Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore
Authors
Kidd, Jackie F.Pilkington, Mary F.
Schell, Michael J.
Fogarty, Kevin E.
Skepper, Jeremy N.
Taylor, Colin W.
Thorn, Peter
Document Type
Journal ArticlePublication Date
2001-11-29Keywords
AnimalsCalcium Signaling
Cell Membrane
Cyclosporine
Intracellular Membranes
Kinetics
Mice
Microscopy, Fluorescence
Microtubules
Mitochondria
Paclitaxel
Pancreas
Permeability
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
We have characterized the effects of the antimitotic drug paclitaxel (Taxol(TM)) on the Ca(2+) signaling cascade of terminally differentiated mouse pancreatic acinar cells. Using single cell fluorescence techniques and whole-cell patch clamping to record cytosolic Ca(2+) and plasma membrane Ca(2+)-dependent Cl(-) currents, we find that paclitaxel abolishes cytosolic Ca(2+) oscillations and in more than half of the cells it also induces a rapid, transient cytosolic Ca(2+) response. This response is not affected by removal of extracellular Ca(2+) indicating that paclitaxel releases Ca(2+) from an intracellular Ca(2+) store. Using saponin-permeabilized cells, we show that paclitaxel does not affect Ca(2+) 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 non-endoplasmic reticulum source for the intracellular Ca(2+) 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 Ca(2+). Cyclosporin A, a blocker of the mitochondrial permeability transition pore, blocked both the paclitaxel-induced loss of mitochondrial Ca(2+) and the effect on Ca(2+) spikes. We conclude that paclitaxel exerts rapid effects on the cytosolic Ca(2+) 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 Ca(2+) signal cascade.Source
J Biol Chem. 2002 Feb 22;277(8):6504-10. Epub 2001 Nov 27. Link to article on publisher's siteDOI
10.1074/jbc.M106802200Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42376PubMed ID
11724773Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1074/jbc.M106802200