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 pharmacological profile of metabotropic glutamate receptor (mGluR) activation of phospholipase D (PLD), and the associated signalling pathways, were examined in rat cerebrocortical synaptosomes. The assay was conducted using a transphosphatidylation reaction in synaptosomes which were pre-labelled with either [(3)H]-arachidonic acid or [(32)P]-orthophosphate. The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S, 3R-ACPD) and (RS)-3,5-dihydroxyphenylglycine (DHPG), both activated PLD, while phorbol 12,13-dibutyrate (PDBu) treatment caused receptor-independent activation of PLD and had an additive effect on 1S,3R-ACPD induced PLD activity. A protein kinase C (PKC) inhibitor, GF109203X, failed to antagonize mGluR receptor-coupled PLD activity. We could not detect any increase in the products of PI (phosphoinositide)-specific phospholipase C (PI-PLC), inositol(1,4, 5)trisphosphate or diacylglycerol, by 1S, 3R-ACPD at 15 s. However, diacylglycerol increased monophasically in response to mGluR agonists and remained elevated for at least 15 min. Phosphatidic acid phosphohydrolase (PAP) activity, which converts PA to DAG, was present in the synaptosomes. These data suggest that, in rat cerebrocortical synaptosomes, the 1S,3R-ACPD-sensitive mGluR is coupled to PLD through a mechanism that is independent of both PKC and PI-PLC.
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PMID:Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes. 1105 24

We investigated whether tetanic-stimulation and activation of metabotropic glutamate receptors (mGluRs) can modify field-synaptic-potentials and protein kinase activity in rat auditory cortex, specifically protein kinase A (PKA) and protein kinase C (PKC). Tetanic stimulation (50 Hz, 1 s) increases PKA and PKC activity only if the CNQX-sensitive field-EPSP (f-EPSP) is also potentiated. If the f-EPSP is unchanged, then PKA and PKC activity remains unchanged. Tetanic stimulation decreases a bicuculline-sensitive field-IPSP (f-IPSP), and this occurs whether the f-EPSP is potentiated or not. Potentiation of the f-EPSP is blocked by antagonists of mGluRs (MCPG) and PKC (calphostin-C, tamoxifen), suggesting that the potentiation of the f-EPSP is dependent on mGluRs and PKC. PKC antagonists block the rise in PKC and PKA activity, which suggests that these may be coupled. In contrast, ACPD (agonist at mGluRs) decreases both the f-EPSP and the f-IPSP, but increases PKC and PKA activity. Quisqualate (group I mGluR agonist), decreases the f-IPSP, and increases PKA activity, suggesting that the increase in PKA activity is a result of activation of group I mGluRs. Additionally, the increase in PKC and PKA activity appears to be independent of the decrease of the f-EPSP and f-IPSP, because PKC antagonists block the increase in PKC and PKA activity levels but do not block ACPD's effect on the f-EPSP or f-IPSP. These data suggest that group I mGluRs are involved in potentiating the f-EPSP by a PKC and possibly PKA dependent mechanism which is separate from the mechanism that decreases the f-EPSP and f-IPSP.
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PMID:Tetanic stimulation and metabotropic glutamate receptor agonists modify synaptic responses and protein kinase activity in rat auditory cortex. 1125 Nov 95

The mechanism responsible for long-term depression (LTD) of pharmacologically isolated N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic potential (EPSP(NMDA)) was studied. Intracellular recordings were made from CA1 cells of rat hippocampal slices in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (10 &mgr;M) and picrotoxin (50 &mgr;M), which block non-NMDA and GABA(A) receptors, respectively. Intracellular injections of depolarizing pulses (500 ms, 0.3-0.7 nA) at 1 Hz for 5 min in the absence of synaptic stimulation caused a persistent increase in the amplitude of EPSP(NMDA). However, coupling postsynaptic depolarization with synaptic activity induced LTD. The EPSP(NMDA) LTD could be blocked by L-2-amino-3-phosphonopropionic acid (50 &mgr;M) or (RS)-alpha-methyl-4-carboxyphenylglycine (200 &mgr;M), specific antagonists for metabotropic glutamate receptors (mGluR). Furthermore, application of trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 50 &mgr;M), a specific mGluR agonist, in conjunction with postsynaptic depolarizing elicited LTD. In contrast, the mGluR agonists quisqualate or t-ACPD when given alone produced a sustained enhancement of EPSP(NMDA). Finally, coupled depolarization did not evoke LTD in slices pretreated with the protein kinase C (PKC) inhibitor calphostin c (60 nM). The present results demonstrate that activation of mGluR is necessary for the induction of LTD of EPSP(NMDA) and suggest that NMDA receptors are subject to bidirectional regulation by mGluR. Furthermore, the induction of LTD is likely to involve the stimulation of PKC. Copyright 1995 S. Karger AG, Basel
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PMID:Activation of Metabotropic Glutamate Receptors in Conjunction with Postsynaptic Depolarization Triggers a Long-Term Depression of the N-Methyl-D-Aspartate Receptor-Mediated Synaptic Potential in the Rat Hippocampus. 1172 53

We report here that metabotropic glutamate 1a (mGlu1a) receptors, stably expressed in CHO cells, stimulate phospholipase D (PLD) activity. Several mGlu receptor agonists were found to exert this effect, with a rank order of potency of: L-quisqualate>L-glutamate>(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]=(S)-3,5-dihydroxyphenylglycine [(S)-DHPG]. Both L-glutamate- and (1S,3R)-ACPD-stimulated PLD activity were attenuated by the selective mGlu receptor antagonist (S)-alpha-methyl-4-carboxyphenylglycine. mGlu1a receptor-stimulated PLD was inhibited either by the selective protein kinase C (PKC) inhibitor, GF109203X, or via PKC downregulation. MGlu1a receptor-PLD coupling required extracellular Ca2+ and was sensitive to La3+ and Zn2+, inhibitors of intracellular Ca2+ store-operated Ca2+ influx. mGlu1a receptor-PLD coupling was inhibited by the selective tyrosine kinase inhibitor, genistein. In addition, mGlu1a receptor-PLD coupling was also inhibited by cell transfection with the selective Rho (small GTP-binding protein) inhibitors: C3-exoenzyme and dominant negative mutant RhoA constructs. Brefeldin A, a selective ADP-ribosylation factor (ARF) inhibitor, and a dominant negative ARF6 mutant, failed to significantly influence mGlu1a receptor-stimulated PLD activity. We conclude that mGlu1a receptors activate PLD via a mechanism that is dependent on extracellular Ca2+, PKC, tyrosine kinase and RhoA but independent of ARF.
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PMID:Functional coupling of rat metabotropic glutamate 1a receptors to phospholipase D in CHO cells: involvement of extracellular Ca2+, protein kinase C, tyrosine kinase and Rho-A. 1175 Sep 11

Using intracellular and extracellular recordings in rat hippocampal slices, we have investigated the interactions between the quisqualate metabotropic receptor (QP) and currents mediated by N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). We found that trans-(t)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) and 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) potentiated NMDA but not AMPA-mediated currents. Intracellular injections of selective protein kinase C inhibitors prevented the up-regulation of the NMDA response. The physiological consequence of the up-regulation by ACPD of the NMDA response on the threshold of long-term potentiation induction was tested. We found that a subthreshold train of electrical stimulation that produced short-term potentiation generated long-term potentiation when coupled with ACPD application, an effect which was not produced by AMPA or NMDA. This effect was blocked by an inhibitor of protein kinase C. These results demonstrate for the first time that one subtype of glutamate receptor (QP) can regulate another subtype of glutamate receptor (NMDA) through the activation of protein kinase C. Our results also suggest that the NMDA receptor is regulated by protein kinase C, and that the intracellular level of protein kinase C may determine the threshold for induction of long-term potentiation.
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PMID:Quisqualate Metabotropic Receptors Modulate NMDA Currents and Facilitate Induction of Long-Term Potentiation Through Protein Kinase C. 1210 36

Na/K-ATPase prepared from cerebellum granule cells of 10-12-day-old mice is inhibited by glutamate and its agonists, NMDA (ligand for ionotropic receptors) and ACPD (ligand for metabotropic receptors). The inhibition is specific and prevented by subsequent antagonists (MK-801 for ionotropic NMDA-receptors and MCPG for metabotropic receptors). The inhibiting effect of NMDA is significantly reversed by cysteine and that of ACPD by chelerythrine or indolyl maleimide. It is concluded that ionotropic receptors inhibit Na/K-ATPase because of intracellular production of reactive oxygen species, and metabotropic receptors mediate their effect via protein kinase C.
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PMID:Activation of glutamate receptors inhibits Na/K-ATPase of cerebellum granule cells. 1238 13

The G-protein coupled metabotropic glutamate receptor mGlu5 plays a pivotal role as a modulator of synaptic plasticity, ion channel activity and excitotoxicity. Two splice variants, hmGlu5a and -5b have been reported previously. During screening of a human brain cDNA library for hmGlu5a, we identified a novel variant (hmGlu5d) generated by alternative splicing at the C-terminal domain. The predicted hmGlu5d protein has a C-terminal 267 amino acid shorter than that of hmGlu5a. The pattern of mRNA expression of mGluR5 variants in human brain were analyzed by RT-PCR and in situ hybridization histochemistry. RT-PCR analysis demonstrated the presence of the hmGlu5d transcript, although at low level, in human whole brain, cerebellum, cerebral cortex and hippocampus. [3H]Quisqualate displayed similar affinity at the hmGlu5 splice variants (K(D) values of 80+/-8 and 54+/-17 nM for hmGlu5a and -5d receptors, respectively). For the five mGlu agonists studied, a similar rank order of potency was observed on both hmGlu5a and -5d receptors: quisqualate>glutamate>DHPG>L-CCGI approximately ACPD. MPEP inhibited the glutamate (2 microM)-induced [Ca(2+)](i) response in hmGlu5a and -5d-HEK293 cells also with similar potency (IC(50) values 25+/-1.5 and 20+/-1.4 nM, respectively). Therefore, the large truncation of the C-terminal tail of mGlu5 does not have any apparent major effect on the potency and efficacy of agonists as measured by the [Ca(2+)](i) responses or by activation of recombinant G-protein coupled inwardly rectifying K(+) (GIRK) channel currents. The only major functional difference is the increased sensitivity of hmGlu5d to protein kinase C (PKC)-mediated desensitization, relative to hmGlu5a.
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PMID:Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum. 1253 26

1. We have examined excitatory postsynaptic potentials and paired-pulse interactions in rat hippocampal slices to obtain more information about the site and mechanism of interactions between metabotropic glutamate receptors and adenosine receptors. 2. The results show that the suppression of adenosine sensitivity is explained by a selectively reduced responsiveness to A(1) receptor stimulation, and does not involve any facilitation of A(2A) adenosine receptors, since it can be obtained in the absence of endogenous adenosine and is not prevented by the A(2A) receptor blocker ZM241385. 3. The glutamate receptors involved are of the group I class since the suppression of adenosine sensitivity is produced by ACPD and the group I selective compound DHPG. Furthermore, the effects of DHPG could be prevented by LY367385, a selective antagonist at the mGlu(1a) subtype of group I receptors. The selective antagonist at mGlu(5) receptors, SIB1893, did not prevent the suppression of adenosine sensitivity by DHPG. Blockade of the DHPG/adenosine interaction was also obtained by superfusion with the protein kinasae C inhibitor chelerythrine. 4. Since the suppression of adenosine responses by metabotropic receptor agonists was seen in the paired-pulse paradigm, we conclude that the observed interactions occur at the level of the presynaptic terminals. 5. The interaction with adenosine receptors is not specific, but applies also to a suppression of responses mediated by the GABA(B) receptor agonist baclofen. 6. We conclude that activation of the mGlu1a subtype of receptor can suppress responses mediated via adenosine A1 receptors, probably by activating protein kinase C. Since the changes induced by metabotropic glutamate receptor agonists last for at least 60 min, the data also imply that these interactions could play an important role in changes of synaptic function long after even transient increases of glutamate release in the CNS.
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PMID:Interactions between adenosine and metabotropic glutamate receptors in the rat hippocampal slice. 1268 61

Dysfunction of the hypocretin/orexin (Hcrt/Orx) peptide system is closely linked to the sleep disorder narcolepsy, suggesting that it is also central to the normal regulation of sleep and wakefulness. Indeed, Hcrt/Orx peptides produce long-lasting excitation of arousal-related neurons, including those in the laterodorsal tegmentum (LDT) and the dorsal raphe (DR), although the mechanisms underlying these actions are not understood. Since Hcrt/Orx mobilizes intracellular calcium ([Ca(2+)](i)) in cells transfected with orexin receptors and since receptor-mediated Ca(2+) transients are ubiquitous signaling mechanisms, we investigated whether Hcrt/Orx regulates [Ca(2+)](i) in the LDT and DR. Changes in [Ca(2+)](i) were monitored by fluorescence changes of fura-2 AM loaded cells in young mouse brain slices. We found Hcrt/Orx (Orexin-A, 30-1,000 nM) evoked long-lasting increases in [Ca(2+)](i) with differing temporal profiles ranging from spiking to smooth plateaus. A fragment of Hcrt/Orx (16-33) failed to evoke changes in [Ca(2+)](i) and changes were not blocked by TTX or ionotropic glutamate receptor antagonists, suggesting they resulted from specific activation of postsynaptic orexin receptors. Unlike orexin receptor-transfected cells, Hcrt/Orx-responses were not attenuated by depletion of Ca(2+) stores with cyclopiazonic acid (CPA; 3-30 microM), thapsigargin (3 microM), or ryanodine (20 microM), although store-depletion by either CPA or ryanodine blocked Ca(2+) mobilization by the metabotropic glutamate receptor agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 30 microM). In contrast, Hcrt/Orx responses were strongly attenuated by lowering extracellular Ca(2+) ( approximately 20 microM) but were not inhibited by concentrations of KB-R7943 (10 microM) selective for blockade of sodium/calcium exchange. Nifedipine (10 microM), inhibited Hcrt/Orx responses but was more effective at abolishing spiking than plateau responses. Bay K 8644 (5-10 microM), an L-type calcium channel agonist, potentiated responses. Finally, responses were attenuated by inhibitors of protein kinase C (PKC) but not by inhibitors of adenylyl cyclase. Collectively, our findings indicate that Hcrt/Orx signaling in the reticular activating system involves elevation of [Ca(2+)](i) by a PKC-involved influx of Ca(2+) across the plasma membrane, in part, via L-type calcium channels. Thus the physiological release of Hcrt/Orx may help regulate Ca(2+)-dependent processes such as gene expression and NO production in the LDT and DR in relation with behavioral state. Accordingly, the loss of Hcrt/Orx signaling in narcolepsy would be expected to disrupt calcium-dependent processes in these and other target structures.
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PMID:Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. 1499 52

Several excitatory amino acid ligands were found potently to inhibit forskolin-stimulated cAMP accumulation in rat cultured cerebellar astrocytes: L-cysteine sulfinic acid (L-CSA) = L-aspartate > L-glutamate >/= the glutamate uptake inhibitor, L-PDC. This property did not reflect activation of conventional glutamate receptors, since the selective ionotropic glutamate receptor agonists NMDA, AMPA, and kainate, as well as several mGlu receptor agonists [(1S,3R)-ACPD, (S)-DHPG, DCG-IV, L-AP4, L-quisqualate, and L-CCG-I], were without activity. In addition, the mGlu receptor antagonists, L-AP3, (S)-4CPG, Eglu, LY341495, (RS)-CPPG, and (S)-MCPG failed to reverse 30 microM glutamate-mediated inhibitory responses. L-PDC-mediated inhibition was abolished by the addition of the enzyme glutamate-pyruvate transaminase. This finding suggests that the effect of L-PDC is indirect and that it is mediated through endogenously released L-glutamate. Interestingly, L-glutamate-mediated inhibitory responses were resistant to pertussis toxin, suggesting that G(i)/G(o) type G proteins were not involved. However, inhibition of protein kinase C (PKC, either via the selective PKC inhibitor GF109203X or chronic PMA treatment) augmented glutamate-mediated inhibitory responses. Although mGlu3 receptors (which are negatively coupled to adenylyl cyclase) are expressed in astrocyte populations, in our study Western blot analysis indicated that this receptor type was not expressed in cerebellar astrocytes. We therefore suggest that cerebellar astrocytes express a novel mGlu receptor, which is negatively coupled to adenylyl cyclase, and possesses an atypical pharmacological profile.
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PMID:Novel metabotropic glutamate receptor negatively coupled to adenylyl cyclase in cultured rat cerebellar astrocytes. 1499 8


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