Figure 6 – Inhibition of RyR has biphasic effects on SCRs, DADs, and SAPs.

A) Rate threshold for SCRs (i), DADs (ii) and SAP (iii) in dense, intermediate and sparsely tubulated cells. Biphasic dependence on RyR inhibition is observed in all settings and cell types, with the exception of SCRs in sparsely tubulated cells. Here, the lowest observed baseline rate threshold for SCRs is unaltered by RyR inhibition. B) Effect of altered RyR fraction on voltage (i) and global cytosolic Ca²⁺ concentration (ii) in cells with sparse (left), intermediate (middle), and dense (right) tubules following pacing at 4 Hz to examine the occurrence of DADs, SAPs and SCRs. C) Mechanism underlying RyR inhibition having biphasic effects on SCRs, DADs and SAP. Biomarkers were determined from the first 100 ms of no-stimulation period and normalized to those of cells with a retained RyR fraction of 1.0. Lower RyR expression is associated with reduced RyR release, leading to elevated SR load (i) and augmented RyR P_o (ii). While higher RyR P_o causes RyR leak leading to increased SCRs, lower RyR expression itself inhibits RyR leak. This results in the biphasic effect of RyR reduction on SCRs, DADs and SAPs.