Contribution of gamma-secretase to calcium-mediated cell death.
Presenilins are the catalytic subunit of the large gamma-secretase complex, that promotes intramembranous proteolysis of the beta-amyloid precursor protein (APP), resulting in the production of beta-amyloid (A beta). Mutant presenilin causes early-onset familial Alzheimer's disease (FAD), is related to abnormal Ca(2+) signaling, and render cells vulnerable to cell death. In the present study, we demonstrated that Ca(2+)-mediated cell death is functionally associated with gamma-secretase activity. We found that gamma-secretase activity was elevated during Ca(2+)-mediated cell death. Using selective gamma-secretase inhibitors, we examined the role of gamma-secretase in cell death triggered by increased intracellular Ca(2+). Indeed, treatment with the selective gamma-secretase inhibitors, compound E, DAPT, or L-685.458 significantly decreased Ca(2+)-triggered cell death with that of the controls, but did not affect staurosporin or tunicamycin-mediated cell death. These results implicate the role of gamma-secretase activity in Ca(2+)-mediated cell death.
Choi
Yun-Hyung
YH
College of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
Gwon
A-Ryeong
AR
Jeong
Hye-Young
HY
Park
Jong-Sung
JS
Baik
Sang-Ha
SH
Arumugam
Thiruma V
TV
Jo
Dong-Gyu
DG
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D042541:Intracellular Space / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium