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 depression (LTD) at the parallel fiber-Purkinje cell synapse in the cerebellum is a well-known example of synaptic plasticity. Although LTD is thought to reflect an enduring loss of postsynaptic AMPA receptor sensitivity, the underlying mechanisms are unclear. Protein-tyrosine kinases (PTKs) are able to modulate ionotropic receptor function and are enriched in Purkinje cells. Using intracellular recording from Purkinje cells, it is shown that two structurally and mechanistically distinct PTK inhibitors, lavendustin A and herbimycin A, block LTD induced by pairing parallel fiber stimulation with postsynaptic Ca2+ spiking. Intracellular application of the protein kinase C (PKC) activator, (-)-indolactam V, consistently depressed parallel fiber-Purkinje cells EPSPs and occluded pairing-induced LTD. Herbimycin A nullified the run-down produced by (-)-indolactam V. These data suggest that PTKs are necessary for LTD at the parallel fiber-Purkinje cell synapse and that PKC-induced synaptic depression requires PTK activity.
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PMID:Tyrosine kinase is required for long-term depression in the cerebellum. 860 98

The G-protein-coupled metabotropic glutamate receptor mGluR1 alpha and the ionotropic glutamate receptor GluR6 were examined for posttranslational palmitoylation. Recombinant receptors were expressed in baculovirus-infected insect cells or in human embryonic kidney cells and were metabolically labeled with [3H]palmitic acid. The metabotropic mGluR1 alpha receptor was not labeled whereas the GluR6 kainate receptor was labeled after incubation with [3H]palmitate. The [3H]palmitate labeling of GluR6 was eliminated by treatment with hydroxylamine, indicating that the labeling was due to palmitoylation at a cysteine residue via a thioester bond. Site-directed mutagenesis was used to demonstrate that palmitoylation of GluR6 occurs at two cysteine residues, C827 and C840, located in the carboxyl-terminal domain of the molecule. A comparison of the electrophysiological properties of the wild-type and unpalmitoylated mutant receptor (C827A, C840A) showed that the kainate-gated currents produced by the unpalmitoylated mutant receptor were indistinguishable from those of the wild-type GluR6. The unpalmitoylated mutant was a better substrate for protein kinase C than the wild-type GluR6 receptor. These data indicate that palmitoylation may not modulate kainate channel function directly but instead affect function indirectly by regulating the phosphorylation state of the receptor.
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PMID:Palmitoylation of the GluR6 kainate receptor. 861 50

1. Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD-coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2. The mGluR-selective agonist (1S,3R)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 microM) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3. The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-ACPD > L-cysteine sulphinic acid > L-aspartate > L-glutamate. L-(+)-2-Amino-4-phosphonobutyric acid and the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate failed to activate PLD. (RS)-3,5-dihydroxyphenylglycine (100300 microM), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 microM (1S,3R)-ACPD. 4. (+)-alpha-Methyl-4-carboxyphenylglycine (0.1-1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L-(+)-2-Amino-3-phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 microM (1S,3R)-ACPD-induced PLC response but produced a robust stimulation of PLD. 5. 12-O-Tetradecanoylphorbol 13-acetic acid and phorbol 12,13-dibutyrate (PDBu), activators of protein kinase C, at 1 microM had a stimulatory effect on mGluRs linked to PLD but depressed (1S,3R)-ACPD-induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 microM) reduced PLD activation induced by 1 microM PDBu but not by 100 microM (1S,3R)-ACPD. 6. Our results suggest that PLD-linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC-independent mechanism.
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PMID:Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. 879 79

Developmental changes in glutamate receptor agonist-produced enhancement of 4-beta-[3H]phorbol-12,13-dibutyrate binding ([3H]-PDBu binding), indicative of an intracellular translocation of protein kinase C (PKC), were investigated in cerebellar granule cells. Our observations demonstrate that the magnitude of glutamate-, NMDA-, and kainate-produced enhancement of PKC translocation was dramatically decreased between 2 and 12 DIV, whereas there was only a minor reduction in the corresponding response caused by the non-NMDA receptor agonist, AMPA. The maximally enhanced stimulation of PKC translocation caused by glutamate and NMDA was significantly reduced already at 4 DIV, whereas a significant reduction of the kainate-induced enhancement of [3H]PDBu binding was not observed until 8 DIV. Glutamate- and NMDA-induced responses were effectively blocked by the specific NMDA receptor antagonists MK-801 (1 microM) and APV (100 microM) as well as by the addition of Mg2+ into assay media. In contrast, the non-NMDA receptor antagonist, CNQX (10 microM), effectively blocked the kainate-induced enhancement of [3H]PDBu binding, but had no effect on the NMDA- and glutamate-induced stimulation of PKC translocation. The metabotropic glutamate receptor agonist, ACPD (up to 250 microM), had no effect on the translocation of PKC. Taken together, our data support the working hypothesis that the rapidly occurring changes in the glutamate receptor agonist-produced translocation of PKC are most likely due to a differential maturation of glutamate ionotropic receptor subtypes and/or to development-dependent alterations in mechanisms responsible for the coupling between the glutamate receptor subtypes and the activation of PKC translocation in cerebellar granule neurons.
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PMID:Developmental changes in glutamate receptor-activated translocation of protein kinase C in cerebellar granule neurons. 881 73

The effect of glutamate on c-fos expression in oligodendrocyte progenitors was investigated by Northern blot analysis. Glutamate caused rapid and transient induction. Both 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), two competitive non-NMDA ionotropic receptor antagonists, reduced glutamate-induced c-fos expression, whereas the NMDA antagonist MK-801 was ineffective. In addition, the glutamate receptor agonists (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) and kainate strongly induced c-fos. However, the metabotropic receptor agonist trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (trans-(+/-)-ACPD) did not increase c-fos mRNA level and the antagonist L-(+)-2-amino-3-phosphonopropionic acid did not block glutamate-induced c-fos mRNA. These findings indicate that c-fos induction in oligodendrocyte progenitors is mediated through the AMPA/kainate receptors, while NMDA and metabotropic receptor subtypes are not involved. Chelation of extracellular calcium by EDTA prevented glutamate-induced c-fos expression. Similarly, the protein kinase C inhibitor 1-(5-isoquinoline-sulphonyl)-2-methylpiperazine dihydrochloride (H7) and down-regulation of protein kinase C by prolonged exposure to phorbol-12-myristate 13-acetate blocked c-fos induction. These results suggest that induction of c-fos through AMPA/kainate receptors is dependent on extracellular calcium influx and involves downstream activation of phorbol ester-sensitive protein kinase C. The effect of glutamate on oligodendrocyte progenitor proliferation was assessed by [3H]thymidine incorporation. Glutamate and the agonists kainate and AMPA, but not trans-(+/-)-ACPD, caused a dose-dependent decrease in [3H]thymidine incorporation. All these pharmacological agents were not toxic to oligodendrocyte progenitors. CNQX reversed the inhibitory effects produced by glutamate and the various agonists. These results suggest that glutamate may modulate the growth and differentiation of oligodendrocytes in the central nervous system.
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PMID:Glutamate induces c-fos proto-oncogene expression and inhibits proliferation in oligodendrocyte progenitors: receptor characterization. 884 39

The mechanisms by which stimuli that raise cytosolic free Ca2+ concentrations in neurons can increase protein tyrosine phosphorylation are not known. Using rat hippocampal slices and cortical synaptosomes, we have examined the regulation of two highly related cytoplasmic tyrosine kinases, pp125 focal adhesion kinase (pp125(FAK)) and proline-rich tyrosine kinase 2/cell adhesion kinase beta (PYK2/CAKbeta). Membrane depolarization increased tyrosine phosphorylation of PYK2/CAKbeta and pp125(FAK). These effects were blocked by EGTA or by protein kinase C inhibitors (RO31-8220; GF109203X) and mimicked by ionomycin or phorbol 12-myristate 13-acetate, in the case of pp125(FAK), or their combination in the case of PYK2/CAKbeta. Glutamate and specific agonists of ionotropic (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate) or metabotropic (trans-1-aminocyclopentane-1,3, -dicarboxylate) glutamate receptors stimulated the phosphorylation of pp125(FAK), but not of PYK2/CAKbeta. Glutamate effects were prevented by GF109203X. Thus, in hippocampal slices, tyrosine phosphorylation of pp125(FAK) and PYK2/CAKbeta are regulated differentially by pathways involving Ca2+ and protein kinase C. pp125(FAK) and PYK2/CAKbeta may provide specific links between neuronal activity, increases in cytosolic Ca2+ and protein tyrosine phosphorylation, which may be important for neuronal survival, and synaptic plasticity.
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PMID:Differential regulation of proline-rich tyrosine kinase 2/cell adhesion kinase beta (PYK2/CAKbeta) and pp125(FAK) by glutamate and depolarization in rat hippocampus. 891 May 43

The underlying mechanism(s) of the glutamate (Glu)-induced membrane hyperpolarizing response in identified Euhadra neurons was investigated using the voltage-clamp technique, pressure injection method, and pharmacologic agents. Under voltage-clamp conditions, bath-applied Glu elicits a slow outward potassium current (Glu current) accompanied by an increase in membrane conductance whose amplitude is dose dependent. Of the agonists tested, the Glu current was mimicked only by quisqualate (QA); its potency was approximately 10 times greater than that of Glu. Typical antagonists for the ionotropic type of Glu receptors and G protein inhibitors do not block this current. The Glu current is markedly enhanced by a specific inhibitor of Ca2+/ calmodulin-dependent protein kinase II (CaM-KII), KN-62 (1-[N,O-bis (1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine) in a dose-dependent manner, while intracellularly injected CaM-KII suppresses the current. The potent protein kinase A inhibitors, H-8 (N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) and H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) or the specific protein kinase C inhibitors staurosporine and K-252b had no effect on the Glu current. These results suggest the presence of a novel subtype of Glu receptor in Euhadra neurons, which may be coupled to the activation of potassium channels normally suppressed by CaM-KII.
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PMID:A novel glutamate-mediated inhibitory mechanism linked with Ca2+/calmodulin-dependent protein kinase II in identified Euhadra neurons. 903 58

In a previous study we indicated the involvement of the N-methyl-D-aspartate (NMDA) receptor in the development of morphine dependence as assessed by naloxone-induced rise in norepinephrine release in chronically morphine-treated rats. In the present experiments, we studied (1) the possible role of protein kinases in the increased norepinephrine release occurring after naloxone injection and (2) the effects of NMDA receptor antagonists on chronic morphine exposure-induced changes in protein kinase activity. The naloxone-induced rise in norepinephrine release was attenuated by concomitant administration of a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine hydrochloride (H-7) or an NMDA receptor antagonist, (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine hydrogen maleate (dizocilpine, MK-801) with morphine. Both cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), which mediate neurotransmitter release, were clearly activated in the cytosol of the pons/medulla, but not in that of the hippocampus, in chronically morphine-treated rats. This activation of PKA and PKC by chronic morphine treatment was inhibited by infusion of dizocilpine or D(-)-2-amino-5-phosphonopentanoic acid (AP-5), an ionotropic glutamate receptor antagonist, together with morphine. These results suggest that NMDA receptor antagonists inhibit the increase in protein kinase activity produced by chronic morphine treatment, thus suppressing the naloxone-induced rise in norepinephrine release.
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PMID:Effect of NMDA receptor antagonists on protein kinase activated by chronic morphine treatment. 907 57

The diadenosine polyphosphates, diadenosine tetraphosphate and diadenosine pentaphosphate (Ap5A), can activate an ionotropic dinucleotide receptor that induces Ca2+ transients into synaptosomes prepared from rat brain. This receptor, also termed the P4 purinoceptor, is sensitive only to adenine dinucleotides and is insensitive to ATP. Studies on the modulatory role of protein kinase A (PKA), protein kinase C (PKC), and protein phosphatases on the response of diadenosine polyphosphate receptors were performed by measuring the changes in the intracellular Ca2+ levels with fura-2. Activation and inhibition of PKA were carried out by means of forskolin and the PKA inhibitory peptide (PKA-IP), respectively. The Ap5A response was inhibited by forksolin to 35% of control values, but PKA-IP induced an increase of 37%. The effect of PKC activation was similar to that observed for PKA. PKC stimulation with phorbol 12,13-dibutyrate produced an inhibition of 67%, whereas the PKC inhibitors staurosporine and PKC inhibitory peptide enhanced the responses elicited by Ap5A to 40% in both cases. Protein phosphatase inhibitors diminished the responses elicited by Ap5A to 17% in the case of okadaic acid, to 50% for microcystin, and to 45% in the case of cyclosporin A. Thus, the activity of dinucleotide receptors in rat brain synaptosomes appears to be modulated by phosphorylation/dephosphorylation. These processes could be of physiological significance in the control of transmitter release from neurons that are postsynaptic to nerves that release diadenosine polyphosphates.
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PMID:Dinucleotide receptor modulation by protein kinases (protein kinases A and C) and protein phosphatases in rat brain synaptic terminals. 916 52

1. An inward current (I[in]) was produced by gamma-aminobutyric acid (GABA) and muscimol, but not by baclofen, in an identifiable giant neuron type, v-LCDN (ventral-left cerebral distinct neuron), of an African giant snail (Achatina fulica Ferussac) under voltage clamp. 2. The pharmacological features of the excitatory GABA receptors in this Achatina neuron type, termed the Achatina muscimol II type GABA receptors, were mainly comparable to those of the mammalian GABA(C) receptors. 3. It was demonstrated in the present study that the following inhibitors for intracellular signal transduction systems showed no significant effect on the I(in) produced by GABA in this Achatina neuron type: H-7 [1-(5-isoquinolinyl sulfonyl)-2-methylpiperazine], an inhibitor of cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC); H-8 (N-[2-(methylamino)-ethyl]-5-isoquinolinesulfonamide), a PKA and PKG inhibitor; H-9 [N-(2-aminoethyl)-5-isoquinolinesulfonamide], a PKA inhibitor; staurosporine ((9alpha,10beta,11beta,13alpha)-(+)-2,3,10,11,12 ,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-d iindolo[1,2,3-gh: 3',2',1'-1m]pyrrolo[3,4-j] [1,7]benzodiazonin-1-one), a PKA and PKC inhibitor; KT5823 ((8R,9S, 11S)-9-methoxy-9-methoxycarbonyl-2N,8-dimethyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]- trinden-1-one), a PKG inhibitor; W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], a calmodulin inhibitor; ML-9 [1-(5-chloronaphthalene-1-sulfonyl-1H-hexahydro-1,4-diazepine hydrochloride], a myosin light-chain kinase inhibitor; genistein [5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one], a tyrosine protein kinase inhibitor; IBMX (3-isobutyl-1-methylxanthine), a cyclic nucleotide phosphodiesterase (PDE) inhibitor; fluphenazine nitrogen-mustard (2-chloroethyl)-4[3-(2-trifluoromethyl-10-phenothiazinyl)-propyl]p iperazine dihydrochloride), a calmodulin-dependent PDE inhibitor; calyculin A, a type 1 protein phosphatase inhibitor; and okadaic acid (9,10-deepithio-9,10-didehydroacanthifolicin), a type 1, 2A and 2B protein phosphatase inhibitor. 4. With these results, it was proposed that the excitatory Achatina muscimol II type GABA receptors in v-LCDN are not metabotropic but ionotropic.
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PMID:Effects of inhibitors for intracellular signal transduction systems on the inward current produced by GABA in a snail neuron. 950 77


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