Abstract
Calsequestrin (CASQ) is a major Ca 2+ storage protein within the sarcoplasmic reticulum (SR) of both cardiac and skeletal muscles. CASQ reportedly acts as a Ca 2+ buffer and Ca 2+-channel regulator through its unique Ca 2+-dependent oligomerization, maintaining the free Ca 2+ concentration at a low level (0.5–1 mM) and the stability of SR Ca 2+ releases. Our approach, employing isothermal titration calorimetry and light scattering in parallel, has provided valuable information about the affinity of human cardiac CASQ (hCASQ2) for a variety of drugs, which have been associated with heart- or muscle-related side effects. Those strongly binding drugs included phenothiazines, anthracyclines and Ca 2+ channel blockers, such as trifluoperazine, thioridazine, doxorubicin, daunorubicin, amlodipine and verapamil, having an average affinity of ~ 18 μM. They exhibit an inhibitory effect on in vitro Ca 2+-dependent polymerization of hCASQ2 in a manner proportional to their binding affinity. Therefore accumulation of such drugs in the SR could significantly hinder the Ca 2+-buffering capacity of the SR and/or the regulation of the Ca 2+ channel, RyR2. These effects could result in serious cardiac problems in people who have genetically impaired hCASQ2, defects in other E–C coupling components or problems with metabolism and clearance of those drugs.
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