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Termination of Cardiac Ca2+Sparks: An Investigative Mathematical Model of Calcium-Induced Calcium Release

Biophysical Journal
Publication Date
DOI: 10.1016/s0006-3495(02)75149-7
  • Biophysical Theory And Modeling


Abstract A Ca 2+ spark arises when a cluster of sarcoplasmic reticulum (SR) channels (ryanodine receptors or RyRs) opens to release calcium in a locally regenerative manner. Normally triggered by Ca 2+ influx across the sarcolemmal or transverse tubule membrane neighboring the cluster, the Ca 2+ spark has been shown to be the elementary Ca 2+ signaling event of excitation–contraction coupling in heart muscle. However, the question of how the Ca 2+ spark terminates remains a central, unresolved issue. Here we present a new model, “sticky cluster,” of SR Ca 2+ release that simulates Ca 2+ spark behavior and enables robust Ca 2+ spark termination. Two newly documented features of RyR behavior have been incorporated in this otherwise simple model: “coupled gating” and an opening rate that depends on SR lumenal [Ca 2+]. Using a Monte Carlo method, local Ca 2+-induced Ca 2+ release from clusters containing between 10 and 100 RyRs is modeled. After release is triggered, Ca 2+ flux from RyRs diffuses into the cytosol and binds to intracellular buffers and the fluorescent Ca 2+ indicator fluo-3 to produce the model Ca 2+ spark. Ca 2+ sparks generated by the sticky cluster model resemble those observed experimentally, and Ca 2+ spark duration and amplitude are largely insensitive to the number of RyRs in a cluster. As expected from heart cell investigation, the spontaneous Ca 2+ spark rate in the model increases with elevated cytosolic or SR lumenal [Ca 2+]. Furthermore, reduction of RyR coupling leads to prolonged model Ca 2+ sparks just as treatment with FK506 lengthens Ca 2+ sparks in heart cells. This new model of Ca 2+ spark behavior provides a “proof of principle” test of a new hypothesis for Ca 2+ spark termination and reproduces critical features of Ca 2+ sparks observed experimentally.

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