Abstract
A molecular basis of survival from neuronal injury is essential for the development of therapeutic strategy to remedy neurodegenerative disorders. In this study, we demonstrate that an EF-hand Ca2+-binding protein neuronal Ca2+ sensor-1 (NCS-1), one of the key proteins for various neuronal functions, also acts as an important survival factor. Overexpression of NCS-1 rendered cultured neurons more tolerant to cell death caused by several kinds of stressors, whereas the dominant-negative mutant (E120Q) accelerated it. In addition, NCS-1 proteins increased upon treatment with glial cell line-derived neurotrophic factor (GDNF) and mediated GDNF survival signal in an Akt (but not MAPK)-dependent manner. Furthermore, NCS-1 is significantly up-regulated in response to axotomy-induced injury in the dorsal motor nucleus of the vagus neurons of adult rats in vivo, and adenoviral overexpression of E120Q resulted in a significant loss of surviving neurons, suggesting that NCS-1 is involved in an antiapoptotic mechanism in adult motor neurons. We propose that NCS-1 is a novel survival-promoting factor up-regulated in injured neurons that mediates the GDNF survival signal via the phosphatidylinositol 3-kinase-Akt pathway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Axotomy
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Calcium-Binding Proteins / physiology
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Cell Survival / drug effects
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Cells, Cultured
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects
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Glial Cell Line-Derived Neurotrophic Factor / pharmacology
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Growth Substances / deficiency
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Hydrogen Peroxide / pharmacology
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In Situ Nick-End Labeling
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Morpholines / pharmacology
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Neuronal Calcium-Sensor Proteins
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Neuropeptides / genetics
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Neuropeptides / metabolism*
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Neuropeptides / physiology
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Oxidative Stress / physiology
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PC12 Cells
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Transfection
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Up-Regulation
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Vagus Nerve / physiopathology
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Vagus Nerve Injuries
Substances
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Calcium-Binding Proteins
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Chromones
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Enzyme Inhibitors
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Glial Cell Line-Derived Neurotrophic Factor
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Growth Substances
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Morpholines
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Neuronal Calcium-Sensor Proteins
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Neuropeptides
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Phosphoinositide-3 Kinase Inhibitors
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frequenin calcium sensor proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Hydrogen Peroxide
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Proto-Oncogene Proteins c-akt