Tao Guo1, Dirk Gillespie, Michael Fill. 1. Department of Molecular Biophysics and Physiology, Section of Cellular Signaling, Rush University Medical Center, Chicago, IL 60112, USA.
Abstract
RATIONALE: In cardiac muscle, Ca(2+)-induced Ca(2+) release (CICR) from the sarcoplasmic reticulum (SR) is mediated by ryanodine receptor (RyR) Ca(2+) 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(2+) load, largely because load determines the single RyR current amplitude that drives inter-RyR CICR. METHODS AND RESULTS: We differentially manipulated single RyR Ca(2+) flux amplitude and SR Ca(2+) 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(2+) 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(2+) load. Despite the increased load, Ca(2+) spark (inter-RyR CICR events) frequency decreased and sparks terminated earlier. CONCLUSIONS: Spark local control follows single RyR current amplitude, not simply SR Ca(2+) 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(2+) release ends.
RATIONALE: In cardiac muscle, Ca(2+)-induced Ca(2+) release (CICR) from the sarcoplasmic reticulum (SR) is mediated by ryanodine receptor (RyR) Ca(2+) 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(2+) load, largely because load determines the single RyR current amplitude that drives inter-RyRCICR. METHODS AND RESULTS: We differentially manipulated single RyRCa(2+) flux amplitude and SR Ca(2+) 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(2+) 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(2+) load. Despite the increased load, Ca(2+) spark (inter-RyRCICR events) frequency decreased and sparks terminated earlier. CONCLUSIONS: Spark local control follows single RyR current amplitude, not simply SR Ca(2+) 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-RyRCICR. Thus, RyRs that spontaneously close no longer reopen and local Ca(2+) release ends.
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