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Published online 20 March 2006. doi:10.1083/jcb.200508156
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 7, 1081-1091
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Article

Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons



Tomoe Y. Nakamura1,2, Andreas Jeromin4, George Smith5, Hideaki Kurushima3, Hitoshi Koga2, Yusaku Nakabeppu3, Shigeo Wakabayashi1, and Junichi Nabekura2,6,7

1 Department of Molecular Physiology, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
2 Department of Cellular and System Physiology, Graduate School of Medical Sciences and 3 Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
4 Neuroscience, Baylor College of Medicine, Houston, TX 77030
5 Department of Physiology, University of Kentucky Medical School, Lexington, KY 50536
6 Division of Homeostatic Development, National Institute of Physiological Sciences, Okazaki 444-8585, Japan
7 Core Research for Evolutional Science and Technology, the Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Correspondence to Tomoe Y. Nakamura: tomoen{at}ri.ncvc.go.jp

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.

Abbreviations used in this paper: BDNF, brain-derived neurotrophic factor; DMV, dorsal motor nucleus of the vagus; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GDNF, glial cell line–derived neurotrophic factor; MEK, MAPK kinase; NCS-1, neuronal Ca2+ sensor-1; PH, pleckstrin homology; PI3-K, phosphatidylinositol 3-kinase; PI4-K, phosphatidylinositol 4-hydroxykinase.


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