The effects of a number of phenothiazines and other calmodulin antagonists on the Ca2+ ATPase activity of sarcoplasmic reticulum (SR) and endoplasmic reticulum (ER) were investigated. The drugs used in this study were trifluoperazine, calmidazolium, fluphenazine, chlorpromazine, W-l, and calmodulin-binding peptide. Our results showed that calmidazolium and calmodulin-binding peptide were the most potent inhibitors of skeletal muscle SR Ca2+-ATPase activity (isoform SERCA 1) (IC50 values of 0.5 and 1 muM, respectively), while W-7 was the least potent inhibitor (IC50, 125 muM). All of the antagonists had little effect on the cerebellar ER Ca2+-ATPase activity (isoform SERCA 2b), except for trifluoperazine, which had a biphasic effect, causing stimulation at low concentrations and inhibition at higher concentrations. Our results suggest that the effects of these calmodulin antagonists are independent of calmodulin and that they inhibit the Ca2+ ATPase in an isoform-specific manner. It was found that these antagonists inhibit the skeletal muscle isoform of the Ca2+ pump by altering the Ca2+ affinity and the associated Ca2+- binding steps, as well as possibly stabilising the El conformational state of the enzyme. BIOCHEM PHARMACOL 60;12:1797-1806, 2000. (C) 2000 Elsevier Science Inc.
|Number of pages||10|
|Publication status||Published - 1 Dec 2000|
- calmodulin antagonists
- Ca2+ pumps
- Ca2+ homeostasis