that of an internal model. It is important to note that a model for an unknown system can be built based on the same principle, by feeding errors derived from their comparison to adjust the model. It may thus be conceived that an internal model is built within the cerebellum in the manner of model reference adaptive control, and that an internal model so formed is utilized for adaptive control of movement. A recent simulation study successfully reproduced learning in formation of an arm trajectory based on these principles of model reference control (Kawato et al 1987). On the experimental side, however, the complex neural organization for control of locomotion, posture, and voluntary movements still eludes full elucidation. Nevertheless, evidence is accumulating to support the cerebellar learning hypothesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Long-term depression. 264 61

With the use of appropriate reagents, LTP may be divided into at least two stages, induction and maintenance. Induction of LTP is dependent upon the activation of the NMDA receptor, and the consequent influx of calcium into the postsynaptic cell. Both correlational evidence (measures of PKC activity, protein F1 phosphorylation, and PI turnover) and interventive evidence (application of PKC inhibitors and activators) indicate that PKC activation is necessary for maintenance of the LTP response. An important regulatory pathway for PKC activation is the liberation of c-FAs from membrane phospholipids by PLA2. In LTP, activation of this pathway may stabilize PKC in an activated state, and thus contribute to maintenance of the potentiated response. LTP maintenance could result from presynaptic alteration (increased neurotransmitter release), postsynaptic alteration (increases in receptor number or sensitivity, or alterations of postsynaptic morphology), synapse addition, or any of these processes in combination. If LTP maintenance is mediated by presynaptic alteration, as has been indicated by measurement of glutamate release, then one must posit a signal that travels from the postsynaptic to the presynaptic membrane to activate presynaptic PKC. Alternatively, if LTP maintenance is mediated by postsynaptic alteration, a signal contained within the dendritic spine would suffice to activate postsynaptic PKC-mediated maintenance processes. We suggest that the contributions of presynaptic and postsynaptic processes to LTP maintenance may be determined by the differential distribution of PKC subtypes and substrates among hippocampal synaptic zones.
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PMID:The role of protein kinase C in long-term potentiation: a testable model. 267 42

In primary cultures of cerebellar granule cells, protein kinase C (PKC) translocation and activation can be triggered by the stimulation of excitatory amino acid neurotransmitter receptors. Glutamate evokes a dose-related translocation of 4-beta-[3H]phorbol 12,13-dibutyrate ([3H]-P(BtO)2) binding sites from the cytosol to the neuronal membrane and stimulates the incorporation of 32P into a number of membrane proteins, particularly protein bands in the range of 80, 50, and 40 kDa. The glutamate-evoked PKC translocation is Mg2+ sensitive, is prevented by 2-amino-5-phosphonovalerate and phencyclidine, is not inhibited by nitrendipine (a voltage-dependent Ca2+-channel blocker) but is abolished by the removal of Ca2+ from the incubation medium, suggesting that glutamate-mediated Ca2+ influx is operative in the redistribution of PKC. Exposure of granule cells to the gangliosides trisialosylgangliotetraglycosylceramide (GT1b) or monosialosylgangliotetraglycosylceramide (GM1) inhibits the translocation and activation of PKC evoked by glutamate. These glycosphingolipids fail to interfere with glutamate binding to its high-affinity recognition site or with the [3H]P(BtO)2 binding, nor do they affect the Ca2+ influx. These gangliosides may prevent PKC translocation by interfering with the PKC binding to the neuronal membrane phosphatidylserine.
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PMID:Ganglioside inhibition of glutamate-mediated protein kinase C translocation in primary cultures of cerebellar neurons. 282 5

In 16-18 days in vitro (DIV) primary astrocyte cultures prepared from 7- to 9-day-old rats, 48 h exposure to 12,13-phorbol dibutyrate (PDBU) (1 microM) or dibutyryl cAMP (dbcAMP) (1 mM) reduced cellular taurine content, and both basal and 50 mM K+-evoked taurine efflux, but did not alter cellular glutamate or total protein content. Decreases in cellular taurine content first became apparent between 1 and 6 h and were maximal after 24 h. Treatment also rapidly altered astrocyte morphology to a more process-bearing form within 1 h. In contrast, fibroblast growth factor (FGF), epidermal growth factor (EGF), dbcGMP and alpha-PDBU did not affect cellular morphology, amino acid content or taurine efflux at any time tested. These findings suggest that, while protein kinase C translocation and adenylate cyclase activation may be only indirectly involved in the regulation of astrocyte morphology, long-term decreases in cellular taurine content and efflux may be the more direct result of these second messenger systems.
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PMID:Phorbol ester and dibutyryl cyclic AMP reduce content and efflux of taurine in primary cerebellar astrocytes in culture. 285 22

Phorbol esters enhance synaptic transmission in the rat hippocampal slice preparation most likely by acting at a presynaptic locus. To more directly examine the actions of phorbol esters on neurotransmitter release we have measured their effects on the occurrence of spontaneous postsynaptic potentials as well as on the potassium stimulated release of endogenous glutamate. Both measures of transmitter release were increased by phorbol esters suggesting a functional or regulatory role for protein kinase C in controlling the release of neurotransmitter in the mammalian CNS.
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PMID:Phorbol esters enhance transmitter release in rat hippocampal slices. 288 5

The effects of phorbol esters on neurotransmitter-stimulated phosphoinositide (PI) hydrolysis in neurons in primary culture were investigated. Ten-day-old neuronal cultures were incubated with [3H]inositol for 2-3 days, exposed to phorbol esters, and the release of [3H]inositol phosphates was measured in the presence of 10 mM lithium. Pretreatment of the neuronal cultures with 1 microM phorbol myristate acetate (PMA) inhibited alpha 1, muscarinic, and glutamate receptor-mediated PI hydrolysis in a time-dependent manner with maximal inhibition observed after a 20-30 min preincubation. The active beta-phorbol didecanoate inhibited stimulated PI hydrolysis, but its stereo-isomer alpha-phorbol didecanoate was without effect at 1 microM. PMA was about 10 times more potent at inhibiting PI hydrolysis stimulated by norepinephrine and glutamate compared to carbachol. The order of potency of the various phorbol esters for inhibition of stimulated PI hydrolysis and the differences between active and inactive stereoisomers suggests that the activation of protein kinase C may mediate the inhibitory effects. Thus, stimulation of neuronal protein kinase C may represent a mechanism for the regulation of agonist-stimulated PI hydrolysis.
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PMID:Phorbol esters inhibit agonist-stimulated phosphoinositide hydrolysis in neuronal primary cultures. 289 35

1. Actions of protein kinase C activators, 1,2-oleoylacetylglycerol (OAG) and 12-O-tetradecanoylphorbol-13-acetate (TPA), on the glutamate-mediated neuromuscular transmission in the mealworm, Tenebrio molitor, were studied by the microelectrode current-clamp and voltage-clamp techniques. 2. The activators OAG and TPA stimulate the evoked and spontaneous transmitter releases from the presynaptic terminal, as evidenced by an increase in the quantum content estimated by the number of failures of extracellular excitatory postsynaptic potentials (EPSPs), and in the frequency of miniature EPSPs. 3. Both OAG and TPA act on the postsynaptic membrane to enhance responses to the transmitter L-glutamate. Protein kinase C activators increased the apparent maximum of the ionophoretic dose-response curve for glutamate-induced depolarization, without affecting the reversal potential and the voltage-dependent decay rate for the excitatory postsynaptic current (EPSC) under voltage-clamp conditions. 4. The postsynaptic effect of OAG and TPA is distinctly different from that of activators of cyclic nucleotide-dependent protein kinases, such as octopamine, forskolin, CPT-cyclic AMP (8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate), and 8-bromo-cyclic GMP (8-bromoguanosine 3',5'-cyclic monophosphate) which decreased the postsynaptic sensitivity to L-glutamate. 5. I suggest that the responsiveness of the receptor to L-glutamate is under the control of these counteracting enzyme systems in the insect neuromuscular junction.
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PMID:Activation of protein kinase C promotes glutamate-mediated transmission at the neuromuscular junction of the mealworm. 290 91

Using a sensitive histofluorescence staining method that allows for a quantitation of neuronal death, we compared the protective effects of gangliosides (a group of naturally occurring glycosphingolipids), phencyclidine (PCP), and MK-801 (dibenzocyclohepteneimine) on glutamate- and kainate-induced neuronal death in primary cultures of cortical and cerebellar neurons prepared from neonatal rats. PCP and MK-801 block neurotoxicity induced by glutamate doses 50 times higher than the LD50 (LD50 in Mg2+-free medium, 10 microM) but only partially block the kainate neurotoxicity (LD50 in presence of Mg2+, 100 microM). In contrast, pretreatment with gangliosides (GT1b greater than GD1b greater than GM1) results in complete and insurmountable protection against the neurotoxicity elicited by glutamate or kainate. In primary cultures of cerebellar granule cells gangliosides, unlike PCP and MK-801, fail to block glutamate-gated cationic currents and the glutamate-evoked increase of (i) inositol phospholipid hydrolysis (ii) c-fos mRNA content, and (iii) nuclear accumulation of c-fos protein. Protection of glutamate neurotoxicity by gangliosides does not require their presence in the incubation medium; however, it is proportional to the amount of glycosphingolipid accumulated in the neuronal membranes. The ganglioside concentration (30-60 microM) that blocks glutamate-elicited neuronal death also prevents glutamate- and kainate-induced protein kinase C translocation from cytosol to neuronal membranes.
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PMID:Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. 290 28


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