Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore

Jackie F. Kidd, Mary F. Pilkington, Michael J. Schell, Kevin E. Fogarty, Jeremy N. Skepper, Colin W. Taylor, Peter Thorn

Research output: Contribution to journalArticle

Abstract

We have characterized the effects of the antimitotic drug paclitaxel (Taxol™) on the Ca2+ signaling cascade of terminally differentiated mouse pancreatic acinar cells. Using single cell fluorescence techniques and whole-cell patch clamping to record cytosolic Ca2+ and plasma membrane Ca2+-dependent Cl- currents, we find that paclitaxel abolishes cytosolic Ca2+ oscillations and in more than half of the cells it also induces a rapid, transient cytosolic Ca2+ response. This response is not affected by removal of extracellular Ca2+ indicating that paclitaxel releases Ca2+ from an intracellular Ca2+ store. Using saponin-permeabilized cells, we show that paclitaxel does not affect Ca2+ release from an inositol trisphosphate-sensitive store. Furthermore, up to 15 min after paclitaxel application, there is no significant effect on either microtubule organization or on endoplasmic reticulum organization. The data suggest a nonendoplasmic reticulum source for the intracellular Ca2+ response. Using the mitochondrial fluorescent dyes, JC-1 and Rhod-2, we show that paclitaxel evoked a rapid decline in the mitochondrial membrane potential and a loss of mitochondrial Ca2+. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, blocked both the paclitaxel-induced loss of mitochondrial Ca2+ and the effect on Ca2+ spikes. We conclude that paclitaxel exerts rapid effects on the cytosolic Ca2+ signal via the opening of the mitochondrial permeability transition pore. This work indicates that some of the more rapidly developing side effects of chemotherapy might be due to an action of antimitotic drugs on mitochondrial function and an interference with the Ca2+ signal cascade.

Original languageEnglish (US)
Pages (from-to)6504-6510
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number8
DOIs
StatePublished - Feb 22 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kidd, J. F., Pilkington, M. F., Schell, M. J., Fogarty, K. E., Skepper, J. N., Taylor, C. W., & Thorn, P. (2002). Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore. Journal of Biological Chemistry, 277(8), 6504-6510. https://doi.org/10.1074/jbc.M106802200