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J. Biol. Chem., Vol. 266, Issue 34, 22912-22918, 12, 1991
Y Kijima, E Ogunbunmi and S Fleischer
Thapsigargin is found to be a potent inhibitor of the intracellular Ca2+
pump proteins from skeletal muscle sarcoplasmic reticulum (SR), cardiac SR,
and brain microsomes. For skeletal muscle SR, the molar ratio of
thapsigargin to Ca2+ pump protein for complete inhibition (MRc) of the Ca2+
loading rate, Ca(2+)-dependent ATPase activity, and formation of
phosphorylated intermediate (EP) was approximately 1. When the Ca2+ pump
protein of low affinity to Ca2+ (E2 state) was pretreated with
thapsigargin, ATP and Ca2+ binding to the Ca2+ pump protein was completely
inhibited. In the presence of Ca2+ (E1 state), Ca2+ pump protein was
protected from inactivation by thapsigargin with respect to Ca2+ binding
and EP formation. The MRc for brain microsomes, which mediate Ca2+ uptake
into intracellular (inositol 1,4,5-trisphosphate- releasable) Ca2+ pools,
is likewise stoichiometric. Approximately 30% of Ca2+ loading activity of
brain microsomes was insensitive to thapsigargin, indicating the presence
of other Ca2+ pumping system(s). The MRc for heart is 3.8, indicating that
the Ca2+ pump of cardiac SR is less sensitive to thapsigargin.
Phosphorylation of cardiac SR with protein kinase A increased the
sensitivity to thapsigargin to MRc of 2.8. In summary, we find that: 1)
thapsigargin is the most effective inhibitor of the Ca2+ pump protein of
intracellular membranes (SR and endoplasmic reticulum); 2) its primary
inhibitory action appears to inactivate the E2 form of the enzyme
preferentially; 3) cardiac SR shows lesser sensitivity to thapsigargin than
skeletal muscle SR and brain microsomes; protein kinase A treatment of
cardiac SR enhances the sensitivity to the drug.
Drug action of thapsigargin on the Ca2+ pump protein of sarcoplasmic reticulum
Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37235.
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