Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The AMPA receptor subunit GluR2 is downregulated in neurons following a wide range of neurological insults. Here we report that suppression of GluR2 gene promoter activity is associated with kainate (KA)-induced downregulation of GluR2 subunit levels in primary cultured cortical neurons. RT-PCR and Northern blotting showed a significant decrease in GluR2 mRNA in cultured neurons after KA exposure. Transfection of cultured neurons with an expression vector pGL3-GluR2(-298/+283), where the reporter gene firefly luciferase was driven by the GluR2 promoter, revealed that KA exposure suppressed the transcriptional activation of the GluR2 promoter. Furthermore, the expression of the RE1-silencing transcription factor (REST) was increased in KA-exposed cortical neurons; enhanced binding of REST to RE1-like silencer element in the proximal promoter of the GluR2 subunit gene was evidenced by electrophoresis mobility shift assay. Chromatin immunoprecipitation showed that suppressed activity of the GluR2 promoter in cultured neurons after KA exposure was related to deacetylation of histone H4. These results indicate that REST as a crucial factor binds to RE1-like silencer element in the GluR2 promoter, suppressing transcription of the GluR2 subunit gene during KA exposure. Our data suggest that transcriptional suppression of the GluR2 subunit gene may contribute at least in part to downregulation of GluR2 subunit protein in neurons during KA exposure. Because our experiments showed a reduction of glutamate release in KA-exposed cortical neurons, REST may play a latent role in delayed neuronal death or in seizure-induced tolerance.
 ...
PMID:Kainate exposure suppresses activation of GluR2 subunit promoter in primary cultured cerebral cortical neurons through induction of RE1-silencing transcription factor. 1670 50

The glutamate receptor 2 (GluR2) subunit determines many of the functional properties of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate subtype of glutamate receptor. The roles of untranslated regions (UTRs) in mRNA stability, transport, or translation are increasingly recognized. The 3' end of the GluR2 transcripts are alternatively processed to form a short and long 3'UTR, giving rise to two pools of GluR2 mRNA of 4 and 6 kb in length, respectively, in the mammalian brain. However, the role of these alternative 3'UTRs in GluR2 expression has not been reported. We demonstrate that in the cytoplasm of rat hippocampus, native GluR2 mRNAs bearing the long 3'UTR are mostly retained in translationally dormant complexes of ribosome-free messenger ribonucleoprotein (mRNP), whereas GluR2 transcripts bearing the short 3'UTR are predominantly associated with actively translating ribosomes. One day after pilocarpine-induced status epilepticus (SE), the levels of both long and short GluR2 transcripts were markedly decreased in rat hippocampus. However, GluR2 mRNAs bearing the long 3'-UTRs were shifted from untranslating mRNP complexes to ribosome-containing complexes after SE, pointing to a selective translational derepression of GluR2 mRNA mediated by the long 3'UTR. In Xenopus oocytes, expression of firefly luciferase reporters bearing alternative GluR2 3'UTRs confirmed that the long 3'UTR is sufficient to suppress translation. The stability of reporter mRNAs in oocytes was not significantly influenced by alternative 5' or 3'UTRs of GluR2 over the time period examined. Overall, our findings that the long 3'UTR of GluR2 mRNA alone is sufficient to suppress translation, and the evidence for seizure-induced derepression of translation of GluR2 via the long 3'UTR strongly suggests that a regulatory signaling mechanism exists that differentially targets GluR2 transcripts with alternative 3'UTRs.
 ...
PMID:Translational regulation of GluR2 mRNAs in rat hippocampus by alternative 3' untranslated regions. 1922

Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein of astrocytes, and its expression changes dramatically during development and following injury. To facilitate study of the regulation of GFAP expression, we have generated dual transgenic mice expressing both firefly luciferase under the control of a 2.2 kb human GFAP promoter and Renilla luciferase under the control of a 0.5 kb human Glyceraldehyde 3 phosphate dehydrogenase (GAPDH) promoter for normalization of the GFAP signal. The GFAP-fLuc was highly expressed in brain compared to other tissues, and was limited to astrocytes, whereas the GAPDH-RLuc was more widely expressed. Normalization of the GFAP signal to the GAPDH signal reduced the inter-individual variability compared to using the GFAP signal alone. The GFAP/GAPDH ratio correctly reflected the up-regulation of GFAP that occurs following retinal degeneration in FVB/N mice because of the rd mutation. Following kainic acid-induced seizures, changes in the GFAP/GAPDH ratio precede those in total GFAP protein. In knock-in mice expressing the R236H Alexander disease mutant, GFAP promoter activity is only transiently elevated and may not entirely account for the accumulation of GFAP protein that takes place.
 ...
PMID:Dual transgenic reporter mice as a tool for monitoring expression of glial fibrillary acidic protein. 1945 99