Zinc inhibits protein synthesis in neurons -: Potential role of phosphorylation of translation initiation factor-2α

In the central nervous system, Zn2+ is concentrated in the cerebral cortex and hippocampus and has been found to be toxic to neurons. In this study, we show that exposure of cultured cortical neurons from mouse to increasing concentrations of Zn2+ (10-300 mu M) induces a progressive decrease in global protein synthesis. The potency of Zn2+ was increased by about 2 orders of magnitude in the presence of Na+-pyrithione, a Zn2+ ionophore. The basal rate of protein synthesis was restored 3 h after Zn2+ removal. Zn2+ induced a sustained increase in phosphorylation of the Lu subunit of the translation eukaryotic initiation factor-2 (eIF-2 alpha), whereas it triggered a transient increase in phosphorylation of eukaryotic elongation factor-2 (eEF-2). Protein synthesis was still depressed 60 min after the onset of Zn2+ exposure while the state of eEF-2 phosphorylation had already returned to its basal level. Moreover, Zn2+ was less effective than glutamate to increase eEF-2 phosphorylation, whereas it induced a more profound inhibition of protein synthesis. These results suggest that Zn2+-induced inhibition of protein synthesis mainly correlates with the increase in eIF-2 alpha phosphorylation. Supporting further that Zn2+ acts at the initiation step of protein synthesis, it strongly decreased the amount of polyribosomes.