Diastolic Calcium Release Controls the Beating Rate of Rabbit Sinoatrial Node Cells: Numerical Modeling of the Coupling Process

Recent studies employing Ca²⁺ indicators and confocal microscopy demonstrate substantial local Ca²⁺ release beneath the cell plasma membrane (subspace) of sinoatrial node cells (SANCs) occurring during diastolic depolarization. Pharmacological and biophysical experiments have suggested that the released Ca²⁺ interacts with the plasma membrane via the ion current (/_NaCa) produced by the Na ⁺/Ca²⁺ exchanger and constitutes an important determinant of the pacemaker rate. This study provides a numerical validation of the functional importance of diastolic Ca²⁺ release for rate control. The subspace Ca²⁺ signals in rabbit SANCs were measured by laser confocal microscopy, averaged, and calibrated. The time course of the subspace [Ca²⁺] displayed both diastolic and systolic components. The diastolic component was mainly due to the local Ca²⁺ releases; it was numerically approximated and incorporated into a SANC cellular electrophysiology model. The model predicts that the diastolic Ca²⁺ release strongly interacts with plasma membrane via /_NaCa and thus controls the phase of the action potential upstroke and ultimately the final action potential rate.