Identification of eukaryotic elongation factor-2 as a novel cellular target of lithium and glycogen synthase kinase-3.
Inhibition of glycogen synthase kinase-3 (GSK-3) is thought to be a major consequence of the biological and clinical activity of the mood stabilizer lithium, however, lithium and GSK-3 may activate distinct cellular pathways. We employed a proteomic method to uncover new downstream targets of lithium, and then examined how these proteins are related to GSK-3. Proteomic analysis identified eukaryotic elongation factor-2 (eEF-2) as a cellular target of lithium. This was verified in SH-SY5Y cells and animal models. In cells, lithium decreased eEF-2 phosphorylation at its key inhibitory site, threonine 56, and blocked the enhancement of eEF-2 phosphorylation normally coupled with stress conditions such as nutrient and serum deprivation. Unexpectedly, inhibition of GSK-3 enhanced eEF-2 phosphorylation, and overexpression of GSK-3α or GSK-3β resulted in a strong reduction in eEF-2 phosphorylation. Chronic administration of lithium reduced the hippocampal fraction of phospho-eEF-2 (phospho-eEF-2/total eEF-2) twofold in two different mouse strains. In summary, unexpectedly eEF-2 is activated by both lithium and GSK-3, whereas, lithium treatment and inhibition of GSK-3 have opposing effects on eEF-2.
Karyo
Racheli
R
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Eskira
Yael
Y
Pinhasov
Albert
A
Belmaker
Rh
R
Agam
Galila
G
Eldar-Finkelman
Hagit
H
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002460:Cell Line; D015180:Electrophoresis, Gel, Two-Dimensional; D054736:Elongation Factor 2 Kinase / Q000187:drug effects* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018020:Lithium Compounds / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation
D000928:Antidepressive Agents; D018020:Lithium Compounds; C517689:EEF2K protein, human; D054736:Elongation Factor 2 Kinase; D038362:Glycogen Synthase Kinase 3