Fig. 1.

Prior to membrane depolarization, the SR Ca²⁺ interacts with CASQ2 functionally detaching it from the RyR2 complex rendering RyR2 primed for activation (primed cytosolic RyR2 activation site highlighted in red) by cytosolic Ca²⁺ (1). During RyR2 activation and the resulting systolic Ca²⁺ release, SR Ca²⁺ content is partially reduced thereby facilitating CASQ2 interaction with the RyR2 complex [via triadin (TRD) and/or junctin (JNT) (2). This interaction results in an allosteric inhibition of cytosolic activation site of the RyR2. The time between systolic SR Ca²⁺ release and spontaneous diastolic Ca²⁺ release is composed by refilling of SR Ca²⁺ store and latency during which the Ca²⁺ within the SR remains constant (2 and 3). The refractory phase reflects the time required for recovery of RyR2 from luminal Ca²⁺ deactivation and can be determined by a 2-pulse protocol (insets 1 and 2). At the completion of the refractory phase, refilling of the SR Ca²⁺ stores leads to dissociation of CASQ2 rendering RyR2 again functionally primed (primed cytosolic RyR2 activation site highlighted in red, 3) underlying thereby an idle phase during which stochastic activation of the recovered SR Ca²⁺ release sites triggers spontaneous diastolic Ca²⁺ waves (SCW). Phosphorylation (P) and redox modification (R) of RyR2 along with mutations in CASQ2 or the SR Ca²⁺ release complex (M) promote shortened recovery of RyR2 from luminal Ca²⁺ deactivation reducing thereby the refractory period and the time to spontaneous diastolic Ca²⁺ waves.