Rate-adapted dynamic-clamp of the funny current in sinoatrial pacemaker cells

A typical feature of sinoatrial node (SAN) pacemaker cells is the presence of an ionic current, named 'funny current', If, that activates upon hyperpolarization. We aimed to: 1) test the impact of different mathematical models of If (Maltsev-Lakatta and Severi-DiFrancesco) in real cells by using the Dynamic Clamp (DC) technique; 2) adapt the DC protocol to adequately simulate a shift of the If activation curve. Two different protocols were implemented: i) the If was selectively blocked by Ivabradine and substituted with a "synthetic" If dynamically reconstructed from the experimentally recorded action potentials of a single isolated rabbit SAN cell according to the mathematical models; ii) virtual negative shift of the If activation curve by the injection of a compensatory current using DC. The Severi-DiFrancesco model allowed the restoration of control pacemaking rate while the MaltsevLakatta model did not. The compensatory current used to reproduce the negative shift of the activation curve did not yield the expected results; we therefore adapted the Dynamic Clamp to the single-cell specific behavior by scaling the estimated If current based on the spontaneous firing rate. This adaptation protocol succeeded in reproducing the effects of a negative activation shift. The Ivabradine protocol was then repeated with this adjustment and the results were fully consistent with those previously obtained