Abstract
Ryanodine receptors (RyRs) represent a central component in sinoatrial node (SAN) pacemaker system, as dysregulated RyRs associated with catecholaminergic polymorphic ventricular tachycardia are linked with SAN dysfunction. Within each SAN cell (SANC), the subcellular distribution pattern of RyRs is region-dependent, varying from central SAN (mostly underneath the surface sarcolemma) to peripheral SAN (striated pattern). A similar distribution pattern is also reported for the PKA- and/or Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation of RyRs. The impact and functional implication of their distribution patterns on the SANC pacemaker activity have not been fully elucidated. Here, we employed our recently developed 3D spatial model of mouse SANCs to investigate how the subcellar distribution and phosphorylation of RyRs affect spontaneous firing. Our model that features a high surface-to-center gradient of RyR expression well recapitulates the coupled-clock mechanisms, and the biomarkers of simulated spontaneous action potentials agree well with those from previous experimental studies. When abolishing the gradient without changing the whole-cell expression of RyRs in the SANCs, the model predicts 15.0% slowing of the firing rate. Reversing the surface-to-center gradient of RyR distribution (i.e., higher density in the cell center vs surface sarcolemma) further reduced the firing rate (by 25.3%) while increasing the beat-to-beat variation in cycle length, due to disrupted coupling between local Ca2+ releases and the membrane clock. Likewise, preventing RyR phosphorylation caused a substantial slowing in the firing rate (17.6%) while also augmenting beat-to-beat variability. Our simulations mechanistically uncover the functional significance of subcellar RyR distribution and its phosphorylation in maintaining robust automaticity of SANCs. The modeling framework will be applied to systematically delineate the impact of Ca2+-clock protein phosphorylation, distribution, and their interplay with the membrane-clock proteins on the SANC automaticity.
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