Journal article
Potential adverse interaction of human cardiac calsequestrin
European journal of pharmacology, Vol.646(1), pp.12-21
2010
Handle:
https://hdl.handle.net/2376/115738
PMID: 20713040
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.
Metrics
5 Record Views
Details
- Title
- Potential adverse interaction of human cardiac calsequestrin
- Creators
- ChulHee Kang - School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USAMark S Nissen - School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USAEmiliano J Sanchez - School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USAKa-Sum Lam - School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USAHendrik Milting - Herz- und Diabeteszentrum NRW, Klinik der Ruhr Universitaet Bochum Klinik der Ruhr-Universitat Bochum, Erich und Hanna Klessmann-Institut für Kardiovaskuläre Forschung und Entwicklung, 32545 Bad Oeynhausen, Germany
- Publication Details
- European journal of pharmacology, Vol.646(1), pp.12-21
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier B.V
- Identifiers
- 99900547718901842
- Language
- English
- Resource Type
- Journal article