PMID- 12488453
OWN - NLM
STAT- MEDLINE
DCOM- 20030408
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 278
IP  - 9
DP  - 2003 Feb 28
TI  - Calmodulin mediates brain-derived neurotrophic factor cell survival signaling 
      upstream of Akt kinase in embryonic neocortical neurons.
PG  - 7591-9
AB  - 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 Ca(2+)-binding sites 
      (CaM(1-4)) or with disabled C-terminal Ca(2+)-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 Ca(2+)-binding sites are critical 
      for calmodulin-mediated cell survival signaling.
FAU - Cheng, Aiwu
AU  - Cheng A
AD  - Laboratories of Neurosciences and Cardiovascular Science, Gerontology Research 
      Center, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
FAU - Wang, Shuqin
AU  - Wang S
FAU - Yang, Dongmei
AU  - Yang D
FAU - Xiao, Ruiping
AU  - Xiao R
FAU - Mattson, Mark P
AU  - Mattson MP
LA  - eng
PT  - Journal Article
DEP - 20021217
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Calmodulin)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 2.7.11.1 (Akt1 protein, rat)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.2.1.23 (beta-Galactosidase)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Binding Sites
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Calcium/metabolism
MH  - Calmodulin/*metabolism
MH  - Cell Survival
MH  - DNA Fragmentation
MH  - Enzyme Activation
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Microscopy, Phase-Contrast
MH  - Mitogen-Activated Protein Kinases
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Neocortex/embryology
MH  - Neurons/*cytology/metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - *Protein Serine-Threonine Kinases
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins/*metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Signal Transduction
MH  - Time Factors
MH  - beta-Galactosidase/metabolism
EDAT- 2002/12/19 04:00
MHDA- 2003/04/09 05:00
CRDT- 2002/12/19 04:00
PHST- 2002/12/19 04:00 [pubmed]
PHST- 2003/04/09 05:00 [medline]
PHST- 2002/12/19 04:00 [entrez]
AID - S0021-9258(19)32701-2 [pii]
AID - 10.1074/jbc.M207232200 [doi]
PST - ppublish
SO  - J Biol Chem. 2003 Feb 28;278(9):7591-9. doi: 10.1074/jbc.M207232200. Epub 2002 
      Dec 17.