Mechanism of Ca++ release from the sarcoplasmic reticulum: a computer model

The proposed model describes myocyte calcium (Ca++) cycling, emphasizing the kinetics of sarcoplasmic reticulum (SR) Ca++ release channels. The suggested SR channel regulating mechanism includes two types of Ca++ binding sites: (1) low affinity sites with high binding rates, regulating the opening of Ca++ channels and (2) high affinity sites with low binding rates, which regulate their closing. The amount of Ca++ released from the SR and the peak value of Ca++ ion concentration [Ca++] in the cytoplasm were found to depend on the rate of the increase of [Ca++], similar to Ca++ induced Ca++ release experiments. The model describes spontaneous release of Ca++ from overloaded SR. The dependence of the control mechanism on the activating and inactivating sites is substantiated by simulations of ryanodine intervention, providing results similar to experimental results. Simulations under conditions of isolated SR vesicles produced Ca++ release results similar to measured data. Consequently, it is suggested that the recovery of Ca++ release channels represents the rate limiting factor in the process of mechanical restitution.