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

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, w e show that exposure of cultured cortical neurons from mouse to increasing concentrations of Zn2+ (10-300 mu M) induces a progressive decrease in glob al protein synthesis. The potency of Zn2+ was increased by about 2 orders o f 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 translati on eukaryotic initiation factor-2 (eIF-2 alpha), whereas it triggered a tra nsient increase in phosphorylation of eukaryotic elongation factor-2 (eEF-2 ). Protein synthesis was still depressed 60 min after the onset of Zn2+ exp osure while the state of eEF-2 phosphorylation had already returned to its basal level. Moreover, Zn2+ was less effective than glutamate to increase e EF-2 phosphorylation, whereas it induced a more profound inhibition of prot ein synthesis. These results suggest that Zn2+-induced inhibition of protei n synthesis mainly correlates with the increase in eIF-2 alpha phosphorylat ion. Supporting further that Zn2+ acts at the initiation step of protein sy nthesis, it strongly decreased the amount of polyribosomes.