Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Figure 1. A schematic illustration of human RyR2 domain organization and boundaries. Color-coded distribution of mutations associated with disease (top value) and their frequency within individual structural domains (bottom value). The six transmembrane segments (S) are represented by a vertical line. See Figure 2 below for a corresponding cartoon representation showing the arrangement of domains in 3D (using same color coding).

Figure 2. A schematic representation of the RyR2 3D architecture depicting 4 regulatory layers from the cytoplasmic side. The pore-forming region, comprised of the TMD and CTD, is modulated by the CSol (Layer 1), NTD, JSol and BSol (Layer 2), SPRY1/2/3 and RY1/2/3/4 (Layer 3), and accessory proteins (Layer 4), e.g., FKBP. The colors of regions in the RyR2 3D structure correspond to the colors in the RyR2 sequence in Figure 1.

Figure 3. Simplified schematic to illustrate the proposed pathways linking RyR2 loss-of-function (LoF, red) and gain-of-function (GoF, blue) abnormalities to pro-arrhythmic behavior. In GoF, excess Ca2+ leak leads to diastolic Ca2+ waves and DADs which tend to decrease the Ca2+ load. In LoF, evoked Ca2+ release is impaired resulting in Ca2+ loading and less Ca2+-dependent inactivation (CDI) of ICa, ultimately resulting in prolonged systolic Ca2+ release and EADs. Increasing Ca2+ load worsens Ca2+ regulation and hastens arrhythmia development.