Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells

作者：Lee CS^*; Han ES; Han YS; Bang H

来源：Brain Research Bulletin, 2005, 67(3): 225-234.

DOI：10.1016/j.brainresbull.2005.07.003

• calmodulin antagonists
• MG132
• mitochondrial membrane permeability
• cell injury
• PC12 cells

Defects in proteasome function have been suggested to be involved in the pathogenesis of neurodegenerative diseases. We examined the effect of calmodulin antagonists on proteasome inhibitor-induced mitochondrial dysfunction and cell viability loss in undifferentiated PC12 cells. Caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk) and antioxidants attenuated cell death and decrease in GSH contents in PC12 cells treated with 20 mu M MG132, a proteasome inhibitor. Calmodulin antagonists (trifluoperazine, W-7 and calmidazolium) had a differential inhibitory effect on the MG132-induced cell death and GSH depletion depending on concentration with a maximal inhibitory effect at 0.5-1 mu M. Addition of trifluoperazine and W-7 reduced the MG132-induced nuclear damage, loss of the mitochondrial transmembrane potential followed by cytochrome c release, formation of reactive oxygen species and elevation of intracellular Ca2+ levels in PC12 cells. Calmodulin antagonists at 5 mu M exhibited a cytotoxic effect on PC12 cells but attenuated the cytotoxicity of MG132. The results suggest that the toxicity of MG132 on PC12 cells is mediated by activation of caspase-8, -9 and -3. Trifluoperazine and W-7 at the concentrations of 0.5-1 mu M may attenuate the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability and by lowering of the intracellular Ca2+ levels as well as calmodulin inhibition.

• 出版日期2005-10-15