Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Behavioral reactions to stress are altered in numerous psychiatric and neurodegenerative syndromes, but the corresponding molecular processes and signal transduction pathways are yet unknown. Here, we report that, in mice, the stress-induced splice variant of acetylcholinesterase, AChE-R, interacts intraneuronally with the scaffold protein RACK1 and through it, with its target, protein kinase CbetaII (PKCbetaII), which is known to be involved in fear conditioning. In stress-responsive brain regions of normal FVBN mice, the mild stress of i.p. injection increased AChE and PKCbetaII levels in a manner suppressible by antisense prevention of AChE-R accumulation. Injection stress also prolonged conflict between escape and hiding in the emergence into an open field test. Moreover, transgenic FVBN mice overexpressing AChE-R displayed prolonged delay to emerge into another field (fear-induced behavioral inhibition), associated with chronically intensified neuronal colabeling of RACK1 and PKCbetaII in stress-responsive brain regions. These findings are consistent with the hypothesis that stress-associated changes in cholinergic gene expression regulate neuronal PKCbetaII functioning, promoting fear-induced conflict behavior after stress.
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PMID:Interaction of "readthrough" acetylcholinesterase with RACK1 and PKCbeta II correlates with intensified fear-induced conflict behavior. 1250 14

We previously isolated a nerve growth factor (NGF)-dependent neurite outgrowth promoting substance MC14 (sargaquinoic acid) from a marine brown alga, Sargassum macrocarpum. In the present study, the NGF-potentiating activity of MC14 to neural differentiation of PC12D cells was investigated in detail. The treatment of cells with 3 microg/ml MC14 in the presence of 1.25-100 ng/ml NGF markedly enhanced the proportion of neurite-bearing cells compared with the NGF-only controls. In addition, MC14 significantly elevated the NGF-induced specific acetylcholinesterase (AchE) activity in PC12D cells, suggesting that MC14 could morphologically and biochemically promote the differentiation of PC12D cells. The mechanism of action of MC14 was further investigated by pharmacological inhibition of several intracellular signaling molecules. Results indicated that the neurite outgrowth promoting activity of MC14 was almost completely blocked by 10 microM PD98059, suggesting that a TrkA-dependent MAP kinases-mediated signaling pathway may play a crucial role in modulating the effect of MC14. Besides, the MC14-enhanced neurite outgrowth was substantially suppressed by the pretreatment with 10 ng/ml protein kinase A (PKA) inhibitor, demonstrating that the adenylate cyclase-PKA signaling cascade was also involved in the action of MC14. In contrast, a PKC inhibitor chelerythrine chloride did not inhibit the neurite outgrowth promoting activity of MC14. Altogether, these results demonstrate that MC14 enhances the neurite outgrowth by cooperating at least two separated signaling pathways, a TrkA-MAP kinases pathway and an adenylate cyclase-PKA pathway, in PC12D cells.
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PMID:Sargaquinoic acid promotes neurite outgrowth via protein kinase A and MAP kinases-mediated signaling pathways in PC12D cells. 1285 58

Previous work has identified a role for synaptic activity in the development of excitable properties of motoneurons in the Drosophila embryo. In this study the underlying mechanism that enables two such neurons, termed aCC and RP2, to respond to increased exposure to synaptic excitation is characterized. Synaptic excitation is increased in genetic backgrounds that lack either a cAMP-specific phosphodiesterase (EC:3.1.4, dunce) or acetylcholinesterase (EC:3.1.1.7, ace), the enzyme that terminates the endogenous cholinergic excitation of these motoneurons. Analysis of membrane excitability in aCC/RP2, in either background, shows that these neurons have a significantly reduced capability to fire action potentials (APs) in response to injection of depolarizing current. Analysis of underlying voltage-gated currents show that this effect is associated with a marked reduction in magnitude of the voltage-dependent inward Na+ current (INa). Partially blocking INa in these motoneurons, using low concentrations of TTX, demonstrates that a reduction of INa is, by itself, sufficient to reduce membrane excitability. An analysis of firing implicates an increased AP threshold to underlie the reduction in membrane excitability observed because of heightened exposure to synaptic excitation. Genetic or pharmacological manipulations that either elevate cAMP or increase protein kinase A (PKA) activity in wild-type aCC/RP2 mimic both the reductions in membrane excitability and INa. In comparison, increasing cAMP catabolism or inhibition of PKA activity is sufficient to block the induction of these activity-dependent changes. The induced changes in excitability can be rapid, occurring within 5 min of exposure to a membrane-permeable cAMP analog, indicative that threshold can be regulated in these neurons by a post-translational mechanism that is dependent on phosphorylation.
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PMID:Postsynaptic protein kinase A reduces neuronal excitability in response to increased synaptic excitation in the Drosophila CNS. 1450 65

Galantamine, a new Alzheimer's drug approved in the United States, is known to inhibit acetylcholinesterase and potentiate acetylcholine-induced currents in brain neurons. However, because both cholinergic and N-methyl-D-aspartate (NMDA) systems are down-regulated in the brain of Alzheimer's patients, we studied the effects of galantamine on NMDA receptors. NMDA-induced whole-cell currents were recorded from the rat multipolar cortical neurons in primary culture. NMDA currents recorded in Mg2+-free media without addition of glycine were reversibly potentiated by bath and U-tube applications of galantamine at 10 to 10,000 nM, showing a bell-shaped dose-response relationship. However, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate currents were not affected by galantamine. The maximum potentiation of NMDA currents to approximately 130% of the control was obtained at 1 microM galantamine. The potentiation was due to a shift of the NMDA dose-response curve in the direction of lower NMDA concentrations. Glycine at 1 to 3000 nM enhanced NMDA currents, and potentiation by 1 microM galantamine and 1 to 300 nM glycine was additive. The glycine site antagonist 7-chlorokynurenic acid did not prevent the galantamine action. These results suggested that galantamine did not interact with the glycine binding site. Experiments with various concentrations of Mg2+ indicated that galantamine did not affect the Mg2+ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, Gi/Go proteins, and Gs proteins were not involved. Potentiation of the activity of NMDA receptors is deemed partially responsible for the improvement of cognition, learning, and memory in Alzheimer's patients.
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PMID:Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. 1512 61

We have recently shown that the anti-Parkinson-propargyl-containing monoamine oxidase B (MAO-B) inhibitor drug, rasagiline [N-propargyl-(1R)-aminoindan], and its cholinesterase inhibitor derivatives TV3326 and TV3279, regulate amyloid precursor protein (APP) processing by a protein kinase C (PKC)-dependent mechanism in SH-SY5Y neuroblastoma and PC12 cells. In the present study, we investigated the effect of rasagiline and its derivatives on the regulation of the PKC-dependent mechanism and APP processing under in vivo conditions. Administration of rasagiline (0.1 mg/kg) to male C57/BL mice for 14 days significantly decreased membrane-bound holoprotein APP levels in the hippocampus. Additionally, we observed that rasagiline up-regulated p-PKC levels and the expression of alpha and epsilon PKC isozymes in the hippocampus, indicating that the mechanism by which rasagiline affects APP processing may be related to PKC-associated signalling. The results also demonstrate that rasagiline treatment significantly elevated the levels of phosphorylated myristoylated alanine-rich C kinase substrate (p-MARCKS), a major substrate for PKC, as well as the levels of receptors for activated C kinase 1 (RACK1). Similar effects on APP and PKC levels were also demonstrated for the two cholinesterase inhibitor derivatives of rasagiline, TV3326 and TV3279. These results indicate that rasagiline and its derivatives regulate PKC-dependent mechanisms and APP processing. The activation and induction of PKC and MARCKS by these drugs may have a crucial role not only in their neuroprotective activity, but also in their ability to affect neuronal plasticity and spatial learning processes.
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PMID:Regulation of protein kinase C by the anti-Parkinson drug, MAO-B inhibitor, rasagiline and its derivatives, in vivo. 1514 4

We examined the effect of the acetylcholinesterase (AChE) inhibitor, donepezil hydrocloride (DONP), on group II metabotropic glutamate (mGlu) receptor agonist- or antagonist-induced amnesia in the step-through passive avoidance task in male mice. DCG-IV, a group II mGlu receptor agonist, at dose of 50 ng and LY341495, a group II mGlu receptor antagonist, at dose of 300 ng, significantly attenuated the latency on the step-through task. The subcutaneous injection of DONP at dose of 1 mg/kg 1 hour before passive avoidance performance ameliorated the amnesia induced by DCG-IV and LY341495, whereas donepezil alone did not affect task latency. The results suggest that activation of group II mGlu receptors and disinhibition of the cAMP/PKA signaling pathway (caused by group II mGlu receptor antagonist) have a negative action on step-through passive avoidance memory performance, and that group II mGlu receptors and ACh interact to modulate learning and memory function.
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PMID:Effect of donepezil on group II mGlu receptor agonist- or antagonist-induced amnesia on passive avoidance in mice. 1515 85

The cyclic adenosine monophosphate (AMP) response element-binding protein, CREB, often modulates stress responses. Here, we report that CREB suppresses the glioblastoma proliferative effect of the stress-induced acetylcholinesterase variant, AChE-R. In human U87MG glioblastoma cells, AChE-R formed a triple complex with protein kinase C (PKC) epsilon and the scaffold protein RACK1, enhanced PKCepsilon phosphorylation, and facilitated BrdU incorporation. Either overexpressed CREB, or antisense destruction of AChE-R mRNA, PKC, or protein kinase A (PKA) inhibitors-but not CREB combined with PKC inhibition suppressed-this proliferation, suggesting that CREB's repression of this process involves a PKC-mediated pathway, whereas impaired CREB regulation allows AChE-R-induced, PKA-mediated proliferation of glioblastoma tumors.
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PMID:CREB regulates AChE-R-induced proliferation of human glioblastoma cells. 1515 40

Histone acetyltransferase and histone deacetylase (HDAC) determine the acetylation status of histones, and thereby control the regulation of gene expression. HDAC inhibitors have been found to inhibit the growth of a variety of tumor cells in vitro and in vivo. We demonstrated previously that the short-chain fatty acid compound butyrate and its derivative tributyrin (both HDAC inhibitors) arrest cell growth and induce differentiation in human neuroblastoma (NB) cells. In the current study we investigated the effect of the HDAC inhibitor valproic acid (VPA) on proliferation and differentiation in human NB cells (SJ-N-KP, AF8). Treatment with VPA resulted in a strong inhibition of cell proliferation and induction of cell differentiation, as revealed by neurite outgrowth and increase of acetylcholinesterase specific activity. Moreover, we addressed the question of whether the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1) are involved in the mechanism of action of members of the short-chain fatty acids class (VPA, sodium butyrate and tributyrin) of HDAC inhibitors, in human NB cells. We demonstrated that p21(Cip1) is a common target of induction of transcription and protein expression for all the three compounds, while only VPA induced a concomitant increase of p27(Kip1) gene expression. These results suggest that p21(Cip1) could be involved in the inhibition of proliferation and induction of differentiation in human NB cells induced by treatment with VPA or tributyrin or sodium butyrate. Moreover, p21(Cip1) could be applied in the molecular monitoring of drug action in the possible therapeutic application of these short-chain fatty acid members of HDAC inhibitors for human NB treatment.
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PMID:p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. 1587 Sep 34

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of -70 mV in Mg2+-free solutions. In multipolar neurons, NMDA currents were decreased by bath and U-tube applications of 1 to 10 microM donepezil but were increased by 30 to 100 microM donepezil. Donepezil suppression occurred in a manner independent of NMDA concentrations ranging from 3 to 1000 microM. The donepezil suppression of NMDA currents was prevented by inhibition of protein kinase C (PKC) but unaffected by protein kinase A (PKA) and G proteins. In bipolar neurons, however, NMDA currents were potently augmented by bath and U-tube applications of 0.01 to 100 microM donepezil. Donepezil potentiation occurred at high NMDA concentrations that evoked the saturating responses and in a manner independent of NMDA concentrations ranging from 3 to 1000 microM. The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01-1 microM) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease.
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PMID:Modulation of N-methyl-D-aspartate receptors by donepezil in rat cortical neurons. 1595 96

MicroRNAs (miRNAs) are abundant small regulatory RNAs with multiple roles in cell fate determination. The processes regulating cellular miRNA levels are still unclear and experimental oligonucleotide tools to readily mimic their effects are not yet available. Here, we report that thapsigargin-induced intracellular Ca(++) release suppressed pre-miR-181a levels in human promegakaryotic Meg-01 cells, induced differentiation-associated nuclear endoreduplication and caspase-3 activation and replaced the acetylcholinesterase 3' splice variant AChE-S with AChE-R. AChE, PKC and PKA inhibitors all attenuated the pre-miR-181a decline and the induced differentiation. AChmiON, a synthetic 23-mer 2'-oxymethylated oligonucleotide mimicking the miR-181a sequence, blocked the calcium-induced differentiation while elevating cellular pre-miR-181a levels and inducing DNA fragmentation and cell death. Moreover, when added to RW 264.7 macrophages, AChmiON at 100 nM induced nitric oxide production with efficiency close to that of bacterial endotoxin, demonstrating physiologically relevant activities also in blood-born monocytes/macrophages. The stress-induced modulation of hematopoietic miR-181a levels through AChE, PKC and PKA cascade(s) suggests using miRNA mimics for diverting the fate of hematopoietic tumor cells towards differentiation and/or apoptosis.
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PMID:MicroRNA modulation of megakaryoblast fate involves cholinergic signaling. 1624 78


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