Quarky Calcium Release in the Heart

Abstract

In cardiac myocytes, "Ca(2+) sparks" represent the stereotyped elemental unit of Ca(2+) release arising from activation of large arrays of ryanodine receptors (RyRs), whereas "Ca(2+) blinks" represent the reciprocal Ca(2+) depletion signal produced in the terminal cisterns of the junctional sarcoplasmic reticulum. Emerging evidence, however, suggests possible substructures in local Ca(2+) release events. 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. We directly visualized small solitary release events amid noise: spontaneous Ca(2+) quark-like or "quarky" Ca(2+) release (QCR) events in rabbit ventricular myocytes. Because the frequency of QCR events in paced myocytes is much higher than the frequency of Ca(2+) sparks, the total Ca(2+) leak attributable to the small QCR events is approximately equal to that of the spontaneous Ca(2+) sparks. Furthermore, the Ca(2+) 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 Ca(2+) buffering by EGTA, suggesting that the QCR component is attributable to a Ca(2+)-induced Ca(2+) release mechanism. Experimental evidence, together with modeling, suggests that QCR events may depend on the opening of rogue RyR2s (or small cluster of RyR2s). QCR events play an important role in shaping elemental Ca(2+) release characteristics and the nonspark QCR events contribute to "invisible" Ca(2+) leak in health and disease.