Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligodendroglia play an important role in axonal conduction in the CNS and are sensitive to oxidative toxicity induced by glutamate in the absence of ionotropic glutamate receptors. In this study, oligodendrocyte signalling cascades were examined, in response to glutamate-induced oxidative injury and to excitotoxicity. Rat cortical oligodendrocytes, differentiated in culture, were highly vulnerable to glutamate-induced cell death. Competitive inhibition of cystine uptake and increased oxidative stress appeared responsible for this death, and caused an accumulation of intracellular peroxides as well as chromatin fragmentation and condensation. Glutamate receptor subtype agonists (quisqualate, ibotenate) known to inhibit cystine uptake were cytotoxic, but not NMDA itself; moreover, glutamate receptor antagonists were not protective. Oligodendrocytes were also vulnerable to overactivation of glutamate receptors, as kainic acid and AMPA proved to be toxic. AMPA toxicity required the presence of cyclothiazide, suggesting rapid desensitization of AMPA receptors. Glutamate-induced oxidative stress and kainate/AMPA receptor stimulation activated the mitogen-activated protein kinase (MAP kinase) pathway, as well as the transcription factor ELK. However, MAP kinase kinase inhibitors only protected against injury from glutamate-induced oxidative stress. Oligodendrocytes were sensitive to oxygen-glucose deprivation injury as well, in a MAP kinase dependent fashion. Glutamate toxicity may conceivably be operative in neuropathological conditions that disrupt neuronal/oligodendrocyte interactions in axons, e.g. multiple sclerosis and ischaemia-reperfusion injury.
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PMID:Excitatory amino acid induced oligodendrocyte cell death in vitro: receptor-dependent and -independent mechanisms. 1531 72

Glutamate-induced oxidative toxicity is mediated by glutathione depletion in the HT22 mouse hippocampal cell line. Previous results with pharmacological agents implicated the extracellular signal-regulated kinases-1/2 (ERK1/2) in glutamate toxicity in HT22 cells and immature embryonic rat cortical neurons. In this report, we definitively establish a role for ERK1/2 in oxidative toxicity using dominant negative MEK1 expression in transiently transfected HT22 cells to block glutamate-induced cell death. In contrast, chronic activation of ERK (i.e. brought about by transfection of constitutively active ERK2 chimera) is not sufficient to trigger HT22 cell death demonstrating that ERK1/2 activation is not sufficient for toxicity. Activation of ERK1/2 in HT22 cells has a distinct kinetic profile with an initial peak occurring between 30 min and 1 h of glutamate treatment and a second peak typically emerging after 6 h. We demonstrate here that the initial phase of ERK1/2 induction is because of activation of metabotropic glutamate receptor type I (mGluRI). ERK1/2 activation by mGluRI contributes to an HT22 cell adaptive response to oxidative stress as glutamate-induced toxicity is enhanced upon pharmacological inhibition of mGluRI. The protective effect of ERK1/2 activation at early times after glutamate treatment is mediated by a restoration of glutathione (GSH) levels that are reduced because of depletion of intracellular cysteine pools. Thus, ERK1/2 appears to play dual roles in HT22 cells acting as part of a cellular adaptive response during the initial phases of glutamate-induced oxidative stress and contributing to toxicity during later stages of stress.
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PMID:Opposing roles for ERK1/2 in neuronal oxidative toxicity: distinct mechanisms of ERK1/2 action at early versus late phases of oxidative stress. 1662 2

Chromogranin A (CgA) is associated with microglial activation cascades implicated in neurodegeneration in Alzheimer's, Pick's and Parkinson's diseases. In primary rat microglia, CgA-mediated inducible nitric oxide (iNOS) expression, nitric oxide (NO) production, mitochondrial depolarisation and apoptosis were inhibited by PP2 (Src kinase inhibitor). CgA-mediated iNOS expression and NO production were also inhibited by U0126 (MEK inhibitor), but mitochondrial depolarisation and apoptosis were not. PP2 inhibited ERK phosphorylation; therefore, Src mediates CgA-induced ERK phosphorylation leading to iNOS expression and NO production. Glutamate release induced by CgA was independent of both pathways. These findings provide insights into the way microglia are activated by CgA and the microglial signalling mechanisms associated with neurological disorders such as Alzheimer's disease.
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PMID:Chromogranin A activates diverse pathways mediating inducible nitric oxide expression and apoptosis in primary microglia. 1726 11

ATP can be significantly released following various brain insults and activates the extracellular signal-regulated protein kinase (ERK) pathway in astrocytes. Glutamate transporter-1 (GLT1) is the major forebrain astroglial glutamate transporter and its expression is stimulated also via ERK1/2 phosphorylation. We thus hypothesized that extracellular ATP could be a signal to GLT1 modulation in hippocampal slices obtained from rat. We indeed observed by western blot analysis that, after 1 mM ATP exposure, GLT1 expression, but not the glutamate-aspartate transporter, was enhanced. At the same time, high ATP induced significant rates of cell death in piramidal and granule cell layers, as shown by propidium iodide uptake, and increased glutamate uptake through GLT1 transporter. Also using confocal laser-scanning microscopy, we observed that ATP induced a vigorous and extensive GLT1-labeling on glial fibrillary acidic protein-positive cells. This stimulation was abolished by purine/pyrimidine nucleotide receptor antagonists and by MEK1/2 inhibitor. The present study demonstrates a novel mechanism of GLT1 regulation by extracellular ATP, reinforcing the evidence of cross talk between glutamatergic and purinergic systems.
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PMID:Extracellular adenosine triphosphate induces glutamate transporter-1 expression in hippocampus. 1733 Aug 63

Glutamate excitotoxicity may culminate with neuronal and glial cell death. Glutamate induces apoptosis in vivo and in cell cultures. However, glutamate-induced apoptosis and the signaling pathways related to glutamate-induced cell death in acute hippocampal slices remain elusive. Hippocampal slices exposed to 1 or 10 mM glutamate for 1 h and evaluated after 6 h, showed reduced cell viability, without altering membrane permeability. This action of glutamate was accompanied by cytochrome c release, caspase-3 activation and DNA fragmentation. Glutamate at low concentration (10 microM) induced caspase-3 activation and DNA fragmentation, but it did not cause cytochrome c release and, it did not alter the viability of slices. Glutamate-induced impairment of hippocampal cell viability was completely blocked by MK-801 (non-competitive antagonist of NMDA receptors) and GAMS (antagonist of KA/AMPA glutamate receptors). Regarding intracellular signaling pathways, glutamate-induced cell death was not altered by a MEK1 inhibitor, PD98059. However, the p38 MAPK inhibitor, SB203580, prevented glutamate-induced cell damage. In the present study we have shown that glutamate induces apoptosis in hippocampal slices and it causes an impairment of cell viability that was dependent of ionotropic and metabotropic receptors activation and, may involve the activation of p38 MAPK pathway.
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PMID:Glutamate-induced toxicity in hippocampal slices involves apoptotic features and p38 MAPK signaling. 1761 14

Cimicifuga rhizoma has long been used in traditional Korean medicine. In particular, a Cimicifuga heracleifolia extract (CHE) was reported to inhibit the formation of glutamate and the glutamate dehydrogenase activity in cultured rat islet. Glutamate activates melanogenesis by activating tyrosinase. Accordingly, it was hypothesized that a CHE might inhibit the melanogenesis-related signal pathways including the inhibition of microphthalmia-associated transcription factor (MITF)-tyrosinase signaling and/or the activation of extracellular signal-regulated kinase (ERK)-Akt signaling. The results showed that CHE inhibits the cellular melanin contents, tyrosinase activity and expression of melanogenesis-related proteins including MITF, tyrosinase and tyrosinase-related protein (TRP)s in alpha-melanocyte-stimulating hormone-stimulated B16 cells. Moreover, CHE phosphorylates MEK, ERK1/2 and Akt, which are melanogenesis inhibitory proteins. The data suggest that CHE inhibits melanogenesis signaling by both inhibiting the tyrosinase directly and activating the MEK-ERK or Akt signal pathways-mediated suppression of MITF and its downstream signal pathway, including tyrosinase and TRPs. Therefore, C. heracleifolia would be a useful therapeutic agent for treating hyperpigmentation and an effective component in whitening and/or lightening cosmetics.
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PMID:Dichloromethane fraction of Cimicifuga heracleifolia decreases the level of melanin synthesis by activating the ERK or AKT signaling pathway in B16F10 cells. 1880 55

Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer patients. Treatment of a tumor-derived cell line with NMDAR antagonists impaired cancer cell proliferation and invasion. Flow conditions mimicking interstitial fluid pressure induced autologous glutamate secretion, activating NMDAR and its downstream MEK-MAPK and CaMK effectors, thereby promoting invasiveness. Congruently, pharmacological inhibition of NMDAR in mice with PNET reduced tumor growth and invasiveness. Therefore, beyond its traditional role in neurons, NMDAR may be activated in human tumors by fluid flow consequent to higher interstitial pressure, inducing an autocrine glutamate signaling circuit with resultant stimulation of malignancy.
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PMID:Hijacking the neuronal NMDAR signaling circuit to promote tumor growth and invasion. 2354 Jun 92

Cooperative gene regulation by different neurotransmitters likely underlies the long-term forms of associative learning and memory, but this mechanism largely remains to be elucidated. Following cDNA microarray analysis for genes regulated by Ca(2+) or cAMP, we found that the secretogranin II gene (Scg2) was cooperatively activated by glutamate and dopamine in primary cultured mouse hippocampal neurons. The Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and the mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 prevented Scg2 activation by glutamate or dopamine; thus, the Ca(2+) /MEK pathway is predicted to include a convergence point(s) of glutamatergic and dopaminergic signaling. Unexpectedly, the protein kinase A inhibitor KT5720 enhanced Scg2 activation by dopamine. The protein-synthesis inhibitor cycloheximide also enhanced Scg2 activation, and the proteasome inhibitor ZLLLH diminished the KT5720-mediated augmentation of Scg2 activation. These results are concordant with the notion that dopaminergic input leads to accumulation of a KT5720-sensitive transcriptional repressor, which is short-lived because of rapid degradation by proteasomes. This repression pathway may effectively limit the time window permissive to Scg2 activation by in-phase glutamate and dopamine inputs via the Ca(2+) /MEK pathway. We propose that the regulatory system of Scg2 expression is equipped with machinery that is refined for the signal integration of in-phase synaptic inputs. We proposed hypothetical mechanism for the regulation of the secretogranin II gene as a signal integrator of glutamate and dopamine inputs. Glutamate or dopamine activates the Ca(2+) /MEK/ERK pathway, which thus contributes to the signal integration. Concurrently, activation of the PKA inhibitor KT5720-sensitive pathway by dopamine leads to accumulation of the repressor protein X that is otherwise susceptible to proteasome degradation. This repression system may determine the time window permissive to the cooperative activation by in-phase glutamate and dopamine inputs.
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PMID:The secretogranin II gene is a signal integrator of glutamate and dopamine inputs. 2411 84

Glutamate can activate NMDA receptor (NMDAR) and subsequently induces excitotoxic neuron loss. However, roles of NMDARs in the blood-brain barrier (BBB) are little known. This study used a mouse cerebrovascular endothelial cell (MCEC) model to evaluate the effects of NMDAR activation on maintenance of the BBB and its possible mechanisms. Analysis of confocal microscopy revealed expressions of NMDAR subunits, GluN1 and GLUN2B, in MCECs. An immunoblot assay further showed the existence of GluN1 in plasma membranes of MCECs. In brain tissues, a confocal microscopic analysis demonstrated co-localization of GluN1 and factor VIII, a biomarker of MCECs. In addition, GluN1 mRNA was detected in MCECs and the brain. Functional assays showed that exposure of MCECs to NMDA increased calcium influx. Separately, NMDA suppressed transendothelial electrical resistance values, levels of occludin, and occludin tight junctions. As to the mechanism, NMDA stimulated sequential phosphorylations of extracellular signal-regulated kinase (ERK)1/2 and mitogen-activated ERK (MEK)1. Interestingly, amounts of matrix metalloproteinase (MMP)2 and MMP9 in MCECs were augmented by NMDA. The NMDA-induced alterations in ERK1/2 phosphorylation and occludin levels were reversed by pretreatment with PD98059, a MEK inhibitor, and MK-801, a NMDAR antagonist, respectively. Therefore, this study shows the functional presence of NMDARs in MCECs, and NMDAR activation can disrupt the MCEC-constructed tight junction barrier via activation of the MEK1/2-ERK1/2 signaling pathway and upregulation of MMP2/9 expressions.
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PMID:Roles of NMDARs in maintenance of the mouse cerebrovascular endothelial cell-constructed tight junction barrier. 2665 82


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