Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion.
Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A, a blocker of mitochondrial permeability transition pore. Caspase inhibitors further inhibited MIN6N8 cell death. PK11195 induced dissipation of mitochondrial potential and cytochrome c translocation to cytoplasm. PK11195 induced an increase in cytoplasmic [Ca(2+)], which was reversed by cyclosporin A. Rhod-2 staining showed decreased mitochondrial [Ca(2+)] after PK11195 treatment. PK11195 potentiated glucose-induced insulin secretion probably due to the increased cytoplasmic [Ca(2+)]. Calpain was activated following Ca(2+) release, and calpain inhibitors attenuated death of insulinoma cells by PK11195. These results suggest that PK11195 induces mitochondrial potential loss, cytochrome c translocation, increased insulin secretion in conjunction with an increase in cytoplasmic [Ca(2+)] and calpain activation, which collectively leads to apoptosis of insulinoma cells.
Park
S Y
SY
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
Cho
N
N
Chang
I
I
Chung
J-H
JH
Min
Y-K
YK
Lee
M-K
MK
Kim
K-W
KW
Kim
S J
SJ
Lee
M-S
MS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D004789:Enzyme Activation; D058785:GABA-A Receptor Agonists; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D014407:Tumor Cells, Cultured
D058785:GABA-A Receptor Agonists; D007328:Insulin; D007546:Isoquinolines; D002154:Calpain; D002118:Calcium; C037850:PK 11195