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.