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Proceedings of the National Academy of Sciences, Vol 87, 2466-2470, Copyright © 1990 by National Academy of Sciences
O Thastrup, PJ Cullen, BK Drobak, MR Hanley and AP Dawson
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 Ca{2+} pump, followed by a rapid
Ca2+ leak from at least two pharmacologically distinct Ca{2+}
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.
ARTICLE
Thapsigargin, a Tumor Promoter, Discharges Intracellular Ca2+ Stores by Specific Inhibition of the Endoplasmic Reticulum Ca2+-ATPase
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