The Role of Sorcin in Excitation-Contraction Coupling in Normal and Diseased Hearts

[摘要] Sorcin, a penta-EF hand Ca2+-binding protein, is known to interact with cardiac ryanodine receptors type 2 (RyR2) and other Ca2+ regulatory proteins, including the L-type Ca2+ channel (LTCC), Na+-Ca2+ exchanger (NCX), and sarcoplasmic/endoplasmic reticulum-Ca2+-ATPase (SERCA). However, sorcin’s influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions are not known. In this study, we generated a sorcin knockout (sorcin KO) mouse model to examine the role of sorcin in intracellular Ca2+ handling and its potential role in disease pathogenesis. Sorcin KO mice had no cardiac structural alterations, but had a shorter life span than WT. Chronic stress, which was induced by transverse aortic constriction, significantly decreased the survival rate of sorcin KO mice. Sorcin KO cardiomyocytes presented a high incidence of spontaneous sarcoplasmic reticulum (SR) Ca2+ release events under isoproterenol stimulation. As the result, isoproterenol-stimulated young (1-month-old) sorcin KO hearts/cardiomyocytes presented ventricular arrhythmia episodes, depleted SR Ca2+, and impaired contractility. The impaired contractility, however, was rescued in adult (6-month-old) sorcin KO hearts. Sorcin KO hearts of adult, but not young mice developed overexpression of L-type Ca2+ channel and Na+-Ca2+ exchanger, which enhanced ICa and INCX. Although the electrophysiological remodeling of ICa and INCX helped to retain SR Ca2+ load and heart contractility, it provided favorable substrate for DADs and EADs, leading to sustained ventricular arrhythmia, cardiac arrest, and sudden death in adult sorcin KO mice. Our study demonstrates that the loss of sorcin would impair contractility and further trigger lethal arrhythmias due to generalized Ca2+ disturbances and electrophysiological remodeling. The results evidenced the detrimental effect of sorcin’s absence in the development of cardiac dysfunction.

[发布机构] University of Michigan

[效力级别] ryanodine receptors

[关键词] sorcin;ryanodine receptors;sodium-calcium exchanger;L-type Ca2+ channel;ventricular myocytes;cardiac ventricular arrhythmias;Physiology;Health Sciences;Molecular and Integrative Physiology