Molecular Medicine Ryanodine Receptor Current Amplitude Controls Ca Sparks in Cardiac Muscle

Rationale: In cardiac muscle, Ca -induced Ca release (CICR) from the sarcoplasmic reticulum (SR) is mediated by ryanodine receptor (RyR) Ca release channels. The inherent positive feedback of CICR is normally well-controlled. Understanding this control mechanism is a priority because its malfunction has life-threatening consequences. Objective: We show that CICR local control is governed by SR Ca load, largely because load determines the single RyR current amplitude that drives inter-RyR CICR. Methods and Results: We differentially manipulated single RyR Ca flux amplitude and SR Ca load in permeabilized ventricular myocytes as an endogenous cell biology model of the heart. Large RyR-permeable organic cations were used to interfere with Ca conductance through the open RyR pore. Single-channel studies show this attenuates current amplitude without altering other aspects of RyR function. In cells, the same experimental maneuver increased resting SR Ca load. Despite the increased load, Ca spark (inter-RyR CICR events) frequency decreased and sparks terminated earlier. Conclusions: Spark local control follows single RyR current amplitude, not simply SR Ca load. Spark frequency increases with load because spontaneous RyR openings at high loads produce larger currents (ie, a larger CICR trigger signal). Sparks terminate when load falls to the point at which single RyR current amplitude is no longer sufficient to sustain inter-RyR CICR. Thus, RyRs that spontaneously close no longer reopen and local Ca release ends. (Circ Res. 2012;111:28-36.)