FIGURE 7.

Disruption of Ca storing and regulatory functions of CASQ2 by the CPVT CASQ2 mutants DEL and R33Q. CASQ2 is present in the junctional SR in two forms (left-hand scheme): polymeric CASQ2 with high Ca binding capacity serves as a Ca storage site and controls [Ca]_SR in the vicinity of RyR2; monomeric CASQ2 regulates RyR2 activity in a [Ca]_SR-dependent manner (through binding to TRD). Ca release by RyR2s results in partial depletion of [Ca]_SR and the release is terminated at a certain threshold [Ca]_SR ([Ca]_SRT). After their deactivation, RyR2s stay refractory until the jSR is refilled with Ca, a process that is influenced by CASQ2 Ca buffering capacity. Expression of CASQ2^DEL disrupts CASQ2 polymerization and reduces SR Ca buffering without altering interactions of WT CASQ2 with the RyR2 complex (middle). This results in accelerated recovery of [Ca]_SR and hence shortened restitution from luminal-Ca dependent deactivation that follows SR Ca release. Expression of CASQ2^R33Q displaces WT CASQ2 from the RyR2 complex without interfering with polymerization and Ca buffering (right). This impairs the ability of CASQ2 to act as a luminal Ca sensor, i.e., inhibit RyR2 activity at low luminal Ca, resulting in lowered [Ca]_SRT and shortened Ca signaling refractoriness. Thus, both CPVT mutant proteins act by disrupting normal control of RyR2 by CASQ2 and luminal Ca required for efficient turning of Ca release during the diastolic phase.