Abstract
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]Cleft), 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]SR) is above a threshold level, but that RyR-mediated SR Ca leak exists without Ca sparks well below this threshold [Ca]SR. We examine here how single RyR opening at lower [Ca]SR 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]SR and [Ca]Cleft. We find that several factors contribute to the failure of Ca sparks as [Ca]SR declines: 1), lower [Ca]SR reduces driving force and thus limits local [Ca]Cleft achieved and the rate of rise during RyR opening; 2), low [Ca]SR limits RyR open time (τO), which further reduces local [Ca]Cleft attained; 3), low τO and fast [Ca]Cleft dissipation after RyR closure shorten the opportunity for neighboring RyR activation; 4), at low [Ca]SR, the RyR exhibits reduced [Ca]Cleft sensitivity. We conclude that all of these factors conspire to reduce the probability of Ca sparks as [Ca]SR 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]SR 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]SR.
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