Zinc is an essential catalytic and structural element of many proteins and a signaling messenger that is released by neuronal activity at many central excitatory synapses. Excessive synaptic release of zinc followed by entry into vulnerable neurons contributes severe neuronal cell death. We have previously observed that zinc-induced neuronal cell death is accompanied by Akt activation in embryonic hippocampal progenitor (H19-7) cells. In the present study, we examined the role of Akt activation and its downstream signaling events during extracellular zinc-induced neuronal cell death. Treatment of H19-7 cells with 10 μM of zinc plus zinc ionophore, pyrithione, led to increased phosphorylation of Akt at Ser-473/Thr-308 and increased Akt kinase activity. Zinc-induced Akt activation was accompanied by increased Tyr-phosphorylated GSK-3β as well as increased GSK-3β kinase activity. Transient overexpression of a kinase-deficient Akt mutant remarkably suppressed GSK-3β activation and cell death. Furthermore, tau phosphorylation, but not the degradation of β-catenin, was dependent upon zinc-induced GSK-3β activation and contributed to cell death. The current data suggest that, following exposure to zinc, the sequential activation of Akt and GSK-3β plays an important role directing hippocampal neural precursor cell death.
Bibliographical noteFunding Information:
The authors are grateful to T.F. Franke, R.A. Roth, J. Sadoshima, E. Krebs, I. Mook-Jung, and Choi K.Y. for providing plasmids and to J.T. Seo for technical assistance for the measurement of intracellular zinc transport. This study was supported by a grant from the Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Science and Technology of Republic of Korea (M103KV010011-06K2201-01110 to K.C.C.), by Basic Science Research Grant from the Korea Research Foundation (KRF2003-015-C00527 to K.C.C.), by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (A050181 and A060440 to K.C.C.), and by Basic Research Grant from the Korea Science and Engineering Foundation (R01-2004-000-10673-0 to K.C.C.). It was also partly supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2004-005-E00017 to K.C.C.).
All Science Journal Classification (ASJC) codes
- Cell Biology