How does stochastic ryanodine receptor-mediated Ca leak fail to initiate a Ca spark?

Spontaneous calcium (Ca) sparks are initiated by single ryanodine receptor (RyR) opening. Once one RyR channel opens, it elevates local [Ca] in the cleft space (Ca), which opens other RyR channels in the same Ca release unit (CaRU) via Ca-induced Ca-release. Experiments by Zima et al. (J. Physiol. 588:4743-4757, 2010) demonstrate that spontaneous Ca sparks occur only when intrasarcoplasmic-reticulum (SR) [Ca] (Ca) is above a threshold level, but that RyR-mediated SR Ca leak exists without Ca sparks well below this threshold Ca. We examine here how single RyR opening at lower Ca can fail to recruit Ca sparks at a CaRU, while still contributing to SR Ca leak. We assess this using a physiologically detailed mathematical model of junctional SR Ca release in which RyR gating is regulated by Ca and Ca. We find that several factors contribute to the failure of Ca sparks as Ca declines: 1), lower Ca reduces driving force and thus limits local Ca achieved and the rate of rise during RyR opening; 2), low Ca limits RyR open time (τ(O)), which further reduces local Ca attained; 3), low τ(O) and fast Ca dissipation after RyR closure shorten the opportunity for neighboring RyR activation; 4), at low Ca, the RyR exhibits reduced Ca sensitivity. We conclude that all of these factors conspire to reduce the probability of Ca sparks as Ca declines, despite continued RyR-mediated Ca leak. In addition, these same factors explain the much lower efficacy of L-type Ca channel opening to trigger local SR Ca release at low Ca during excitation-contraction coupling. Conversely, all of these factors are fundamentally important for increasing the propensity for pro-arrhythmic Ca sparks and waves in cardiac myocytes at high Ca.