Calcium waves driven by "sensitization" wave-fronts.

Cellular Ca(2+) waves are understood as reaction-diffusion systems sustained by Ca(2+)-induced Ca(2+) release (CICR) from Ca(2+) stores. Given the recently discovered sensitization of Ca(2+) release channels (ryanodine receptors; RyRs) of the sarcoplasmic reticulum (SR) by luminal SR Ca(2+), waves could also be driven by RyR sensitization, mediated by SR overloading via Ca(2+) pump (SERCA), acting in tandem with CICR. Confocal imaging of the Ca(2+) indicator fluo-3 was combined with UV-flash photolysis of caged compounds and the whole-cell configuration of the patch clamp technique to carry out these experiments in isolated guinea pig ventricular cardiomyocytes. Upon sudden slowing of the SERCA in cardiomyocytes with a photoreleased inhibitor, waves indeed decelerated immediately. No secondary changes of Ca(2+) signaling or SR Ca(2+) content due to SERCA inhibition were observed in the short time-frame of these experiments. Our findings are consistent with Ca(2+) loading resulting in a zone of RyR 'sensitization' traveling within the SR, but inconsistent with CICR as the predominant mechanism driving the Ca(2+) waves. This alternative mode of RyR activation is essential to fully conceptualize cardiac arrhythmias triggered by spontaneous Ca(2+) release.