Abstract
Recent experiments have shown that Ca leak from the sarcoplasmic reticulum (SR) can occur via spontaneous Ca sparks, non spark ryanodine receptor (RyR) mediated leak, and RyR independent pathways (Zima et al. BJ, 94:104a, 2008). Opening of a single RyR is expected to increase local [Ca] in the cleft space rapidly (<< 1 ms) to levels that are expected to activate neighboring RyR in that cleft via Ca induced Ca release. Our question is how and why RyR-mediated SR Ca leak becomes mainly non-spark mediated at moderate to low SR Ca loads. To answer this question, we analyze Ca flux through RyRs using a physiologically detailed mathematical model of junctional SR Ca release in which RyR gating is regulated by intra SR and cleft [Ca] ([Ca]SR & [Ca]Cleft). In this model, there are one hundred RyR channels in one Ca release unit. Each RyR opens stochastically depending on [Ca]Cleft and [Ca]SR . We find that several factors contribute to the failure of one RyR channel opening to opens adjacent RyRs as [Ca]SR declines: 1) the lower [Ca]SR reduces driving force and thus limits local [Ca]Cleft (both absolute level and rate of rise), 2) low [Ca]SR can inhibit RyR open time (τO) which further reduces local [Ca]Cleft attained, 3) the low τO and fast [Ca]Cleft dissipation after closure shorten the opportunity for neighboring RyR activation, 4) at low [Ca]SR the RyR2 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 SR Ca leak.
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