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)

From experiments using dissociated primary astroglial cultures from newborn rat cerebral cortex, the stimulation of monoamine receptors (alpha, beta and 5HT) was shown to affect the high-affinity uptake kinetics of glutamate, GABA and taurine. In the presence of the alpha 1 agonist phenylephrine, there was an increased uptake (Vmax) of glutamate, while beta adrenoceptor activation slightly inhibited the glutamate uptake and stimulated the GABA and taurine uptakes. 5HT2 receptor stimulation caused a slight inhibition of the taurine uptake. The uptake rate of GABA was not affected by 5HT, alpha 1 or alpha 2 receptor agonists and the glutamate uptake was not affected by 5HT or alpha 2 receptor agonists. Nor was the taurine uptake affected by alpha 1 or alpha 2 receptor agonists. The active uptake of aspartate was unaffected by the presence of any of the monoamine receptor agonists used in this study. When the mechanisms behind these effects were studied, the GABA uptake seemed to be mediated via the G protein-adenylate cyclase complex in the receptor domain. Moreover, the K+ channels seemed to be involved. The taurine uptake, however, did not seem to be regulated by the same mechanism. It seems more probable that there is a direct interaction between the receptor and carrier of taurine at the membrane level. The mechanism underlying the receptor-regulated glutamate uptake is at present unclear, although it does not seem to involve protein kinase C.
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PMID:Receptor regulation of the glutamate, GABA and taurine high-affinity uptake into astrocytes in primary culture. 167 95

The regulation of second-messenger production and protein phosphorylation by glutamate has been investigated in primary cultures of pure hippocampal pyramidal neurons. Embryonic rat pyramidal neurons were prepared according to the procedures of Bartlett and Banker (1984) and studied 1-21 d after plating. Glutamate caused a transient increase in intracellular free [Ca2+], determined with fura-2, in the presence of 1.26 mM extracellular Ca2+, but not in 50 nM free Ca(2+)-containing solution. Glutamate also transiently increased cellular diacylglycerol content in both normal and low-[Ca2+] media. Neurons were prelabeled with 32P-orthophosphate to label intracellular ATP, then stimulated with glutamate (100 microM). A rapid transient incorporation of 32P into primarily three proteins of 120, 87, and 48 kDa was found by analysis of two-dimensional gels. At 30 sec after glutamate stimulation, 32P incorporation into the 87-kDa and 48-kDa proteins peaked (240% and 170% basal levels, respectively), and by 2 min, phosphorylation of the 87-kDa protein had returned to basal levels, while that of the 48-kDa protein decreased but remained above control levels. The phosphorylation of these proteins appeared to be mediated by protein kinase C (PKC) because all three showed an increase in phosphorylation after phorbol ester treatment of cultures. Phosphate incorporation was accompanied by an acidic shift in the isoelectric point of both 87- and 48-kDa proteins. Glutamate stimulation resulted in phosphorylation in the presence and absence of Ca2+ influx. Antibody recognition and biochemical characteristics indicated that the 87-kDa phosphoprotein is the PKC substrate MARCKS (myristoylated, alanine-rich C-kinase substrate). The 48-kDa protein, though very similar to GAP-43, was not recognized by specific antibodies raised against GAP-43. These results suggest that glutamate stimulates the transient generation of second messengers that activate PKC in hippocampal neurons, resulting in a significant increase in the phosphorylation of three specific proteins.
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PMID:Glutamate-stimulated protein phosphorylation in cultured hippocampal pyramidal neurons. 167 25

mu opioids, such as morphine and certain enkephalin analogs, are known to modulate glutamate-evoked activity in dorsal horn neurons in the spinal cord and caudal brain stem. Yet the molecular mechanism by which this modulation occurs is not understood. We examined the interactions between glutamate and a selective mu opioid receptor agonist, D-Ala2-MePhe4-Gly-ol5-enkephalin (DAGO), in spinal trigeminal neurons in thin medullary slices of rats. DAGO caused a sustained increase in glutamate-activated currents that are mediated by N-methyl-D-aspartate receptors. Intracellularly applied protein kinase C (PKC) mimics the effect of DAGO, and a specific PKC inhibitor interrupts the sustained potentiation produced by DAGO. Thus, PKC plays a key role in mediating the action of mu opioid peptides.
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PMID:Sustained potentiation of NMDA receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. 167 15

The effects of 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent activator of protein kinase C, on high-affinity Na(+)-dependent glutamate transport were investigated in primary cultures of neurons and glial cells from rat brain cortex. Incubation of glial cells with TPA led to concentration- and time-dependent increases in the glutamate transport that could be completely suppressed by the addition of the protein kinase C (PKC) inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. The TPA effects could be mimicked by oleoylacetylglycerol and by the diacylglycerol kinase inhibitor R59022. The effects of TPA were potentiated by the Ca2+ ionophore A23187. Under the chosen experimental conditions TPA had no effect on glutamate transport in neurons. We conclude that PKC activates the sodium-dependent high-affinity glutamate transport in glial cells and that it has dissimilar effects on neurons and glial cells.
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PMID:Activation of high-affinity uptake of glutamate by phorbol esters in primary glial cell cultures. 168 Jan 57

Phosphoinositide metabolism stimulated by activation of cholinergic muscarinic, glutamatergic, alpha-adrenergic and serotoninergic receptors was measured in brain regions of the developing rats. Accumulation of [3H]inositol phosphates ([3H]InsPs) in [3H]inositol-prelabeled slices from cerebral cortex, hippocampus, brainstem and cerebellum was measured as an index of phosphoinositide metabolism. Large age-, neurotransmitter receptor-, and brain region-dependent differences were found. Carbachol-stimulated [3H]InsPs accumulation peaked on postnatal day 7 in cerebral cortex and hippocampus while in cerebellum and brainstem the effect of muscarinic stimulation was maximal at birth and then declined to adulthood. The effect of glutamate also showed a peak on day 7 in hippocampus and brainstem and a developmentally related decrease in cerebral cortex. In the cerebellum, on the other hand, the response to glutamate remained sustained through adulthood. Stimulation of phosphoinositide metabolism by norepinephrine increased with age in hippocampus and cerebral cortex, but decreased in the cerebellum, while the effect of serotonin did not change significantly with age except in cerebellum. These changes in receptor-stimulated phosphoinositide metabolism do not parallel, for the most part, the ontogeny of receptor recognition sites. Activation of the phosphoinositide metabolism pathway leads to an increase in intracellular calcium levels and to stimulation of protein kinase C, which are believed to play significant roles in cellular proliferation and differentiation. Thus, the differential ability of neurotransmitters to stimulate phosphoinositide hydrolysis might play a role in the development of brain regions.
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PMID:Regional development of carbachol-, glutamate-, norepinephrine-, and serotonin-stimulated phosphoinositide metabolism in rat brain. 168 40

A large number of neurotransmitters have now been shown to reduce the amplitude and slow the activation kinetics of whole cell HVA ICa in a great diversity of neurons. These transmitters include L-glutamate (AMPA/kainate, metabotropic and NMDA receptors), GABA (via GABAB receptors, NA (via alpha 2 receptors), 5-HT, NA (via alpha 2 receptors), DA and several peptides. Both whole-cell and single-channel studies have demonstrated that the N-channel is the most common channel type to be blocked by transmitters, although an inhibition of the L-type channel has also occasionally been reported. The suppression of the N-type Ca current was commonly shown to be voltage-dependent, with a relief at large positive voltages. Strong evidence has been put forward showing that the transmitter action is mediated by a G-protein, with GDP-beta-S blocking transmitter action, and GTP-gamma-S directly inhibiting the Ca channel. Moreover, pertussis toxin blocked the transmitter action in most neurons, and following such block, injection of the G-protein Go restored transmitter action. A direct link between the G-protein and the Ca channel has been widely theorized to mediate the action of transmitters on certain neurons. There is also some evidence that certain transmitters in specific neurons mediate calcium channel inhibition through a 2nd messenger, perhaps protein kinase C. Transmitters have also been found, although uncommonly, to inhibit HVA L-type and LVA T-type channels. In addition, an enhancement of both HVA and LVA Ca currents by transmitters has been demonstrated, and substantial evidence exists for mediation of this action by cAMP.
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PMID:Modulation of vertebrate neuronal calcium channels by transmitters. 168 17

It has been suggested that the maintenance of long-term potentiation (LTP) in the hippocampal mossy fiber (MF) synapse involves a presynaptic mechanism that does not require the activation of protein kinase C (PKC), since this enzyme appears to be absent in the MF presynaptic terminals. In the present study the authors evaluated this proposal by directly comparing the metabolic properties of hippocampal MF synaptosomes and a conventional P2B synaptosomal preparation prepared from the same hippocampal tissue. Protein kinase C-dependent histone phosphotranferase activity was found to be comparable in MF and P2B synaptosomes. Western blot analysis was performed using antisera prepared against four of the PKC isoforms, and the results demonstrate that the alpha, beta, and gamma PKC isoforms are present in relatively equivalent amounts in these two subcellular fractions. However, the cytosolic fraction derived from the hippocampal MF synaptosomes appeared to contain a greater amount of the PKC-epsilon isoform when compared to the P2B synaptosomal preparation. Four distinct endogenous substrates present in the MF synaptosomes are shown to be phosphorylated in response to PKC activation. A functional role for PKC in the hippocampal MF nerve endings seems to be indicated by the finding that 4 beta-phorbol 12,13-dibutyrate (PDBu) and 4 beta-phorbol 12,13-diacetate produce a dose-dependent potentiation of the K(+)-evoked release of endogenous glutamate and dynorphin B, while the inactive 4-alpha-phorbol was without effect. The PDBu-induced enhancement of transmitter release was blocked by the PKC inhibitor, staurosporine. In addition, PDBu significantly facilitated the rise in cytosolic free calcium that immediately followed depolarization of the MF synaptosomal membrane. It is concluded that hippocampal MF presynaptic terminals possess a variety of PKC isoforms and that their activation may have an important facilitory influence on MF synaptic transmission and plasticity.
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PMID:A presynaptic role for protein kinase C in hippocampal mossy fiber synaptic transmission. 168 79

Exposing primary cultures of cerebellar granule neurons to 100 nM phorbol 12-myristate 13-acetate (PMA) for 24 hr decreases the Ca2+/phosphatidylserine/diolein-dependent protein kinase C (PKC; ATP:protein phosphotransferase, EC 2.7.1.37) by approximately 90% in the 100,000 x g supernatant and pellet fractions of neuronal culture homogenates. Immunoblot analysis of the homogenates with polyclonal antibodies raised against either the beta-type PKC peptide or total rat brain PKC reveals a virtual loss of 78-kDa PKC immunoreactivity in the supernatant and a marked decrease of PKC immunoreactivity in the pellet. Exposure of the cultures to 50 microM glutamate for 15 min (no Mg2+) induces the translocation of supernatant PKC immunoreactivity to the pellet. Such translocation persists after glutamate withdrawal and is followed by a progressive increase in neuronal death, which begins 2 hr later. Neuronal death approaches completion in about 24 hr. PMA-induced down-regulation of PKC decreases glutamate-elicited neurotoxicity. Yet, the culture exposure to 100 nM PMA fails to decrease the high-affinity binding of [3H]glutamate to neuronal membranes and does not reduce glutamate-induced activation of ionotropic or metabolotropic receptors (assayed as total membrane current measured in whole-cell voltage-clamped neurons, 45Ca2+ uptake in intact monolayers, inositolphospholipid hydrolysis, and transcriptional activation and translation of c-fos mRNA). Moreover, the immediate cell-body swelling and activation of spectrin proteolysis elicited by glutamate remain unchanged. On the other hand, PMA-induced PKC down-regulation reduces any increase in 45Ca2+ uptake or Ca2(+)-dependent proteolysis (measured as spectrin degradation) after glutamate withdrawal. These results support the view that PKC translocation is operative in glutamate-induced destabilization of cytosolic ionized Ca2+ homeostasis and neuronal death.
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PMID:Down-regulation of protein kinase C protects cerebellar granule neurons in primary culture from glutamate-induced neuronal death. 168 50

Isolated rod bipolar cells were obtained by enzymatic (papain) and mechanical dissociation of the adult rat retina. Virtually all intact bipolar cells in the dissociates expressed protein kinase C (PKC) immunoreactivity, a selective marker for rod bipolar cells in the in vivo retina. Whole-cell recordings were performed using nystatin in the patch pipette to minimize washout of those cytoplasmic components necessary for the maintenance of ionic currents. At holding potentials of -33 mV, a tonic inward current was observed. The glutamate agonist 2-amino-4-phosphonobutyrate (APB) reduced this current by closing ion channels. Under normal conditions, Na+ appeared to be the main charge carrier. Both the internal and the external Ca2+ concentrations were found to exert a powerful influence on the APB-sensitive current. We conclude that the rod bipolar cell in situ is depolarized at light onset.
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PMID:Responses of rod bipolar cells isolated from the rat retina to the glutamate agonist 2-amino-4-phosphonobutyric acid (APB). 171 92

The mechanism by which protein kinase C (PKC) activates transmitter release from guinea pig cerebrocortical synaptosomes was investigated by employing parallel fluorescent assays of glutamate release, cytoplasmic free Ca2+, and plasma membrane potential. 4 beta-Phorbol dibutyrate (4 beta-PDBu) enhances the Ca(2+)-dependent, 4-aminopyridine (4AP)-evoked release of glutamate from synaptosomes, the 4AP-evoked elevation of cytoplasmic free Ca2+, and the 4AP-evoked depolarization of the plasma membrane. 4 beta-PDBu itself causes a slow depolarization, which may underlie the small effect of 4 beta-PDBu on spontaneous, KCl-evoked, and Ca(2+)-independent/4AP-evoked glutamate release. Because 4AP (but not KCl) generates spontaneous, tetrodotoxin-sensitive action potentials in synaptosomes, a major locus of presynaptic PKC action is to enhance these action potentials, perhaps by inhibiting delayed rectifier K+ channels.
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PMID:An ion channel locus for the protein kinase C potentiation of transmitter glutamate release from guinea pig cerebrocortical synaptosomes. 171 64


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