Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons.
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.
Department of Molecular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan. tomoen@ri.ncvc.go.jp
Tomoe Y
TY
Nakamura
Andreas
A
Jeromin
George
G
Smith
Hideaki
H
Kurushima
Hitoshi
H
Koga
Yusaku
Y
Nakabeppu
Shigeo
S
Wakabayashi
Junichi
J
Nabekura
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019771:Axotomy; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006133:Growth Substances / Q000172:deficiency; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D009025:Morpholines / Q000494:pharmacology; D051580:Neuronal Calcium-Sensor Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D016716:PC12 Cells; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D014630:Vagus Nerve / Q000503:physiopathology; D061223:Vagus Nerve Injuries
D002135:Calcium-Binding Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006133:Growth Substances; D009025:Morpholines; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; C101464:frequenin calcium sensor proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt