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J. Biol. Chem., Vol. 278, Issue 9, 7591-7599, February 28, 2003

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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^**

From the Laboratories of  Neurosciences and ^§ Cardiovascular Science, Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224, the ^¶ National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871 China, and the  Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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 (CaM(1-4)) or with disabled C-terminal Ca²⁺-binding sites (CaM(3,4)) in cultured neocortical neurons by adenoviral gene transfer. Long-term neuronal survival was decreased in neurons overexpressing CaM(1-4) and CaM(3,4), 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 CaM(1-4) or CaM(3,4). In contrast, BDNF-induced activation of p42/44 MAPKs was unaffected by calmodulin mutations. Treatment of neurons with calmodulin antagonists and a phosphatidylinositol 3-kinase 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 phosphatidylinositol 3-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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