{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T23:00:23Z","timestamp":1772751623094,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2009,4,20]],"date-time":"2009-04-20T00:00:00Z","timestamp":1240185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2009,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The developing central nervous system (CNS) is particularly susceptible to ethanol toxicity. The loss of neurons underlies many of the behavioral deficits observed in fetal alcohol spectrum disorders (FASD). The mechanisms of ethanol\u2010induced neuronal loss, however, remain incompletely elucidated. We demonstrated that glycogen synthase kinase 3\u03b2 (GSK3\u03b2), a multifunctional serine\/threonine kinase, was involved in ethanol neurotoxicity. The activity of GSK3\u03b2 is negatively regulated by its phosphorylation at serine 9 (Ser9). Ethanol induced dephosphorylation of GSK3\u03b2 at Ser9 and the activation of Bax as well as caspase\u20103 in the developing mouse brain. These ethanol\u2010induced alterations were ameliorated by the pretreatment of a GSK3\u03b2 inhibitor, lithium. To determine the role of GSK3\u03b2 in ethanol neurotoxicity, we overexpressed wild\u2010type (WT), S9A mutant or dominant\u2010negative (DN) mutant GSK3\u03b2 in a neuronal cell line (SK\u2010N\u2010MC). Ethanol only modestly reduced the viability of parental SK\u2010N\u2010MC cells but drastically induced caspase\u20103 activation and apoptosis in cells overexpressing WT or S9A GSK3\u03b2, indicating that the high levels of GSK3\u03b2 or the active form of GSK3\u03b2 increased cellular sensitivity to ethanol. Contrarily, overexpression of DN GSK3\u03b2 conferred resistance to ethanol toxicity. Lithium and other specific GSK3\u03b2 inhibitors abolished the hypersensitivity to ethanol caused by WT or S9A overexpression. Bax, a proapoptotic protein, is a substrate of GSK3\u03b2. Cells overexpressing WT or S9A GSK3\u03b2 were much more sensitive to ethanol\u2010induced Bax activation than parental SK\u2010N\u2010MC cells. Our results indicate that GSK3\u03b2 may be a mediator of ethanol neurotoxicity, and its expression status in a cell may determine ethanol vulnerability. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22098","type":"journal-article","created":{"date-parts":[[2009,4,20]],"date-time":"2009-04-20T21:03:54Z","timestamp":1240261434000},"page":"2793-2802","source":"Crossref","is-referenced-by-count":54,"title":["Overexpression of glycogen synthase kinase 3\u03b2 sensitizes neuronal cells to ethanol toxicity"],"prefix":"10.1002","volume":"87","author":[{"given":"Ying","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuiling","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly 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