Effect of calmodulin antagonists on calmodulin-induced biphasic modulation of Ca(2+)-induced Ca2+ release.
1. Calmodulin (CaM) has a biphasic effect on Ca(2+)-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR): potentiation and inhibition at low (pCa > 6.0) and high (pCa 5) Ca2+ concentrations, respectively. To characterize the mode of action of CaM, we studied the effect of CaM antagonists on the CICR in skinned muscle fibres of the rabbit. Ca2+ release was measured by microfluorometry with Fura-2. 2. A CaM antagonist, trifluoperazine (TFP), potentiated the CICR in a dose-dependent manner (10-300 microM) at pCa 6, where a simple reversal of the CaM effect would be inhibition of the CICR. Furthermore, 100 microM TFP sensitized the CICR to Ca2+. A similar effect was produced by other CaM antagonists that were tested: chlorpromazine, W-7, mastoparan, and peptide fragment of CaM-binding residues of CaM-dependent protein kinase II. 3. The biphasic effect of CaM on the CICR was observed even in the presence of high concentrations of CaM antagonists or CaM-bindings peptides. 4. From these results we suggest that CaM has a unique mode of action on the CICR which is quite different from the effect of CaM on known enzymes.
Ikemoto
T
T
Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.
Iino
M
M
Endo
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D002147:Calmodulin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects*; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology*
D002147:Calmodulin; D014268:Trifluoperazine; D002118:Calcium