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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7591-7599
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number9
DOIs
StatePublished - Feb 28 2003

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Cell signaling
Brain-Derived Neurotrophic Factor
Calmodulin
Neurons
Cell Survival
Phosphotransferases
Phosphatidylinositol 3-Kinase
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Binding Sites
Chemical activation
Gene transfer
Calcium-Calmodulin-Dependent Protein Kinases
Mutation
Mitogen-Activated Protein Kinase 1
Neurology
Transducers
Neurodegenerative Diseases
Nervous System

ASJC Scopus subject areas

  • Biochemistry

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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; Mattson, Mark P.

In: Journal of Biological Chemistry, Vol. 278, No. 9, 28.02.2003, p. 7591-7599.

Research output: Contribution to journalArticle

Aiwu, Cheng ; Shuqin, Wang ; Dongmei, Yang ; Ruiping, Xiao ; Mattson, Mark P. / Calmodulin mediates brain-derived neurotrophic factor cell survival signaling upstream of Akt kinase in embryonic neocortical neurons. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 9. pp. 7591-7599.
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