The Role of Cav1.3 Channels in Cardiac Pacemaking: Developing a Single-cell Rabbit 3D Model

Robust electrophysiological and functional evidence shows the importance of L-type Cav1.3 channels in sinoatrial node pacemaker activity. However, little is still known about its quantitative contribution in rabbit sinoatrial node cells. Therefore, we developed 0D and 3D computational models of single rabbit sinoatrial node myocytes, starting from previously validated “membrane” and “calcium-clock” models of cardiac pacemaking. A formulation for ICav1.3 gained from mouse sinoatrial myocytes was included, while the Cav1.2 current was modified so that the sum of the Cav1.2 (ICav1.2) and Cav1.3 (ICav1.3) components would reproduce the original ICaL I/V relationship. Additionally, key ion channels (e.g. Cav1.3, Cav1.2, NCX) were spatially co-localized with Ryanodine receptors in different amounts. Numerical simulations show that the mathematical models reproduce basal pacemaker activity, main Action Potential features and cell-wide Calcium Transient features. Further validation was performed against available experimental data on ion channel blocks and autonomic nervous stimulation. In conclusion, we show the relevance of Cav1.3 channels contribution to rabbit sinoatrial activity using a computational model that will allow further highly detailed investigation of pacemaking mechanisms.