Journal article
Potential role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine
Drug and alcohol dependence, Vol.133(2), pp.344-351
12/01/2013
Handle:
https://hdl.handle.net/2376/109266
PMCID: PMC4097383
PMID: 23876860
Abstract
Cocaine-related deaths are continuously rising and its overdose is often associated with lethal cardiotoxic effects.
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.
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.
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Details
- Title
- Potential role of cardiac calsequestrin in the lethal arrhythmic effects of cocaine
- Creators
- Emiliano J Sanchez - School of Molecular Biosciences, Washington State University, Pullman, WA 99164, United StatesRobert P Hayes - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesJohn T Barr - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesKevin M Lewis - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesBrian N Webb - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesArun K Subramanian - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesMark S Nissen - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesJeffrey P Jones - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesEric A Shelden - School of Molecular Biosciences, Washington State University, Pullman, WA 99164, United StatesBarbara A Sorg - Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA 99164, United StatesMichael Fill - Department of Molecular Biophysics & Physiology, Rush University Medical Center, Chicago, IL 60612, United StatesJames O Schenk - Department of Chemistry, Washington State University, Pullman, WA 99164, United StatesChulHee Kang - School of Molecular Biosciences, Washington State University, Pullman, WA 99164, United States
- Publication Details
- Drug and alcohol dependence, Vol.133(2), pp.344-351
- Academic Unit
- Chemistry, Department of; Molecular Biosciences, School of
- Publisher
- Elsevier Ireland Ltd
- Identifiers
- 99900547129401842
- Language
- English
- Resource Type
- Journal article