TY - JOUR T1 - CGP-37157 inhibits the sarcoplasmic reticulum Ca<sup>2+</sup> ATPase and activates ryanodine receptor channels in striated muscle JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.067165 SP - mol.110.067165 AU - Jake T Neumann AU - Paula L Diaz-Sylvester AU - Sidney Fleischer AU - Julio A Copello Y1 - 2010/10/05 UR - http://molpharm.aspetjournals.org/content/early/2010/10/04/mol.110.067165.abstract N2 - CGP-37157 (CGP), a benzothiazepine derivative of clonazepam, is commonly utilized as a blocker of the mitochondrial Na+/Ca2+ exchanger. Yet, 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's were 6.6 and 9.9 μM, respectively). The CGP effects on SERCA activity correlated with a decreased Vmax of ATPase activity of SERCA-enriched skeletal SR fractions. CGP (≥5 μM) 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's = 9.4 and 12.0 μ, respectively). In summary, we found that CPG inhibits SERCA and activates RyR channels. Hence, the action of CGP on cellular Ca2+ homeostasis reported in the literature of cardiac, skeletal muscle as well as other non muscle systems requires further analysis to take into account the contribution of all CGP-sensitive Ca2+ transporters. ER -