Role of the Instantaneous Component of the Funny Current in Murine Sinoatrial Node Pacemaking

Jack Rowley Noble1, Yanwen Wang1, Jue Li1, Mark Boyett1, Henggui Zhang2
1Manchester University, 2University of Manchester


Introduction: The cardiac pacemaker current (If) is responsible for the diastolic depolarization phase of action potentials of cardiac pacemaking cells in the sinoatrial node (SAN). Mathematical formulations of If have focused on the time-dependent current, assuming the instantaneous component was caused by various leak channels. New experimental data suggests that If is the superposition of two components, one part being time-dependent and the other instantaneous. Method: Using experimental current-voltage data the formulation of If in the Kharche model of the murine SAN cell was modified to include an instantaneous component. Using the newly updated model the role of the instantaneous component of If on action potential morphology was studied by reducing the conductance of this channel. The role of If on cardiac conduction was also studied using a 1D chain of cells. Results: In simulation at the single cell level, combined blocking of the instantaneous and time-dependent components by 50% increased the cycle length (CL) by ~200 ms and reduced the slope of the diastolic depolarization (SDD) phase by 0.05 V/s. Applying the same block in isolation to the instantaneous component resulted in an increase in CL and decrease in SDD of ~90 ms and 0.04 V/s respectively. An isolated block of the time-dependent component by 50% had a minimal effect on both CL and SDD. Independently blocking the instantaneous component and total If in the 1D model both resulted in a reduction in the conduction velocity. Conclusion: This new formulation of If represents a significant improvement to the Kharche model, highlighting the important role of If, especially the instantaneous component, in both pacemaking and the conduction of pacemaking action potentials in the murine SAN.