Signal Transduction
Differential Roles of Epac in Regulating Cell Death in Neuronal and Myocardial Cells*

https://doi.org/10.1074/jbc.M109.094581Get rights and content
Under a Creative Commons license
open access

Cell survival and death play critical roles in tissues composed of post-mitotic cells. Cyclic AMP (cAMP) has been known to exert a distinct effect on cell susceptibility to apoptosis, protecting neuronal cells and deteriorating myocardial cells. These effects are primarily studied using protein kinase A activation. In this study we show the differential roles of Epac, an exchange protein activated by cAMP and a new effector molecule of cAMP signaling, in regulating apoptosis in these cell types. Both stimulation of Epac by 8-p-methoxyphenylthon-2′-O-methyl-cAMP and overexpression of Epac significantly increased DNA fragmentation and TUNEL (terminal deoxynucleotidyltransferase-mediated biotin nick end-labeling)-positive cell counts in mouse cortical neurons but not in cardiac myocytes. In contrast, stimulation of protein kinase A increased apoptosis in cardiac myocytes but not in neuronal cells. In cortical neurons the expression of the Bcl-2 interacting member protein (Bim) was increased by stimulation of Epac at the transcriptional level and was decreased in mice with genetic disruption of Epac1. Epac-induced neuronal apoptosis was attenuated by the silencing of Bim. Furthermore, Epac1 disruption in vivo abolished the 3-nitropropionic acid-induced neuronal apoptosis that occurs in wild-type mice. These results suggest that Epac induces neuron-specific apoptosis through increasing Bim expression. Because the disruption of Epac exerted a protective effect on neuronal apoptosis in vivo, the inhibition of Epac may be a consideration in designing a therapeutic strategy for the treatment of neurodegenerative diseases.

Apoptosis
Cell Death
Cyclic AMP (cAMP)
Mitochondrial Apoptosis
Neuron
Protein Kinase A (PKA)
Signal Transduction
Exchange Protein Activated by Cyclic AMP (Epac)
Myocyte

Cited by (0)

*

This work was supported by a grant-in-aid for Scientific Research (KAKENHI) (to U. Y. and S. S.) and by grants from the Ministry of Health, Labor, and Welfare (to Y. I.), the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to Y. I.), the Yokohama Foundation for Advanced Medical Science (to U. Y.), the Kanae Foundation for the Promotion for Medical Science (to U. Y.), the Miyata Cardiology Research Promotion Funds (to U. Y.), the Takeda Science Foundation (to U. Y.), the Sumitomo Foundation (to U. Y.), the Japan Heart Foundation Research Grant (to U. Y.), the Kowa Life Science Foundation (to U. Y.), the Cosmetology Research Foundation (to Y. I.), the Uehara Memorial Foundation (to U. Y.), the Kitsuen Research Foundation (to Y. I.), and the Japan Space Forum (to Y. I.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and Figs. 1–7.