CaMKII represses transcriptionally active β‐catenin to mediate acute ethanol neurodegeneration and can phosphorylate β‐catenin. (24th October 2013)

• Record Type: Journal Article
• Authors: Flentke, George R.; Garic, Ana; Hernandez, Marcos; Smith, Susan M.
• Is Part Of: Journal of neurochemistry. Volume 128:Number 4(2014:Feb.)
• Page Start: 523
• Page End: 535
• Publication Date: 2013-10-24
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12464
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12464-abs-0001"> <title>Abstract</title> <p>Prenatal ethanol exposure causes persistent neurodevelopmental deficits by inducing apoptosis within neuronal progenitors including the neural crest. The cellular signaling events underlying this apoptosis are unclear. Using an established chick embryo model, we previously identified ethanol's activation of calmodulin‐dependent protein kinase II (CaMKII) as a crucial early step in this pathway. Here, we report that CaMKII is pro‐apoptotic because it mediates the loss of transcriptionally active β‐catenin, which normally provides trophic support to these cells. β‐catenin over‐expression normalized cell survival in ethanol's presence. CaMKII inhibition similarly restored β‐catenin content and transcriptional activity within ethanol‐treated cells and prevented their cell death. In contrast, inhibition of alternative effectors known to destabilize β‐catenin, including glycogen synthase kinase‐3β, Protein Kinase C, JNK, and calpain, failed to normalize cell survival and β‐catenin activity in ethanol's presence. Importantly, we found that purified CaMKII can directly phosphorylate β‐catenin. Using targeted mutagenesis we identified CaMKII phosphorylation sites within human β‐catenin at T332, T472, and S552. This is the first demonstration that β‐catenin is a phosphorylation target of CaMKII and represents a novel mechanism by which calcium signals could regulate β‐catenin‐dependent transcription. These results inform ethanol's neurotoxicity and offer unexpected insights into other neurodevelopmental and neurodegenerative disorders having dysregulated calcium or β‐catenin signaling. <boxed-text content-type="graphic" id="jnc12464-blkfxd-0001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg4spcht5q" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>We proposed that ethanol initiates apoptosis in early neuroprogenitors through an intracellular calcium transient that activates CaMKII, which in turn destabilizes transcriptionally‐active beta‐catenin, perhaps through direct phosphorylation at Thr332, Thr472 and Ser552. This represents a novel mechanism of calcium‐modulation of Wnt signaling and of ethanol's neurotoxicity.</p> </abstract>