Calcium waves driven by 'sensitization” wave-fronts

Objective: Cellular Ca2+ waves are understood as reaction-diffusion systems sustained by Ca2+-induced Ca2+ release (CICR) from Ca2+ stores. Given the recently discovered sensitization of Ca2+ release channels (ryanodine receptors; RyRs) of the sarcoplasmic reticulum (SR) by luminal SR Ca2+, waves could also be driven by RyR sensitization, mediated by SR overloading via Ca2+ pump (SERCA), acting in tandem with CICR. Methods: Confocal imaging of the Ca2+ 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. Results: Upon sudden slowing of the SERCA in cardiomyocytes with a photoreleased inhibitor, waves indeed decelerated immediately. No secondary changes of Ca2+ signaling or SR Ca2+ content due to SERCA inhibition were observed in the short time-frame of these experiments. Conclusions: Our findings are consistent with Ca2+ loading resulting in a zone of RyR ‘sensitization' traveling within the SR, but inconsistent with CICR as the predominant mechanism driving the Ca2+ waves. This alternative mode of RyR activation is essential to fully conceptualize cardiac arrhythmias triggered by spontaneous Ca2+ release