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 (0.5-1mM) 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.
journal_name
Eur J Pharmacoljournal_title
European journal of pharmacologyauthors
Kang C,Nissen MS,Sanchez EJ,Lam KS,Milting Hdoi
10.1016/j.ejphar.2010.08.001subject
Has Abstractpub_date
2010-11-10 00:00:00pages
12-21issue
1-3eissn
0014-2999issn
1879-0712pii
S0014-2999(10)00782-Xjournal_volume
646pub_type
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