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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As part of our study, a series of N-phenyl- and N-benzyl-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides [III-XVI], structurally related to the previously described N-phenyl- or N-pirydyl-3-arylpyrrolidine-2,5-dione [I, II], were synthesized and tested for their anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc. MET) tests. The most potent in the maximum electroshock seizure (MES) test were compounds with methyl [III] and chloro [XI] substituents at position -2 of the aromatic ring, whereas of all the synthesized compounds, only N-(2-methoxybenzyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [XII] was active in the sc. MET. Compounds with substituents at position -3 or -4 of the aromatic ring were found to be less active [V, VI, XIII and XIV], or devoid of activity [VII, IX, XV and XVI]. In contrast, the N-(4-chlorophenyl)-bicyclo [2.2.1] hept-5-ene-2,3-dicarboximide [VIII] at a dose of 100 mg/kg was active in the MES test.
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PMID:Synthesis and anticonvulsant activity of a series of N-substituted bicyclo [2.2.1] hept-5-ene-2,3-dicarboximides. 1619 14

SE in the pediatric age group presents challenges in diagnosis and management. There is need for renewed consensus on the temporal definition of SE, both clinical and electrographic. SE in children exhibits an age-dependent vulnerability, with genetic predisposition and etiology as determinants of susceptibility. Nonepileptic phenomena may mimic SE. Clinical and electrographic SE in neonates are relatively rare, while serial (clinical and electrographic) and repetitive seizures are more common. Neurometabolic disease, chromosomal disorders, and abnormalities of cortical development are important etiological considerations. Abrupt discontinuation of or an aberrant response to AEDs can also precipitate SE. Metabolic perturbations and toxins can further aggravate the situation. Clinical and experimental data suggest that the longer a seizure lasts, the more difficult it becomes to control, and that seizures can have immediate and long-term adverse consequences on the immature and developing brain. Hence, treatment (usually with a benzodiazepine) should be started early in the clinical course. A trial of pyridoxine, biotin, or folinic acid should be considered in the appropriate clinical setting (e.g., neonates or young infants, in particular). Phenytoin/fosphenytoin and phenobarbital remain important treatment options. Pentobarbital and midazolam are preferred choices in the management of RSE. Once metabolic causes are excluded, children with RSE should be evaluated for surgical treatment early in the clinical course. Clinical guidelines based on best available evidence have to be periodically reviewed. The clinical consequences and management of electrographic SE, especially in the neonate, have to be addressed. Guidelines for continuous (video) EEG monitoring are needed to facilitate this task. AEDs that do not have an adverse effect on the developing brain have to be developed. Our review suggests a continuing need for prospective studies into all aspects of SE in the pediatric age group.
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PMID:Status epilepticus in pediatric practice: neonate to adolescent. 1638 32

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity. DeltaPK-infected neuronal cells expressed a mutant ICP10 protein that is deleted in the PK domain and is kinase negative (p95). p175 and p95 were expressed in CA3 (86+/-3%) and CA1 (69+/-7%) cells from DeltaRR or DeltaPK-infected organotypic hippocampal cultures (OHC) and 80-85% of the ICP10 positive cells co-stained with antibody to beta(III) Tubulin (neuronal marker). DeltaRR, but not DeltaPK, inhibited KA-induced cell death and caspase-3 activation in CA3 neurons, an inhibition seen whether DeltaRR was delivered 2 days before or 2 days after KA administration (95% neuroprotection). Neuroprotection was associated with ERK and Akt activation and was abrogated by simultaneous treatment with the MEK (U0126) and PI3-K (LY294002) inhibitors. DeltaRR-mediated neuroprotection was associated with increased expression of the anti-apoptotic protein Bag-1 and decreased expression of the pro-apoptotic protein Bad. The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury.
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PMID:The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures. 1702 Jul 50

Activation of c-fos in brain is related to coupling of neuronal activity to gene expression, but also to pathological conditions such as seizures or excitotoxicity-induced cell death. Glutamate activates c-fos in neurons through the calcium-dependent phosphorylation of CREB by ERK and/or CaMKIV kinase pathways downstream NMDA-receptors. In glial cells, however, the activation of c-fos by glutamate is poorly understood. Because glial cells actively modulate neuronal excitability and the brain's response to injury, we studied the mechanisms by which glutamate activates c-fos in rat cortical glial cells. Glutamate potently induced c-fos mRNA in a calcium-dependent manner, as demonstrated by using the calcium chelator BAPTA-AM. Glutamate-induced c-fos mRNA expression was not sensitive to inhibitors of ERK, p38(MAPK), or CaMK pathways, indicating that glial c-fos is activated by a distinct mechanism. Thapsigargin abolished the glutamate effect on c-fos mRNA, indicating ER calcium mobilization. Additionally, glutamate induction of c-fos mRNA was sensitive to the mGluR5 antagonist MPEP but not the NMDA-R antagonist MK-801. In luciferase reporter assays, DRE, which actively represses c-fos by binding the calcium-binding transcriptional repressor DREAM, was activated by glutamate, whereas SRE and CRE were not. Finally, glutamate caused the nuclear export of DREAM in astrocytes, and transfection of astrocytes with a mutant variant of DREAM that constitutively binds DNA inhibited glutamate-induced c-Fos expression. These findings are in sharp contrast to the mechanism described in neurons and suggest a novel pathway activated by glutamate in glial cells that employs mGluR5, ER calcium, and the derepression of c-fos at the DRE.
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PMID:Glutamate activates c-fos in glial cells via a novel mechanism involving the glutamate receptor subtype mGlu5 and the transcriptional repressor DREAM. 1712 Feb 44

Stimulation paradigms that induce perforant path long-term potentiation (LTP) initiate phosphorylation of ERK1/2 and induce expression of a variety of immediate early genes (IEGs). These events are thought to be critical components of the mechanism for establishing the changes in synaptic efficacy that endure for hours or longer. Here we show that in mice, perforant path LTP can be induced using a standard protocol (repeated trains at 250 Hz), without accompanying increases in immunostaining for p-ERK1/2 or increased in expression of representative IEGs (Arc and c-fos). Signaling pathways capable of inducing ERK phosphorylation and IEG transcription are intact in mice because ERK phosphorylation differs strikingly in awake versus anesthetized mice, and IEG expression is strongly induced by electroconvulsive seizures. In pursuing the reasons for the lack of induction with LTP, we found that in rats, one of the stimulation paradigms used to induce perforant path LTP (trains at 250 Hz) also does not activate MAP kinase or induce IEG expression, despite the fact that the LTP induced by 250 Hz stimulation requires NMDA receptor activation and persists for hours. These findings indicate that there are different forms of perforant path LTP, one of which does not require MAP kinase activation or IEG induction. Moreover, these data demonstrate that different LTP induction paradigms do not have identical molecular consequences, which may account for certain discrepancies between previous studies.
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PMID:A form of perforant path LTP can occur without ERK1/2 phosphorylation or immediate early gene induction. 1756 95

The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.
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PMID:ERK activation causes epilepsy by stimulating NMDA receptor activity. 1797 14

A 4-year-old African American male was referred to the Pediatric Neurosurgery Service for evaluation of new onset seizures and worsening mental status. An MRI of the brain revealed a pineal region mass with diffuse leptomeningeal enhancement and compression of the basilar cisterns. A biopsy of the brain revealed histologic and immunophenotypic findings characteristic of ALK-1+ anaplastic large cell lymphoma (ALCL). ALCL rarely occurs in the central nervous system and poses a significant diagnostic challenge often leading to a delay in the initiation of appropriate treatment. We describe a case of a rapidly deteriorating clinical course in a child with central nervous system ALCL and review the current literature on ALCL occurring in the central nervous system.
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PMID:Primary cerebral ALK-1-positive anaplastic large cell lymphoma in a child. Case report and literature review. 1799 44

Proteins are subject to various types of spontaneous modifications that can disrupt their structures with sometimes adverse affects on biological activity. The formation of L-isoaspartyl (or D-aspartyl) residues, through either the deamidation of asparagine or dehydration of aspartate, is one of the most frequent types of deterioration occurring under physiological conditions. Protein L-isoaspartate/D-aspartate o-methyltransferase (PIMT) is a conserved and ubiquitous enzyme that participates in the repair of various isomerized proteins. PIMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine onto the alpha-carboxyl group of an L-isoaspartyl (or the beta-carboxyl group of an D-aspartyl) residue, which initiates the conversion of this residue to an L-aspartyl residue. PIMT-deficient mice have been shown to die at a mean age of 42 days from progressive epileptic seizures with grand mal and myoclonus. Although PIMT-deficiency clearly leads to the accumulation of isomerized proteins, it is currently unclear how this causes progressive epilepsy in PIMT-deficient mice. As a first step towards understanding this, we developed a new assay to measure PIMT activity in cell lysates. Additionally, we isolated PIMT knockdown cells from HEK293 cells that were stably transfected with a PIMT small interfering RNA expression vector. PIMT activities were significantly decreased in the PIMT knockdown cells, and analysis of the transfectants revealed that MEK and ERK were hyperactivated after cell stimulation with epidermal growth factor (EGF). These results indicate that the ability to repair L-isoaspartyl-(or D-aspartyl-) containing proteins is important for the maintenance of normal MEK-ERK signaling.
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PMID:[Role of isomerized protein repair enzyme, PIMT, in cellular functions]. 1805 81

Neuroprotection following status epilepticus should encompass not only the prevention of neuronal death, but also preservation of neuronal and network function. This is critical because these aims are not necessarily equivalent; prevention of neuronal loss, for example, does not inevitably prevent epileptogenesis. There are endogenous neuroprotective mechanisms that can serve dichotomous roles (e.g. ERK 1/2 activation can result in either neuroprotection or promote neuronal death). The roles of potential endogenous mechanisms can depend upon the pattern and timing of their activation. The simplest exogenous neuroprotective mechanism is to halt seizure activity. Other approaches consist of early NMDA receptor antagonism or later inhibition of apoptotic pathways. The problem with the latter approach is that calcium accumulation results in the activation of a number of downstream pathways, the importance of which varies from region to region and in a cell-type specific manner. Neuroprotection in epilepsy is not a straightforward concept, and we need to be clear about our eventual objectives (e.g. preventing cognitive decline). There are numerous possible approaches to neuroprotection, and the efficacy of these depends upon their timing, the specific aims and even the method of status epilepticus induction.
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PMID:Neuroprotection in epilepsy. 1833 4

l-Aspartyl (l-Asp) and l-asparaginyl residues in proteins isomerize or racemize to d,l-isoaspartyl (d,l-isoAsp) or d-aspartyl (d-Asp) residues during protein aging. These atypical aspartyl residues can interfere with the biological function of the protein and lead to cellular dysfunction. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a repair enzyme that facilitates conversion of l-isoAsp and d-Asp to l-Asp. PIMT deficient mice exhibit accumulation of l-isoAsp in several tissues and die, on average, 12 days after birth from progressive epileptic seizures with grand mal and myoclonus features. However, little is known about the molecular mechanisms by which accumulation of the aberrant residues leads to cellular abnormalities. In this study, we established PIMT-knockdown cells using a short interfering RNA expression system and characterized the resultant molecular abnormalities in intracellular signaling pathways. PIMT-knockdown cells showed significant accumulation of proteins with isomerized residues, compared to control cells. In the PIMT-knockdown cells, Raf-1, MEK, and ERK, members of the MAPK cascade, were hyperphosphorylated after EGF stimulation compared to control cells. These results suggest that PIMT repair of abnormal proteins is necessary to maintain normal MAPK signaling.
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PMID:Suppression of protein l-isoaspartyl (d-aspartyl) methyltransferase results in hyperactivation of EGF-stimulated MEK-ERK signaling in cultured mammalian cells. 1838 Dec


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