Quarky Calcium Release in the Heart

Rationale: In cardiac myocytes, Ca2+ sparks represent the stereotyped elemental unit of Ca2+ release arising from activation of large arrays of ryanodine receptors (RyRs), whereas Ca2+ blinks represent the reciprocal Ca2+ depletion signal produced in the terminal cisterns of the junctional sarcoplasmic reticulum. Emerging evidence, however, suggests possible substructures in local Ca2+ release events. Objective: With improved detection ability and sensitivity provided by simultaneous spark-blink pair measurements, we investigated possible release events that are smaller than sparks and their interplay with regular sparks. Methods and Results: We directly visualized small solitary release events amid noise: spontaneous Ca2+ quark-like or quarky Ca2+ release (QCR) events in rabbit ventricular myocytes. Because the frequency of QCR events in paced myocytes is much higher than the frequency of Ca2+ sparks, the total Ca2+ leak attributable to the small QCR events is approximately equal to that of the spontaneous Ca2+ sparks. Furthermore, the Ca2+ release underlying a spark consists of an initial high-flux stereotypical release component and a low-flux highly variable QCR component. The QCR part of the spark, but not the initial release, is sensitive to cytosolic Ca2+ buffering by EGTA, suggesting that the QCR component is attributable to a Ca2+-induced Ca2+ release mechanism. Experimental evidence, together with modeling, suggests that QCR events may depend on the opening of rogue RyR2s (or small cluster of RyR2s). Conclusions: QCR events play an important role in shaping elemental Ca2+ release characteristics and the nonspark QCR events contribute to invisible Ca2+ leak in health and disease. (Circ Res. 2011;108:210-218.)