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)

Cerebellar LTD requires brief activation of PKC and is expressed as a functional downregulation of AMPA receptors. Modulation of vascular smooth-muscle contraction by G protein-coupled receptors (called Ca(2+) sensitization) also involves PKC phosphorylation and activation of a specific inhibitor of myosin/moesin phosphatase (MMP). This inhibitor, called CPI-17, is also expressed in brain. Here, we tested the hypothesis that LTD, like Ca(2+) sensitization, employs a PKC/CPI-17 cascade. Introduction of activated recombinant CPI-17 into cells produced a use-dependent attenuation of glutamate-evoked responses and occluded subsequent LTD. Moreover, the requirement for endogenous CPI-17 in LTD was demonstrated with neutralizing antibodies plus gene silencing by siRNA. These interventions had no effect on basal synaptic strength but blocked LTD induction. Thus, a biochemical circuit that involves PKC-mediated activation of CPI-17 modulates the distinct physiological processes of vascular contractility and cerebellar LTD.
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PMID:Cerebellar long-term synaptic depression requires PKC-mediated activation of CPI-17, a myosin/moesin phosphatase inhibitor. 1249 28

1. Previous studies have shown that phorbol esters induce protein kinase C (PKC) mediated phosphorylation of the vesicular acetylcholine transporter (VAChT) and change its interaction with vesamicol. However, it is not clear whether physiological activation of receptors coupled to PKC activation can alter VAChT behavior. 2. Here we tested whether activation of kaianate (KA) receptors alters VAChT. Several studies suggest that the cholinergic amacrine cells display KA/AMPA receptors that mediate excitatory input to these neurons. In addition, KA in the chicken retina can generate intracellular messengers with the potential to regulate cellular functions. 3. In cultured chicken retina (E8C11) KA reduced vesamicol binding to VAChT by 53%. This effect was potentiated by okadaic acid, a protein phosphatase inhibitor, and was totally prevented by BIM, a PKC inhibitor. 4. Phorbol myristate acetate (PMA), but not alpha-PMA, reduced in more than 85% the number of L-[3H]-vesamicol-specific binding sites in chicken retina, confirming that activation of PKC can influence vesamicol binding to chicken VAChT. 5. The data show that activation of glutamatergic receptors reduces [3H]-vesamicol binding sites (VAChT) likely by activating PKC and increasing the phosphorylation of the ACh carrier.
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PMID:Regulation of vesicular acetylcholine transporter by the activation of excitatory amino acid receptors in the avian retina. 1258 91

We identified four PDZ domain-containing proteins, syntenin, PICK1, GRIP, and PSD95, as interactors with the kainate receptor (KAR) subunits GluR5(2b,) GluR5(2c), and GluR6. Of these, we show that both GRIP and PICK1 interactions are required to maintain KAR-mediated synaptic function at mossy fiber-CA3 synapses. In addition, PKC alpha can phosphorylate ct-GluR5(2b) at residues S880 and S886, and PKC activity is required to maintain KAR-mediated synaptic responses. We propose that PICK1 targets PKC alpha to phosphorylate KARs, causing their stabilization at the synapse by an interaction with GRIP. Importantly, this mechanism is not involved in the constitutive recycling of AMPA receptors since blockade of PDZ interactions can simultaneously increase AMPAR- and decrease KAR-mediated synaptic transmission at the same population of synapses.
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PMID:Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. 1259 60

Sodium-dependent transporters clear extracellular glutamate in the mammalian CNS. Activation of protein kinase C (PKC) rapidly increases the activity of the neuronal glutamate transporter EAAC1 (excitatory amino acid carrier-1). This effect is associated with redistribution of EAAC1 to the cell membrane and appears to be dependent on a particular PKC subtype, PKCalpha. In the present study, we sought to determine whether this specificity for regulation of EAAC1 is associated with the formation of EAAC1-PKCalpha complexes. In C6 glioma cells, activation of PKC with phorbol 12-myristate 13-acetate (PMA) induced formation of EAAC1-PKCalpha complexes but did not induce formation of complexes with PKCdelta, a PKC not thought to regulate EAAC1. Formation of these complexes was blocked by inhibitors of PKC. Confocal microscopy revealed that PMA caused EAAC1 and PKCalpha to colocalize in clusters at or near the cell surface. The EAAC1-PKCalpha complexes were also observed in rat brain synaptosomes, demonstrating that this interaction is not restricted to C6 cells. These data demonstrate that EAAC1 and PKCalpha interact in a PKC-dependent manner that is associated with EAAC1 redistribution. Although PKC activation has been implicated in the regulation of many different neurotransmitter transporters, this study provides the first example of an interaction between a neurotransmitter transporter and PKC. PKCalpha also forms complexes with GluR2 (glutamate receptor subunit 2) and causes a reduction in the levels of GluR2-containing AMPA receptors at the plasma membrane. Together, these data suggest that PKCalpha may simultaneously trigger the redistribution of EAAC1 and glutamate receptors.
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PMID:Phorbol myristate acetate-dependent interaction of protein kinase Calpha and the neuronal glutamate transporter EAAC1. 1284 60

The retinal rod bipolar cell type is involved in the sign-inverting depolarizing ON-type response to light. This response is mediated by the metabotropic glutamate receptor type 6 (mGluR6) expressed on the rod bipolar dendrites. In a previous immunocytochemical study, an unexpected colocalization was reported [W. Kamphuis et al. (2003) J. Comp. Neurol., 455, 172-186] of mGluR6 with the ionotropic AMPA-type glutamate receptor subunit GluR2 in rod bipolar cells of rat retina. The aim of the present study was to investigate whether expression of both genes could be found at the single-cell level. Two approaches were followed. (i). Retinal cells were isolated by enzymatic and mechanical treatment. Single cells with a bipolar morphology were harvested, subjected to multiplex PCR with protein kinase C (PKC)-, mGluR6- and GluR1-4-specific primers, followed by a real-time quantitative PCR assay. Of 23 studied cells, 74% expressed PKC and 87% expressed mGluR6. Using the presence of both transcripts as the criterion for a rod bipolar cell signature (n = 15), 73% of these cells expressed GluR2, with a minor contribution of GluR1 (20%), GluR3 (7%), and GluR4 (20%). Quantification of the transcript levels demonstrated that mGluR6 and GluR2 genes are expressed at similar levels in rod ON-type bipolar cells. (ii). Rod bipolar cells were identified in retinal sections by immunolabelling with a protein kinase C antibody and isolated using laser pressure catapulting (LPC). Quantitative PCR was employed to assess gene expression levels of reference genes, PKCalpha, mGluR6 and the GluR subunits. However, in samples from PKCalpha-immunopositive somata no significant enrichment of PKCalpha transcript levels was observed when compared with control samples from immunonegative somata. We conclude that this approach lacks sufficient spatial specificity. In conclusion, the results show coexpression of mGluR6 and GluR2 in rod bipolar cells; this is in good agreement with the results of previous immunocytochemical studies. The functional implications of AMPA-type glutamate receptors for ON-type rod bipolar-mediated signal transduction remains to be elucidated.
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PMID:Gene expression of AMPA-type glutamate receptor subunits in rod-type ON bipolar cells of rat retina. 1295 8

The cytoplasmic C termini of AMPA receptor subunits contain PDZ (postsynaptic density 95/Discs large/zona occludens 1) ligand domains that can control their synaptic trafficking during plasticity. The glutamate receptor subunit 2 (GluR2) PDZ ligand domain can be phosphorylated at serine 880 (S880), and this disrupts interactions with GRIP/ABP (glutamate receptor-interacting protein/AMPA-binding protein) but not with PICK1 (PKC-interacting protein 1). Here, the impact of GluR2 S880 phosphorylation on synaptic transmission and plasticity was explored by expressing, in hippocampal slice cultures, GluR2 subunits containing point mutations that mimic or prevent phosphorylation at this residue. Our results indicate that mimicking GluR2 S880 phosphorylation excludes these receptors from synapses, depresses transmission, and partially occludes long-term depression (LTD). Conversely, mutations that prevent phosphorylation reduce LTD. Disruption of the interaction between GluR2 and GRIP/ABP by S880 phosphorylation may thus facilitate removal of synaptic AMPA receptors and mediate some forms of activity-dependent synaptic depression.
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PMID:Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. 1453 56

The present project was designed to investigate the role of protein kinase A (PKA) and protein kinase C (PKC) in the regulation of phosphorylation of the GluR1 subunits of AMPA receptors in the spinal cord of rats after capsaicin injection. We found that after capsaicin injection, a significant upregulation of phosphorylated GluR1 both at Ser(831) and Ser(845) was detected on the side ipsilateral to the injection. Intrathecal treatment with a PKA inhibitor, H89 ([N-[2-((3-bromophenyl)-2-propenyl)amino)ethyl]-5-isoquinoline sulfonamide, HCl), or a PKC inhibitor, NPC15473 (2,6-diamino-N-([1-oxotridecyl)-2-piperidinyl]methyl)hexanamide), significantly blocked the increased phosphorylation at different serine sites without affecting the GluR1 protein itself. Our results suggest that increased phosphorylation of the GluR1 subunit of AMPA receptors contributes to central sensitization following acute peripheral inflammation, and the effect may occur at different phosphorylation sites through the activation of the PKA or PKC protein kinase cascades.
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PMID:Protein kinases regulate the phosphorylation of the GluR1 subunit of AMPA receptors of spinal cord in rats following noxious stimulation. 1455 67

This study investigates whether retinal ischemia/reperfusion leads to alterations in the expression of AMPA-type glutamate receptor (AMPAR) subunits GluR1-4. In ischemia-vulnerable hippocampal neurons, a subunit-specific downregulation of GluR2 precedes the actual neurodegeneration. Our purpose was to study whether retinal ischemia induces a similar downregulation of GluR2 preceding the loss of ganglion and amacrine cells. A 60-min ischemic period was followed by reperfusion lasting between 2 h and 7 days. Changes in the expression patterns of GluR1-4 were assessed using immunocytochemistry. In the same sections, alterations in cell density, thickness of retinal layers, and density of apoptotic cells were investigated. Two-hour post-ischemia, GluR1 immunoreactivity was nearly absent from the inner plexiform layer (IPL). Thereafter, labeling intensity recovered slowly and was close to control levels at 7 days, albeit in a thinner IPL. The decrease in GluR2/3 labeling intensity was most profound at 4 h. The recovery of GluR2/3 staining intensity was slow, and staining was still decreased at 7 days. GluR2 immunoreactivity was not attenuated after ischemia. GluR4 labeling showed a similar time course as observed for GluR1, but the decrease in immunoreactivity was less profound and the recovery was nearly complete. The immunostaining of PKCalpha, a rod bipolar cell marker, was unaffected at all reperfusion times. The reduction of GluR staining preceded both the typical thinning of the IPL and the peak of cell loss, but coincided with a significant swelling of the IPL. In conclusion, retinal ischemia/reperfusion leads to differential changes in the expression of the different AMPA-type GluR subunits, which may affect excitatory synaptic transmission in the inner retina. However, no evidence was found for a preferential loss of GluR2 immunoreactivity that could account for selective neurodegeneration of amacrine and ganglion cells after retinal ischemia.
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PMID:Ischemia-induced alterations of AMPA-type glutamate receptor subunit. Expression patterns in the rat retina--an immunocytochemical study. 1470 73

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

Recent work has demonstrated that brief application of insulin to hippocampal slices can induce a novel form of long-term depression (insulin-LTD) in the CA1 region of the hippocampus; however, the molecular details of how insulin triggers LTD remain unclear. Using electrophysiological and biochemical approaches in the hippocampal slices, we show here that insulin-LTD (i) is specific to 3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor- but not NMDA receptor-mediated synaptic transmission; (ii) is induced and expressed postsynaptically but does not require the activation of ionotropic and metabotropic glutamate receptors; (iii) requires a concomitant Ca(2+) influx through l-type voltage-activated Ca(2+) channels (VACCs) and the release of Ca(2+) from intracellular stores; (iv) requires the series of protein kinases, including protein tyrosine kinase (PTK), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC); (v) is mechanistically distinct from low-frequency stimulation-induced LTD (LFS-LTD) and independent on protein phosphatase 1/2 A (PP1/2 A) and PP2B activation; (vi) is dependent on a rapamycin-sensitive local translation of dendritic mRNA, and (vii) is associated with a persistent decrease in the surface expression of GluR2 subunit. These results suggest that a PI3K/PKC-dependent insulin signaling, which controls postsynaptic surface AMPA receptor numbers through PP-independent endocytosis, may be a major expression mechanism of insulin-LTD in hippocampal CA1 neurons.
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PMID:An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus. 1503 Apr 6


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