Document Detail

CaMKII activation is a novel effector of alcohol's neurotoxicity in neural crest stem/progenitor cells.
MedLine Citation:
PMID:  21496022     Owner:  NLM     Status:  MEDLINE    
Prenatal ethanol exposure causes significant neurodevelopmental deficits through its induction of apoptosis in neuronal progenitors including the neural crest. Using an established chick embryo model, we previously showed that clinically relevant ethanol concentrations cause neural crest apoptosis through mobilization of an intracellular calcium transient. How the calcium transient initiates this cell death is unknown. In this study, we identify CaMKII as the calcium target responsible for ethanol-induced apoptosis. Immunostaining revealed selective enrichment of activated phosphoCaMKII(Thr286) within ethanol-treated neural crest. CaMKII activation in response to ethanol was rapid (< 60 s) and robust, and CaMKII activity was increased 300% over control levels. Treatment with CaMKII-selective inhibitors but not those directed against CaMKIV or PKC completely prevented the cell death. Forced expression of dominant-negative CaMKII prevented ethanol's activation of CaMKII and prevented the ethanol-induced death, whereas constitutively active CaMKII in ethanol's absence significantly increased cell death to levels caused by ethanol treatment. In summary, CaMKII is the key signal that converts the ethanol-induced, short-lived Ca(i) (2+) transient into a long-lived cellular effector. This is the first identification of CaMKII as a critical mediator of ethanol-induced cell death. Because neural crest differentiates into several neuronal lineages, our findings offer novel insights into how ethanol disrupts early neurogenesis.
Ana Garic; George R Flentke; Ed Amberger; Marcos Hernandez; Susan M Smith
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-05-13
Journal Detail:
Title:  Journal of neurochemistry     Volume:  118     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-15     Completed Date:  2011-09-16     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  646-57     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
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MeSH Terms
Apoptosis / drug effects
Blotting, Western
Calcium / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
Central Nervous System Depressants / toxicity*
Chick Embryo
DNA, Complementary / biosynthesis,  genetics
Enzyme Activation / drug effects*
Ethanol / toxicity*
Neural Crest / drug effects*,  pathology*
Neural Stem Cells / drug effects*,  pathology*
Protein Kinase C / metabolism
Stimulation, Chemical
Grant Support
R37 AA011085/AA/NIAAA NIH HHS; R37 AA011085-11A1/AA/NIAAA NIH HHS; R37 AA011085-12/AA/NIAAA NIH HHS; R37 AA011085-13/AA/NIAAA NIH HHS; R37 AA011085-14/AA/NIAAA NIH HHS; R37 AA011085-14S1/AA/NIAAA NIH HHS; R37 AA011085-15/AA/NIAAA NIH HHS; R37 AA11085/AA/NIAAA NIH HHS
Reg. No./Substance:
0/Central Nervous System Depressants; 0/DNA, Complementary; 3K9958V90M/Ethanol; EC Kinase C; EC Protein Kinase Type 2; SY7Q814VUP/Calcium

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