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

The Biochemical Journal
Valérie PetegniefAnna M Planas

Abstract

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 ...Continue Reading

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Citations

Aug 8, 2008·Molecular Neurobiology·P S VoslerJ Chen
Dec 14, 2011·Clinical and Experimental Pharmacology & Physiology·Jun ZhouJian-Guo Chen
Dec 11, 2013·Translational Stroke Research·Valérie Petegnief, Anna M Planas
May 22, 2010·Neurological Research·Ling-Ling Tang, Jie-Sheng Zheng
Aug 27, 2011·Biochemical and Biophysical Research Communications·Rikard G FredNils Welsh
Nov 7, 2009·Free Radical Biology & Medicine·Kyril TurpaevJean-Claude Drapier
Aug 6, 2009·Optics Express·Sotiris PsilodimitrakopoulosPablo Loza-Alvarez

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