CGP-37157 Inhibits the Sarcoplasmic Reticulum Ca2+ ATPase and Activates Ryanodine Receptor Channels in Striated Muscle

被引:40
作者
Neumann, Jake T. [1 ]
Diaz-Sylvester, Paula L. [1 ]
Fleischer, Sidney [2 ,3 ]
Copello, Julio A. [1 ]
机构
[1] So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA
[2] Vanderbilt Univ, Sch Med, Dept Biol Sci, Nashville, TN 37212 USA
[3] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA
基金
美国国家卫生研究院;
关键词
INTRACELLULAR CALCIUM-ANTAGONIST; SKELETAL-MUSCLE; ENDOPLASMIC-RETICULUM; HEART-FAILURE; RELEASE; MITOCHONDRIA; MYOCYTES; KT-362; EXCHANGE; K201;
D O I
10.1124/mol.110.067165
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one [CGP-37157 (CGP)], a benzothiazepine derivative of clonazepam, is commonly used as a blocker of the mitochondrial Na+/Ca2+ exchanger. However, evidence suggests that CGP could also affect other targets, such as L-type Ca2+ channels and plasmalemma Na+/Ca2+ exchanger. Here, we tested the possibility of a direct modulation of ryanodine receptor channels (RyRs) and/or sarco/endoplasmic reticulum Ca2+-stimulated ATPase (SERCA) by CGP. In the presence of ruthenium red (inhibitor of RyRs), CGP decreased SERCA-mediated Ca2+ uptake of cardiac and skeletal sarcoplasmic reticulum (SR) microsomes (IC50 values of 6.6 and 9.9 mu M, respectively). The CGP effects on SERCA activity correlated with a decreased V-max of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (>= 5 mu M) also increased RyR-mediated Ca2+ leak from skeletal SR microsomes. Planar bilayer studies confirmed that both cardiac and skeletal RyRs are directly activated by CGP (EC50 values of 9.4 and 12.0 mu M, respectively). In summary, we found that CGP inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca2+ homeostasis reported in the literature of cardiac, skeletal muscle, and other nonmuscle systems requires further analysis to take into account the contribution of all CGP-sensitive Ca2+ transporters.
引用
收藏
页码:141 / 147
页数:7
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