Zinc induces cell death in immortalized embryonic hippocampal cells via activation of Akt-GSK-3beta signaling.
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 microM 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-3beta as well as increased GSK-3beta kinase activity. Transient overexpression of a kinase-deficient Akt mutant remarkably suppressed GSK-3beta activation and cell death. Furthermore, tau phosphorylation, but not the degradation of beta-catenin, was dependent upon zinc-induced GSK-3beta activation and contributed to cell death. The current data suggest that, following exposure to zinc, the sequential activation of Akt and GSK-3beta plays an important role directing hippocampal neural precursor cell death.
Min
Young Kyu
YK
Department of Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
Lee
Jong Eun
JE
Chung
Kwang Chul
KC
D017209:Apoptosis; D016923:Cell Death; D002461:Cell Line, Transformed; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013871:Thiones / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D011725:Pyridines; D013871:Thiones; D051176:beta Catenin; C008704:pyrithione; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D015032:Zinc