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Papers In Press, published online ahead of print December 17, 2002
J. Biol. Chem, 10.1074/jbc.M207232200
Submitted on July 18, 2002
Revised on December 13, 2002
Accepted on December 17, 2002

Calmodulin mediates brain-derived neurotrophic factor cell survival signaling upstream of Akt kinase in embryonic neocortical neurons

Aiwu Cheng, Shuqin Wang, Dongmei Yang, Ruiping Xiao, and Mark P Mattson

Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD 21224

Corresponding Author: mattsonm{at}grc.nia.nih.gov

As a calcium-sensing protein, calmodulin acts as a transducer of the intracellular calcium signal for a variety of cellular responses. Although calcium is an important regulator of neuronal survival during development of the nervous system, and is also implicated in the pathogenesis of neurodegenerative disorders, it is not known if calmodulin mediates these actions of calcium. To determine the role of calmodulin in regulating neuronal survival and death, we overexpressed calmodulin with mutations in all four Ca2+ binding sites (calmodulin1-4) or calmodulin with disabled C-terminal Ca2+ binding sites (calmodulin3,4) in cultured neocortical neurons by adenoviral gene transfer. Long-term neuronal survival was decreased in neurons over-expressing calmodulin1-4 and calmodulin3,4, which could not be rescued by brain-derived neurotrophic factor (BDNF). The basal level of Akt kinase activation was decreased, and the ability of BDNF to activate Akt was completely abolished in neurons overexpressing calmodulin1-4 or calmodulin3,4 mutants. In contrast, BDNF-induced activation of p42/p44 mitogen activated protein (MAP) kinases was unaffected by calmodulin mutations. Treatment of neurons with calmodulin antagonists and a phosphatidylinositol 3-kinase (PI3K) inhibitor blocked the ability of BDNF to prevent neuronal death, whereas inhibitors of calcium/calmodulin-dependent protein kinase II did not. Our findings demonstrate a pivotal role for calmodulin in survival signaling by BDNF in developing neocortical neurons by activating a transduction pathway involving PI3 kinase and Akt. In addition, our findings show that the C terminal Ca2+ binding sites are critical for calmodulin-mediated cell survival signaling.


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