CGP-37157 inhibits the sarcoplasmic reticulum Ca 2+ ATPase and activates ryanodine receptor channels in striated muscle

Abstract

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 +/Ca 2+ exchanger. However, evidence suggests that CGP could also affect other targets, such as L-type Ca 2+ channels and plasmalemma Na +/Ca 2+ exchanger. Here, we tested the possibility of a direct modulation of ryanodine receptor channels (RyRs) and/or sarco/endoplasmic reticulum Ca 2+-stimulated ATPase (SERCA) by CGP. In the presence of ruthenium red (inhibitor of RyRs), CGP decreased SERCA-mediated Ca 2+ uptake of cardiac and skeletal sarcoplasmic reticulum (SR) microsomes (IC 50 values of 6.6 and 9.9 μM, respectively). The CGP effects on SERCA activity correlated with a decreased V max of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (≥5 μM) also increased RyR-mediated Ca 2+ leak from skeletal SR microsomes. Planar bilayer studies confirmed that both cardiac and skeletal RyRs are directly activated by CGP (EC 50 values of 9.4 and 12.0 μM, respectively). In summary, we found that CGP inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca 2+ 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 Ca 2+ transporters. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.