Myocardial excitation-contraction (EC) coupling begins with membrane depolarization, a process that activates voltage-dependent calcium (Ca) channels (dihydropyridine receptors, DHPRs) in the plasma membrane and allows a relatively small amount of Ca to enter the cell (Bers, 2002). l is Ca serves as a trigger to activate the Ca release channels (ryanodine receptors, RyRs) in the sarcoplasmic reticulum (SR), a mechanism known as Ca-induced Ca release (CICR) (Bers, 2002; Fabiato, 1985). It was also shown that Ca entry via DHPR and reverse mode of sodium-calcium exchanger (NCX) could synergistically activate Ca release from RyRs (Viatchenko-Karpinski et al, 2001, 2005). l e combination of Ca inƕ ux and SR Ca release increases the cytosolic free [Ca] ([Ca]c), allowing Ca to bind to troponin C, which then initiates formation of actin-myosin cross-bridges causing contraction. For myoF laments to relax, [Ca]c must be returned to its basal level. l is is predominantly achieved by the SR Ca pump (SERCA), which transports cytosolic Ca to the SR luminal compartment. Accumulated SR Ca is bound to a low-a ǁ nity high-capacity protein calsequestrin (CSQ). While most of the Ca constituting the cytosolic Ca tran- sient is taken up by the SR, some Ca is extruded from the cell by the NCX to make up for one which entered via the Ca channels in the plasmalemma. RyR open probability changes as a direct function of [Ca] at the luminal side of the channel (Gyorke and Gyorke, 1998). l e responsiveness of RyRs to luminal Ca seems to be mediated by the auxiliary proteins triadin, junctin, and CSQ, which are coupled to RyRs at the luminal surface of the SR (Gyorke et al, 2004). During the release process, the reduction in SR luminal free [Ca] ([Ca]SR) leads to deactivation or closure of RyRs, contributing to Ca-induced Ca release termination (Terentyev et al, 2002). At the same time, stimulatory eş ects of high luminal Ca on RyR channel open probability are responsible for the Ca leak pathway activation, which plays a role in setting the SR Ca content during the diastolic phase via leaking excess Ca from the SR.