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)

Recent work has demonstrated that a brief high-frequency conditioning stimulation to the primary afferent nerve fibers can induce a long-term potentiation (LTP) of synaptic transmission in neurons in the superficial layer of the trigeminal caudal nucleus; however, the cellular and molecular mechanisms underlying this synaptic potentiation remain unclear. Using both extracellular field potential and whole-cell patch-clamp recordings in brainstem parasagital slices of juvenile rat with the mandibular nerve attached, we show here that the induction of trigeminal primary afferent LTP: (1) does not require the activation of ionotropic glutamate receptors; (2) is dependent on extracellular Ca(2+) and the release of Ca(2+) from intracellular stores; (3) is specifically prevented by the metabotropic glutamate receptor subtype 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine but not the mGluR1 antagonist LY367385, group II mGluR antagonist LY341495 or group III mGluR antagonist MAP4; (4) is mimicked by the bath-applied group I mGluR agonist (S)-3,5-dihydroxyphenylglycine and mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine; (5) requires the activation of phospholipase C (PLC) and protein kinase C (PKC); and (6) is concomitantly with a decrease in paired-pulse depression. These results demonstrate that the activation of mGluR5 and in turn triggering a PLC/PKC-dependent signaling cascade may contribute to the induction of LTP of primary afferent synaptic transmission in the superficial layer of trigeminal caudal nucleus of juvenile rats. This may be relevant to the processing of nociceptive information.
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PMID:Characterization of long-term potentiation of primary afferent transmission at trigeminal synapses of juvenile rats: essential role of subtype 5 metabotropic glutamate receptors. 1577 67

In several neurological disorders including hyperhomocysteinemia, homocysteine (Hcy) accumulates in the brain, and acts as a potent neurotoxin. However, the molecular mechanisms induced by increased levels of Hcy in brain are not well understood. Here we show an activation of the extracellular signal-regulated kinases (ERK1 and ERK2) and the downstream nuclear targets Elk-1 and calcium/cAMP response element binding protein, in the hippocampus of cystathionine beta synthase deficient mice, a murine model of hyperhomocysteinemia. An ex vivo model of hippocampal slices allowed us to reproduce Hcy -induced ERK activation and to unravel the mechanisms responsible of this activation. Of interest, N-methyl-d-aspartate (NMDA), non-NMDA and metabotropic glutamate receptor antagonists all blocked Hcy -induced ERK activation. Moreover, the ERK activation was blocked in the presence of Na+-channel blocker tetrodotoxin, indicating the existence of a trans-synaptic activity in ERK activation by Hcy in hippocampal slices. The effects of Hcy on ERK cascade activation were also dependent on calcium influx, CaMK-II, PKC as well as PKA activation. Thus, altogether these data support a role of Hcy on ERK activation, via complex mechanisms, starting with a control of glutamate release, which in turn activates ionotropic and metabotropic receptor subtypes and produces increases in intracellular calcium levels.
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PMID:Regulation of extracellular signal-regulated kinase by homocysteine in hippocampus. 1591 60

Glutamate, the major excitatory neurotransmitter in the central nervous system, is critically involved in gene expression regulation at the transcriptional and translational levels. Its activity through ionotropic as well as metabotropic receptors modifies the protein repertoire in neurons and glial cells. In avian cerebellar Bergmann glia cells, glutamate receptors trigger a diverse array of signaling cascades that include activity-dependent transcription factors such as the activator protein-1, the cAMP response-element binding protein, and Oct-2. We analyze the upstream regulatory elements involved in Oct-2 activation. Our results demonstrate that Ca2+ influx, protein kinase C, phosphatidylinositol-3 kinase, Src, and nuclear factor (NF)kappaB are involved in this signaling pathway. Our findings link alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation to a negative phase of chkbp gene regulation, controlled by NFkappaB.
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PMID:Glutamate activation of Oct-2 in cultured chick Bergmann glia cells: involvement of NFkappaB. 1592 72

The phosphorylation of ionotropic glutamate receptors (iGluRs) by protein kinases plays a crucial role in synaptic plasticity. In the cerebellum, protein kinase C (PKC) activation is required for the induction of long-term depression (LTD) at parallel fibre-Purkinje cell synapses. Although delta2 glutamate receptors (GluRdelta2), expressed predominantly in Purkinje cells, are essential for cerebellar LTD, little is known about the mechanism by which GluRdelta2 participates in LTD or its relationship with PKC activation pathways. We found that a PKC activator, phorbol ester, induced postsynaptic LTD in Purkinje cells in mouse cerebellar slice preparations without significantly changing the presynaptic properties. Under this condition, the GluRdelta2 prepared from the cerebellar slices was significantly phosphorylated. Indeed, the C-terminus of the GluRdelta2 fused with glutathione-S-transferase (GST) was directly phosphorylated by purified PKC at a specific serine residue. In addition, two-dimensional phosphopeptide mapping analysis indicated that the major phosphorylation site of the GST-fusion protein containing the C-terminus of GluRdelta2 was identical to that of GluRdelta2 prepared from cerebellar slices. Therefore, GluRdelta2 is phosphorylated by PKC in vitro and by an LTD-inducing stimulus in slice preparations. Because this region of GluRdelta2 is known to associate with certain intracellular molecules, the PKC phosphorylation status of the C-terminus of GluRdelta2 may be involved in new signaling pathways during LTD.
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PMID:Induction of long-term depression and phosphorylation of the delta2 glutamate receptor by protein kinase C in cerebellar slices. 1619 24

The ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor is densely distributed in the mammalian brain and is primarily involved in mediating fast excitatory synaptic transmission. Recent studies in both heterologous expression systems and cultured neurons have shown that the AMPA receptor can be phosphorylated on their subunits (GluR1, GluR2, and GluR4). All phosphorylation sites reside at serine, threonine, or tyrosine on the intracellular C-terminal domain. Several key protein kinases, such as protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and tyrosine kinases (Trks; receptor or nonreceptor family Trks) are involved in the site-specific regulation of the AMPA receptor phosphorylation. Other glutamate receptors (N-methyl-d-aspartate receptors and metabotropic glutamate receptors) also regulate AMPA receptors through a protein phosphorylation mechanism. Emerging evidence shows that as a rapid and short-term mechanism, the dynamic protein phosphorylation directly modulates the electrophysiological, morphological (externalization and internalization trafficking and clustering), and biochemical (synthesis and subunit composition) properties of the AMPA receptor, as well as protein-protein interactions between the AMPA receptor subunits and various intracellular interacting proteins. These modulations underlie the major molecular mechanisms that ultimately affect many forms of synaptic plasticity.
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PMID:Phosphorylation of AMPA receptors: mechanisms and synaptic plasticity. 1638 40

Conventional protein kinase C (PKC) isoforms are abundant neuronal signaling proteins with important roles in regulating synaptic plasticity and other neuronal processes. Here, we investigate the role of ionotropic and metabotropic glutamate receptor (iGluR and mGluR, respectively) activation on the generation of Ca2+ and diacylglycerol (DAG) signals and the subsequent activation of the neuron-specific PKCgamma isoform in hippocampal neurons. By combining Ca2+ imaging with total internal reflection microscopy analysis of specific biosensors, we show that elevation of both Ca2+ and DAG is necessary for sustained translocation and activation of EGFP (enhanced green fluorescent protein)-PKCgamma. Both DAG production and PKCgamma translocation were localized processes, typically observed within discrete microdomains along the dendritic branches. Markedly, intermediate-strength NMDA receptor (NMDAR) activation or moderate electrical stimulation generated Ca2+ but no DAG signals, whereas mGluR activation generated DAG but no Ca2+ signals. Both receptors were needed for PKCgamma activation. This suggests that a coincidence detection process exists between iGluRs and mGluRs that relies on a molecular coincidence detection process based on the corequirement of Ca2+ and DAG for PKCgamma activation. Nevertheless, the requirement for costimulation with mGluRs could be overcome for maximal NMDAR stimulation through a direct production of DAG via activation of the Ca2+-sensitive PLCdelta (phospholipase Cdelta) isoform. In a second important exception, mGluRs were sufficient for PKCgamma activation in neurons in which Ca2+ stores were loaded by previous electrical activity. Together, the dual activation requirement for PKCgamma provides a plausible molecular interpretation for different synergistic contributions of mGluRs to long-term potentiation and other synaptic plasticity processes.
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PMID:Synergistic control of protein kinase Cgamma activity by ionotropic and metabotropic glutamate receptor inputs in hippocampal neurons. 1657 47

Taurine has been thought to function as a regulator of neuronal activity, neuromodulator and osmoregulator. Moreover, it is essential for the development and survival of neural cells and protects them under cell-damaging conditions. Taurine is also involved in many vital functions regulated by the brain stem, including cardiovascular control and arterial blood pressure. The release of taurine has been studied both in vivo and in vitro in higher brain areas, whereas the mechanisms of release have not been systematically characterized in the brain stem. The properties of release of preloaded [(3)H]taurine were now characterized in slices prepared from the mouse brain stem from developing (7-day-old) and young adult (3-month-old) mice, using a superfusion system. In general, taurine release was found to be similar to that in other brain areas, consisting of both Ca(2+)-dependent and Ca(2+)-independent components. Moreover, the release was mediated by Na(+)-, Cl(-)-dependent transporters operating outwards, as both Na(+)-free and Cl(-) -free conditions greatly enhanced it. Cl(-) channel antagonists and a Cl(-) transport inhibitor reduced the release at both ages, indicating that a part of the release occurs through ion channels. Protein kinases appeared not to be involved in taurine release in the brain stem, since substances affecting the activity of protein kinase C or tyrosine kinase had no significant effects. The release was modulated by cAMP second messenger systems and phospholipases at both ages. Furthermore, the metabotropic glutamate receptor agonists likewise suppressed the K(+)-stimulated release at both ages. In the immature brain stem, the ionotropic glutamate receptor agonists N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) potentiated taurine release in a receptor-mediated manner. This could constitute an important mechanism against excitotoxicity, protecting the brain stem under cell-damaging conditions.
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PMID:Characteristics of taurine release in slices from adult and developing mouse brain stem. 1668 Mar 99

Inhibitor-1 becomes a potent inhibitor of protein phosphatase 1 when phosphorylated by cAMP-dependent protein kinase at Thr(35). Moreover, Ser(67) of inhibitor-1 serves as a substrate for cyclin-dependent kinase 5 in the brain. Here, we report that dephosphoinhibitor-1 but not phospho-Ser(67) inhibitor-1 was efficiently phosphorylated by protein kinase C at Ser(65) in vitro. In contrast, Ser(67) phosphorylation by cyclin-dependent kinase 5 was unaffected by phospho-Ser(65). Protein kinase C activation in striatal tissue resulted in the concomitant phosphorylation of inhibitor-1 at Ser(65) and Ser(67), but not Ser(65) alone. Selective pharmacological inhibition of protein phosphatase activity suggested that phospho-Ser(65) inhibitor-1 is dephosphorylated by protein phosphatase 1 in the striatum. In vitro studies confirmed these findings and suggested that phospho-Ser(67) protects phospho-Ser(65) inhibitor-1 from dephosphorylation by protein phosphatase 1 in vivo. Activation of group I metabotropic glutamate receptors resulted in the up-regulation of diphospho-Ser(65)/Ser(67) inhibitor-1 in this tissue. In contrast, the activation of N-methyl-d-aspartate-type ionotropic glutamate receptors opposed increases in striatal diphospho-Ser(65)/Ser(67) inhibitor-1 levels. Phosphomimetic mutation of Ser(65) and/or Ser(67) did not convert inhibitor-1 into a protein phosphatase 1 inhibitor. On the other hand, in vitro and in vivo studies suggested that diphospho-Ser(65)/Ser(67) inhibitor-1 is a poor substrate for cAMP-dependent protein kinase. These observations extend earlier studies regarding the function of phospho-Ser(67) and underscore the possibility that phosphorylation in this region of inhibitor-1 by multiple protein kinases may serve as an integrative signaling mechanism that governs the responsiveness of inhibitor-1 to cAMP-dependent protein kinase activation.
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PMID:Phosphorylation of protein phosphatase inhibitor-1 by protein kinase C. 1677 99

Intracellular Ca2+ regulates a variety of neuronal functions, including neurotransmitter release, protein phosphorylation, gene expression and synaptic plasticity. In a variety of cell types, including neurons, Ca2+ is involved in actin reorganization, resulting in either actin polymerization or depolymerization. Very little, however, is known about the relationship between Ca2+ and the actin cytoskeleton organization in retinal neurons. We studied the effect of high-K+-induced depolarization on F-actin organization in salamander retina and found that Ca2+ influx through voltage-gated L-type channels causes F-actin disruption, as assessed by 53 +/- 5% (n = 23, P < 0.001) reduction in the intensity of staining with Alexa-Fluor488-phalloidin, a compound that permits visualization and quantification of polymerized actin. Calcium-induced F-actin depolymerization was attenuated in the presence of protein kinase C antagonists, chelerythrine or bis-indolylmaleimide hydrochloride (GF 109203X). In addition, phorbol 12-myristate 13-acetate (PMA), but not 4alpha-PMA, mimicked the effect of Ca2+ influx on F-actin. Activation of ionotropic AMPA and NMDA glutamate receptors also caused a reduction in F-actin. No effect on F-actin was exerted by caffeine or thapsigargin, agents that stimulate Ca2+ release from internal stores. In whole-cell recording from a slice preparation, light-evoked 'off' but not 'on' EPSCs in 'on-off' ganglion cells were reduced by 60 +/- 8% (n = 8, P < 0.01) by cytochalasin D. These data suggest that elevation of intracellular Ca2+ during excitatory synaptic activity initiates a cascade for activity-dependent actin remodelling, which in turn may serve as a feedback mechanism to attenuate excitotoxic Ca2+ accumulation induced by synaptic depolarization.
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PMID:Calcium channel and glutamate receptor activities regulate actin organization in salamander retinal neurons. 1677 35

Glycogen synthase kinase (GSK)-3 was identified initially as an enzyme that regulates glycogen synthesis in response to insulin, but more recent studies indicate that it is also involved in numerous cellular processes, including cell survival, cell cycle regulation, proliferation, and differentiation. Because extracellular ATP exerts trophic actions on astrocytes, we investigated a possible signaling linkage from P2 purinergic receptors to GSK3beta. Addition of ATP to primary cultures of rat cortical astrocytes resulted in phosphorylation of Ser9 on GSK3beta and a concomitant decrease in GSK3 activity. UTP and 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP) increased phosphorylation of Ser9 on GSK3beta indicating that metabotropic P2Y and ionotropic P2X receptors are coupled to GSK3beta. Signaling studies showed that phosphorylation of Ser9-GSK3beta in response to ATP was inhibited by downregulation of protein kinase C (PKC) but not by blockade of Akt or p70 S6 kinase pathways. PKC also links P2 receptors to ERK in astrocytes, but inhibition of ERK signaling did not block phosphorylation of Ser9-GSK3beta stimulated by P2 receptors. Mechanical strain, which releases ATP, also stimulated Ser9 phosphorylation and this was attenuated by hydrolysis of extracellular ATP with apyrase or by blockade of P2 receptors. We conclude that P2 receptors are coupled to GSK3beta by a PKC-dependent pathway that is independent of Akt, p70 S6 kinase, and ERK pathways. These findings suggest that purinergic signaling contributes to the regulation of GSK3beta functions, one of which may be the response of astrocytes to CNS injury on release of ATP.
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PMID:P2 purinergic receptors signal to glycogen synthase kinase-3beta in astrocytes. 1681 Jun 87


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