Linked Life Data

18215131

Source:http://linkedlifedata.com/resource/pubmed/id/18215131

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-4-9
pubmed:abstractText
Cerebral ischaemia causes long-lasting protein synthesis inhibition that is believed to contribute to brain damage. Energy depletion promotes translation inhibition during ischaemia, and the phosphorylation of eIF (eukaryotic initiation factor) 2alpha is involved in the translation inhibition induced by early ischaemia/reperfusion. However, the molecular mechanisms underlying prolonged translation down-regulation remain elusive. NMDA (N-methyl-D-aspartate) excitotoxicity is also involved in ischaemic damage, as exposure to NMDA impairs translation and promotes the synthesis of NO (nitric oxide), which can also inhibit translation. In the present study, we investigated whether NO was involved in NMDA-induced protein synthesis inhibition in neurons and studied the underlying molecular mechanisms. NMDA and the NO donor DEA/NO (diethylamine-nitric oxide sodium complex) both inhibited protein synthesis and this effect persisted after a 30 min exposure. Treatments with NMDA or NO promoted calpain-dependent eIF4G cleavage and 4E-BP1 (eIF4E-binding protein 1) dephosphorylation and also abolished the formation of eIF4E-eIF4G complexes; however, they did not induce eIF2alpha phosphorylation. Although NOS (NO synthase) inhibitors did not prevent protein synthesis inhibition during 30 min of NMDA exposure, they did abrogate the persistent inhibition of translation observed after NMDA removal. NOS inhibitors also prevented NMDA-induced eIF4G degradation, 4E-BP1 dephosphorylation, decreased eIF4E-eIF4G-binding and cell death. Although the calpain inhibitor calpeptin blocked NMDA-induced eIF4G degradation, it did not prevent 4E-BP1 dephosphorylation, which precludes eIF4E availability, and thus translation inhibition was maintained. The present study suggests that eIF4G integrity and hyperphosphorylated 4E-BP1 are needed to ensure appropriate translation in neurons. In conclusion, our data show that NO mediates NMDA-induced persistent translation inhibition and suggest that deficient eIF4F activity contributes to this process.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1470-8728
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
411
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
667-77
pubmed:meshHeading
pubmed-meshheading:18215131-Animals, pubmed-meshheading:18215131-Carrier Proteins, pubmed-meshheading:18215131-Cell Survival, pubmed-meshheading:18215131-Cells, Cultured, pubmed-meshheading:18215131-Coculture Techniques, pubmed-meshheading:18215131-Cytoprotection, pubmed-meshheading:18215131-Eukaryotic Initiation Factor-4G, pubmed-meshheading:18215131-N-Methylaspartate, pubmed-meshheading:18215131-Neurons, pubmed-meshheading:18215131-Nitric Oxide, pubmed-meshheading:18215131-Nitric Oxide Synthase, pubmed-meshheading:18215131-Phosphoproteins, pubmed-meshheading:18215131-Phosphorylation, pubmed-meshheading:18215131-Protein Binding, pubmed-meshheading:18215131-Protein Biosynthesis, pubmed-meshheading:18215131-Rats, pubmed-meshheading:18215131-Rats, Sprague-Dawley, pubmed-meshheading:18215131-Sirolimus
pubmed:year
2008
pubmed:articleTitle
Nitric oxide mediates NMDA-induced persistent inhibition of protein synthesis through dephosphorylation of eukaryotic initiation factor 4E-binding protein 1 and eukaryotic initiation factor 4G proteolysis.
pubmed:affiliation
Departamento de Isquemia Cerebral y Neurodegeneración, Instituto de Investigaciones Biomédicas de Barcelona, CSIC-IDIBAPS, Rosselló 161, Barcelona 08036, Spain. vpefat@iibb.csic.es
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't