Ryanodine Receptor Current Amplitude Controls Ca2+ Sparks in Cardiac Muscle
Rationale: In cardiac muscle, Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is mediated by ryanodine receptor (RyR) Ca2+ 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 Ca2+ load, largely because load determines the single RyR current amplitude that drives inter-RyR CICR.
Methods and Results: We differentially manipulated single RyR Ca2+ flux amplitude and SR Ca2+ load in permeabilized ventricular myocytes as an endogenous cell biology model of the heart. Large RyR-permeable organic cations were used to interfere with Ca2+ 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 Ca2+ load. Despite the increased load, Ca2+ spark (inter-RyR CICR events) frequency decreased and sparks terminated earlier.
Conclusion: Spark local control after single RyR current amplitude, not SR Ca2+ load per se. 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 Ca2+ release ends.
- Received January 25, 2012.
- Revision received May 14, 2012.
- Accepted May 16, 2012.
- © 2012 American Heart Association, Inc.