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

Recent studies employing Ca 2+ indicators and confocal microscopy demonstrate substantial local Ca 2+ 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 Ca 2+ interacts with the plasma membrane via the ion current ( I NaCa) produced by the Na +/Ca 2+ exchanger and constitutes an important determinant of the pacemaker rate. This study provides a numerical validation of the functional importance of diastolic Ca 2+ release for rate control. The subspace Ca 2+ signals in rabbit SANCs were measured by laser confocal microscopy, averaged, and calibrated. The time course of the subspace [Ca 2+] displayed both diastolic and systolic components. The diastolic component was mainly due to the local Ca 2+ releases; it was numerically approximated and incorporated into a SANC cellular electrophysiology model. The model predicts that the diastolic Ca 2+ release strongly interacts with plasma membrane via I NaCa and thus controls the phase of the action potential upstroke and ultimately the final action potential rate.