A calcium-induced calcium release mechanism mediated by calsequestrin

Calcium (Ca2+Ca2+)-induced Ca2+Ca2+ 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 Ca2+Ca2+ with ryanodine receptors (RyRs) and inducing Ca2+Ca2+ release from the sarcoplasmic reticulum (SR). However, recent experiments suggest that SR lumenal Ca2+Ca2+ may also participate in regulating RyR gating through calsequestrin (CSQ), the SR lumenal Ca2+Ca2+ buffer. We investigate how SR Ca2+Ca2+ release via RyR is regulated by Ca2+Ca2+ 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 Ca2+Ca2+ activation and inactivation, and one SR lumenal site for CSQ binding. The open probability (Po)(Po) of the RyR is found by simulation under controlled cytosolic and SR lumenal Ca2+Ca2+. Both peak and steady-state PoPo effectively increase as SR lumenal Ca2+Ca2+ 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 Ca2+Ca2+ loads, CSQs are more likely to bind with the RyR and act to inhibit jSR Ca2+Ca2+ release, while at high SR loads CSQs are more likely to detach from the RyR, thereby increasing jSR Ca2+Ca2+ release. Furthermore, this CICR model produces a nonlinear relationship between fractional jSR Ca2+Ca2+ release and jSR load. These findings agree with experimental observations in lipid bilayers and cardiac myocytes.