Figure 14 – Increasing CSQ fraction inhibits SCRs and DADs with no effect on SAPs.

A) Increasing CSQ fraction (i.e., both CSQ-mediated Ca²⁺ buffering and RyR regulation) monotonically raises the rate threshold of SCRs (i) and DADs (ii), with SAP (iii) remaining absent in all conditions. While CSQ-mediated changes in SCRs are solely observed in cells with intermediate tubular structures, the effect of reduced CSQ fraction on DADs is greater in cells with dense and intermediate tubular structures vs cells with sparse tubules. B) Effect of altered CSQ fraction on voltage (i) and global cytosolic Ca²⁺ concentration (ii) in cells with sparse (left), intermediate (middle), and dense (right) tubules following pacing at 3 Hz to examine the occurrence of DADs and SCRs. C) Mechanism underlying increased CSQ fraction inhibiting SCRs and DADs without affecting SAPs. Biomarkers were determined from the first 100 ms of no-stimulation period and normalized to those of cells with a retained CSQ fraction of 1.0. Since CSQ is a jSR Ca²⁺ buffer and regulates RyR P_o, there is interplay between varying CSQ buffering effects (1), CSQ-RyR regulation (2) and CSQ fraction (1+2). Lower CSQ expression is associated with reduced CSQ-mediated jSR Ca²⁺ buffering (1) and increased RyR systolic P_o (2). Reduced CSQ Ca²⁺ buffering (1) decreases SR load (i) but promotes RyR leak (ii), and thus SCRs. Conversely, enhanced systolic RyR P_o (2) increases SR release fraction, which lowers SR load (iii) and diminishes RyR leak (iv), leading to reduced SCRs. Combining these two effects, although decreasing CSQ expression lowers down SR Ca²⁺ load (v), RyR leak is enhanced (vi), which leads to promotion of SCRs, DADs, and SAPs.