Differential roles of Epac in regulating cell death in neuronal and myocardial cells.
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.
Suzuki
Sayaka
S
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Yokoyama
Utako
U
Abe
Takaya
T
Kiyonari
Hiroshi
H
Yamashita
Naoya
N
Kato
Yuko
Y
Kurotani
Reiko
R
Sato
Motohiko
M
Okumura
Satoshi
S
Ishikawa
Yoshihiro
Y
D000818:Animals; D017209:Apoptosis; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases