Potential role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine

Abstract Background Cocaine-related deaths are continuously rising and its overdose is often associated with lethal cardiotoxic effects. Methods and results Our approach, employing isothermal titration calorimetry (ITC) and light scattering in parallel, has confirmed the significant affinity of huma...

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Published in:Drug and alcohol dependence 2013-12, Vol.133 (2), p.344-351
Main Authors: Sanchez, Emiliano J, Hayes, Robert P, Barr, John T, Lewis, Kevin M, Webb, Brian N, Subramanian, Arun K, Nissen, Mark S, Jones, Jeffrey P, Shelden, Eric A, Sorg, Barbara A, Fill, Michael, Schenk, James O, Kang, ChulHee
Format: Article
Language:English
Subjects:
Absorption
Affinity
Animals
Arrhythmias, Cardiac - chemically induced
Arrhythmias, Cardiac - physiopathology
Calcium Channels - physiology
Calorimetry
Calsequestrin
Calsequestrin - metabolism
Calsequestrin - physiology
Cell Line
Cocaine
Cocaine - adverse effects
Cocaine - metabolism
Dialysis
Heart - physiopathology
Light
Metabolism
Methamphetamine
Mice
Models, Molecular
Molecular Weight
Muscles
Myocardium - cytology
Myocardium - metabolism
Protein Binding
Protein Conformation
Psychiatry
Rats
Rats, Sprague-Dawley
Recording
Ryanodine receptor
Sarcoplasmic reticulum
Sarcoplasmic Reticulum - metabolism
Scattering, Radiation
Spectrophotometry, Atomic
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Summary:Abstract Background Cocaine-related deaths are continuously rising and its overdose is often associated with lethal cardiotoxic effects. Methods and results Our approach, employing isothermal titration calorimetry (ITC) and light scattering in parallel, has confirmed the significant affinity of human cardiac calsequestrin (CASQ2) for cocaine. Calsequestrin (CASQ) is a major Ca2+ -storage protein within the sarcoplasmic reticulum (SR) of both cardiac and skeletal muscles. CASQ acts as a Ca2+ buffer and Ca2+ -channel regulator through its unique Ca2+ -dependent oligomerization. Equilibrium dialysis and atomic absorption spectroscopy experiments illustrated the perturbational effect of cocaine on CASQ2 polymerization, resulting in substantial reduction of its Ca2+ -binding capacity. We also confirmed the accumulation of cocaine in rat heart tissue and the substantial effects cocaine has on cultured C2C12 cells. The same experiments were performed with methamphetamine as a control, which displayed neither affinity for CASQ2 nor any significant effects on its function. Since cocaine did not have any direct effect on the Ca2+ -release channel judging from our single channel recordings, these studies provide new insights into how cocaine may interfere with the normal E-C coupling mechanism with lethal arrhythmogenic consequences. Conclusion We propose that cocaine accumulates in SR through its affinity for CASQ2 and affects both SR Ca2+ storage and release by altering the normal CASQ2 Ca2+ -dependent polymerization. By this mechanism, cocaine use could produce serious cardiac problems, especially in people who have genetically-impaired CASQ2, defects in other E–C coupling components, or compromised cocaine metabolism and clearance.
ISSN:0376-8716
1879-0046
DOI:10.1016/j.drugalcdep.2013.06.012