Sorcin ablation plus β-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes

Sorcin, a penta-EF hand Ca²⁺-binding protein expressed in cardiomyocytes, is known to interact with ryanodine receptors and other Ca²⁺ regulatory proteins. To investigate sorcin's influence on cardiac excitation-contraction coupling and its role in the development of cardiac malfunctions, we generated a sorcin knockout (KO) mouse model. Sorcin KO mice presented ventricular arrhythmia and sudden death when challenged by acute stress induced by isoproterenol plus caffeine. Chronic stress, which was induced by transverse aortic constriction, significantly decreased the survival rate of sorcin KO mice. Under isoproterenol stimulation, spontaneous Ca²⁺ release events were frequently observed in sorcin KO cardiomyocytes. Sorcin KO hearts of adult, but not young mice developed overexpression of L-type Ca²⁺ channel and Na⁺-Ca²⁺ exchanger, which enhanced I_Ca and I_NCX. Consequently, spontaneous Ca²⁺ release events in sorcin KO cardiomyocytes were more likely to induce arrhythmogenic delayed afterdepolarizations. Our study demonstrates sorcin deficiency may trigger cardiac ventricular arrhythmias due to Ca²⁺ disturbances, and evidences the critical role of sorcin in maintaining Ca²⁺ homeostasis, especially during the adrenergic response of the heart.