Abstract
Many cells depend on ‘calcium-induced calcium release' (CICR), an inherently regenerative process due to the Ca2+-dependent gating of ryanodine receptors (RyRs) in the SR. Ca2+ sparks, as seen in muscle, reflect the concerted gating of groups of RyRs in specialized signalling domains in the junctions between the SR and surface membrane. However, the mechanism(s) responsible for the termination of regenerative CICR during the evolution of Ca2+ sparks remain uncertain. Rat cardiac RyR gating was recorded at physiological Ca2+, Mg2+ and ATP levels and incorporated into a 3D spatial model of the cardiac dyad which reproduced the time-course of Ca2+ sparks, Ca2+ blinks and Ca2+ spark restitution. Model CICR termination was robust, relatively insensitive to the number dyadic RyRs and automatic. This emergent behavior arose from the rapid development and dissolution of nanoscopic Ca2+ gradients within the dyad. These simulations show that CICR does not require intrinsic inactivation mechanisms for stability and cessation of regeneration arises from local control at the molecular scale via a process we call ‘induction decay'.
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