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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
Potential adverse interaction of human cardiac calsequestrin
Chulhee Kang1, Mark S Nissen, Emiliano J Sanchez
1School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4660, USA. chkang@wsu.edu
European Journal of Pharmacology
|August 18, 2010
Summary
Certain drugs, including phenothiazines and calcium channel blockers, bind to cardiac calsequestrin (hCASQ2). This binding can impair calcium buffering and release in the sarcoplasmic reticulum, potentially causing cardiac issues.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Physiology
Background:
- Calsequestrin (CASQ) is crucial for calcium (Ca2+) storage and regulation in muscle sarcoplasmic reticulum (SR).
- CASQ's Ca2+-dependent oligomerization maintains low free Ca2+ levels and SR Ca2+ release stability.
- Drug-induced side effects on cardiac function are a significant clinical concern.
Purpose of the Study:
- To investigate the binding affinity of human cardiac CASQ (hCASQ2) to various drugs.
- To determine the functional impact of drug binding on hCASQ2's Ca2+-dependent polymerization.
- To elucidate potential mechanisms linking drug-SR interactions to cardiac dysfunction.
Main Methods:
- Isothermal titration calorimetry (ITC) to quantify drug-hCASQ2 binding.
- Light scattering assays to monitor hCASQ2 polymerization.
- In vitro studies to assess drug effects on hCASQ2 polymerization kinetics.
Main Results:
- Strong binding of phenothiazines (trifluoperazine, thioridazine), anthracyclines (doxorubicin, daunorubicin), and Ca2+ channel blockers (amlodipine, verapamil) to hCASQ2 was observed, with average affinity around 18 μM.
- These drugs inhibited hCASQ2's in vitro Ca2+-dependent polymerization in a dose-dependent manner, proportional to their binding affinity.
- Binding and polymerization inhibition suggest interference with CASQ's Ca2+ buffering and RyR2 channel regulation.
Conclusions:
- Certain commonly prescribed drugs can directly interact with cardiac calsequestrin (hCASQ2).
- This interaction can disrupt the normal calcium handling capacity of the sarcoplasmic reticulum.
- Such disruptions may contribute to cardiac problems, particularly in individuals with pre-existing hCASQ2 defects or impaired drug metabolism.
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