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1 Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
2 Molecular Genetics, University of Cincinnati, Cincinnati, OH, USA
3 Genome Sciences, University of Cincinnati, Cincinnati, OH, USA; Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: Louis.Kutcher{at}UC.edu.
Ca2+/calmodulin regulated protein kinase II (CaMKII) mediates many cellular events. The four CaMKII isoforms have numerous splice variants, three of which contain nuclear localization signals. Little is known about the role of nuclear-localized CaMKII in neuronal development. To study this process, PC12 cells were transfected to produce CaMKII targeted to either the cytoplasm or the nucleus, then treated with nerve growth factor (NGF). NGF triggers a signaling cascade (MAPK) that results in the differentiation of PC12 cells into a neuronal phenotype, marked by neurite outgrowth. The present study found that cells expressing nuclear targeted CaMKII failed to grow neurites, while cells expressing cytoplasmic CaMKII readily produced neurites. Inhibition of neuronal differentiation by nuclear CaMKII was independent of MAPK, as sustained Erk phosphorylation was not affected. Phosphorylation of CREB was also unaffected. Thus nuclear CaMKII modifies neuronal differentiation by a mechanism independent of MAPK and CREB activation.
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