@hake

Termination of cardiac Ca$^2+$ sparks: an investigative mathematical model of calcium-induced calcium release.

, , , , and . Biophys. J. 83 (1): 59--78 (July 2002)

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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