钙调蛋白拮抗剂对钙调蛋白诱导的钙诱导钙释放双相调节的影响。

Effect of calmodulin antagonists on calmodulin-induced biphasic modulation of Ca(2+)-induced Ca2+ release.

Ikemoto T, Iino M, Endo M

Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.

Br J Pharmacol. 1996 Jun;118(3):690-4. doi: 10.1111/j.1476-5381.1996.tb15455.x.

Abstract

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.

摘要

钙调蛋白（CaM）对肌浆网（SR）的钙诱导钙释放（CICR）具有双相作用：在低钙（pCa > 6.0）和高钙（pCa 5）浓度下分别表现为增强和抑制作用。为了表征CaM的作用模式，我们研究了CaM拮抗剂对兔皮肤肌肉纤维中CICR的影响。通过使用Fura-2的显微荧光测定法测量钙释放。2. CaM拮抗剂三氟拉嗪（TFP）在pCa 6时以剂量依赖性方式（10 - 300 microM）增强CICR，而在该条件下CaM效应的简单逆转应为对CICR的抑制。此外，100 microM TFP使CICR对钙更敏感。所测试的其他CaM拮抗剂也产生了类似的效果：氯丙嗪、W - 7、蜂毒肽以及CaM依赖性蛋白激酶II的CaM结合残基的肽片段。3. 即使存在高浓度的CaM拮抗剂或CaM结合肽，仍观察到CaM对CICR的双相作用。4. 根据这些结果，我们认为CaM对CICR具有独特的作用模式，这与CaM对已知酶的作用效果有很大不同。