Potential adverse interaction of human cardiac calsequestrin.
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.
Kang
Chulhee
C
School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USA. chkang@wsu.edu
Nissen
Mark S
MS
Sanchez
Emiliano J
EJ
Lam
Ka-Sum
KS
Milting
Hendrik
H
D002118:Calcium; D002151:Calorimetry; D002155:Calsequestrin / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D002155:Calsequestrin; D004364:Pharmaceutical Preparations; D002118:Calcium