Calcium Release Channel of Sarcoplasmic Reticulum: An Important Target for Doxorubicin-Mediated Cardiotoxicity

Abstract

Sarcoplasmic reticulum (SR) of cardiac muscle makes essential contributions to excitation-contraction (E-C) coupling by regulating the free calcium (Ca²⁺) levels in the myoplasm. The ryanodine receptor constitutes the ligand-gated Ca²⁺ channel localized at junctional regions of SR through which Ca²⁺ is released in response to the action potential at the T tubule membrane. The ryanodine receptor complex appears to be co-associated with the voltage-dependent Ca²⁺ channels of the sarcolemma at the triad junction and the interaction of these proteins is critical to the process of E-C coupling. The role of triadic receptors in the etiology of drug-induced cardiomyopathy is explored. Doxorubicin and its anthraquinone (AQ) congeners are clinically valuable chemotherapeutic agents effective against a broad spectrum of human cancers. The repetitive doses of AQ required for control of malignancies coincides with induction of a progressive and irreversible cardiomyopathy which results in arrhythmias, tachycardia, declining ventricular output, and eventually congestive heart failure. Greater than 65% of patients receiving the maximal acceptable cumulative dosages of doxorubicin develop debilitating ventricular dysfunction. The etiology of AQ cardiomyopathy is unknown, but like genetic dilated cardiomyopathy, the drug-induced disease exhibits a similar progression of abnormal diastolic filling and impaired rates of ventricular relaxation.