A Model of Ca2+ Release from the Sarcoplasmic Reticulum

Abstract

Various functions in the myocyte depend on Ca2+ transport, yet the control of these processes is still obscure. In order to better understand the intracellular Ca2+ processes, a model of Ca2+ release from the cardiac sarcoplasmic reticulum (SR) is suggested, in which the release of Ca2+ from the SR is mainly regulated by the kinetics of Ca2+ channels within the SR membrane. These kinetics are controlled by changes in the concentration of free Ca2+ near the openings of Ca2+ channels, and are affected by Ca2+ competitors, e.g., ryanodine. The control mechanism is based on a combination of positive and negative control loops, associated with two respective types of Ca2+ binding sites located on the SR membrane: 1) activating sites with low affinity to Ca2+ and high binding rate, and 2) inactivating sites with high affinity but low binding rate. The model also assumes that the activation of the Ca2+ channels depends on the preceding stimulation pattern (short term memory), an additional activation mechanism which is Ca2+ independent. This report describes the cytoplasmatic Ca2+ concentration in response to Ca2+ release from the SR, including the dependence on the beat intervals, either in the steady state or during response to premature and delayed beats. The analysis of ryanodine intervention supports a control mechanism based on two feedback loops, and available interval-dependent data favors inclusion of the short-term memory mechanism in the proposed model.