Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells
- Authors
- Lee, Chung Soo; Han, Eun Sook; Han, Young Su; Bang, Hyoweon
- Issue Date
- Oct-2005
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- calmodulin antagonists; MG132; mitochondrial membrane permeability; cell injury; PC12 cells
- Citation
- BRAIN RESEARCH BULLETIN, v.67, no.3, pp 225 - 234
- Pages
- 10
- Journal Title
- BRAIN RESEARCH BULLETIN
- Volume
- 67
- Number
- 3
- Start Page
- 225
- End Page
- 234
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/24500
- DOI
- 10.1016/j.brainresbull.2005.07.003
- ISSN
- 0361-9230
1873-2747
- Abstract
- 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. (c) 2005 Elsevier Inc. All rights reserved.
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