Calcium (Ca(2+))-induced Ca(2+) release (CICR) is widely accepted as the 
principal mechanism linking electrical excitation and mechanical contraction in 
cardiac cells. The CICR mechanism has been understood mainly based on binding of 
cytosolic Ca(2+) with ryanodine receptors (RyRs) and inducing Ca(2+) release 
from the sarcoplasmic reticulum (SR). However, recent experiments suggest that 
SR lumenal Ca(2+) may also participate in regulating RyR gating through 
calsequestrin (CSQ), the SR lumenal Ca(2+) buffer. We investigate how SR Ca(2+) 
release via RyR is regulated by Ca(2+) and calsequestrin (CSQ). First, a 
mathematical model of RyR kinetics is derived based on experimental evidence. We 
assume that the RyR has three binding sites, two cytosolic sites for Ca(2+) 
activation and inactivation, and one SR lumenal site for CSQ binding. The open 
probability (P(o)) of the RyR is found by simulation under controlled cytosolic 
and SR lumenal Ca(2+). Both peak and steady-state P(o) effectively increase as 
SR lumenal Ca(2+) increases. Second, we incorporate the RyR model into a CICR 
model that has both a diadic space and the junctional SR (jSR). At low jSR 
Ca(2+) loads, CSQs are more likely to bind with the RyR and act to inhibit jSR 
Ca(2+) release, while at high SR loads CSQs are more likely to detach from the 
RyR, thereby increasing jSR Ca(2+) release. Furthermore, this CICR model 
produces a nonlinear relationship between fractional jSR Ca(2+) release and jSR 
load. These findings agree with experimental observations in lipid bilayers and 
cardiac myocytes.