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Thapsigargin, a Tumor Promoter, Discharges Intracellular Ca2+ Stores by Specific Inhibition of the Endoplasmic Reticulum Ca2+-ATPase
Ole Thastrup, Peter J. Cullen, Bjorn K. Drobak, Michael R. Hanley and Alan P. Dawson
Proceedings of the National Academy of Sciences of the United States of America
Vol. 87, No. 7 (Apr., 1990), pp. 2466-2470
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/2354243
Page Count: 5
You can always find the topics here!Topics: Cell membranes, Hepatocytes, Skeletal muscle, Pumps, Liver, Carcinogens, Liver microsomes, Adenosine triphosphatases, Endoplasmic reticulum, Erythrocytes
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Thapsigargin, a tumor-promoting sesquiterpene lactone, discharges intracellular Ca2+ in rat hepatocytes, as it does in many vertebrate cell types. It appears to act intracellularly, as incubation of isolated rat liver microsomes with thapsigargin induces a rapid, dose-dependent release of stored Ca2+. The thapsigargin-releasable pool of microsomal Ca2+ includes the pools sensitive to inositol 1,4,5-trisphosphate and GTP. Thapsigargin pretreatment of microsomes blocks subsequent loading with 45Ca2+, suggesting that its target is the ATP-dependent Ca2+ pump of endoplasmic reticulum. This hypothesis is strongly supported by the demonstration that thapsigargin causes a rapid inhibition of the Ca2+-activated ATPase activity of rat liver microsomes, with an identical dose dependence to that seen in whole cell or isolated microsome Ca2+ discharge. The inhibition of the endoplasmic reticulum isoform of the Ca2+-ATPase is highly selective, as thapsigargin has little or no effect on the Ca2+-ATPases of hepatocyte or erythrocyte plasma membrane or of cardiac or skeletal muscle sarcoplasmic reticulum. These results suggest that thapsigargin increases the concentration of cytosolic free Ca2+ in sensitive cells by an acute and highly specific arrest of the endoplasmic reticulum Ca2+ pump, followed by a rapid Ca2+ leak from at least two pharmacologically distinct Ca2+ stores. The implications of this mechanism of action for the application of thapsigargin in the analysis of Ca2+ homeostasis and possible forms of Ca2+ control are discussed.
Proceedings of the National Academy of Sciences of the United States of America © 1990 National Academy of Sciences