Abstract
There is an ongoing debate on the mechanism underlying the pacemaker activity of sinoatrial node (SAN) cells, focusing on the relative importance of the “membrane clock” and the “Ca2+ clock” in the generation of the small net membrane current that depolarizes the cell towards the action potential threshold. Specifically, the debate centers around the question whether the membrane clock-driven hyperpolarization-activated current, I f, which is also known as the “funny current” or “pacemaker current,” or the Ca2+ clock-driven sodium-calcium exchange current, I NaCa, is the main contributor to diastolic depolarization. In our contribution to this journal's “Special Issue on Cardiac Electrophysiology,” we present a numerical reconstruction of I f and I NaCa in isolated rabbit and human SAN pacemaker cells based on experimental data on action potentials, I f, and intracellular calcium concentration ([Ca2+]i) that we have acquired from these cells. The human SAN pacemaker cells have a smaller I f, a weaker [Ca2+]i transient, and a smaller I NaCa than the rabbit cells. However, when compared to the diastolic net membrane current, I NaCa is of similar size in human and rabbit SAN pacemaker cells, whereas I f is smaller in human than in rabbit cells.
Highlights
Animal studies have demonstrated that pacemaker activity of the sinoatrial node (SAN) is controlled by a complex system of “clocks” composed of voltage-dependent sarcolemmal currents—designated the “membrane clock,” “voltage clock,” or “ion channel clock”—and tightly coupled sarcoplasmic reticulum (SR) Ca2+ cycling molecules together with the electrogenic sodium-calcium exchanger, named the “Ca2+ clock” [1, 2]
We first characterized the action potentials and [Ca2+]i transients that we recorded from single rabbit and human SAN pacemaker cells
We used our experimental data for a numerical reconstruction of the hyperpolarization-activated current and the sodiumcalcium exchange current associated with the recorded action potentials and [Ca2+]i transients, allowing a comparison of these currents between rabbit and human SAN pacemaker cells
Summary
Animal studies have demonstrated that pacemaker activity of the sinoatrial node (SAN) is controlled by a complex system of “clocks” composed of voltage-dependent sarcolemmal currents—designated the “membrane clock,” “voltage clock,” or “ion channel clock”—and tightly coupled sarcoplasmic reticulum (SR) Ca2+ cycling molecules together with the electrogenic sodium-calcium exchanger, named the “Ca2+ clock” [1, 2]. There is an ongoing debate on the relative importance of the “membrane clock” and the “Ca2+ clock” in the generation of the small net membrane current underlying the spontaneous diastolic depolarization that drives the cell towards its action potential threshold [3,4,5,6,7] This debate centers around the contribution of the hyperpolarizationactivated current If, known as “funny current” or “pacemaker current,” as a member of the membrane clock, and the sodium-calcium exchange current INaCa, resulting from the electrogenic sodium-calcium exchange process and driven by the Ca2+ clock. We recorded If in voltage clamp experiments on single pacemaker cells isolated from the SAN of a patient who underwent SAN excision [9] From these cells, we acquired spontaneous action potentials, which showed a clear diastolic depolarization phase resulting in an intrinsic cycle length of ≈ 830 ms (72 beats/min). Our voltage clamp experiments revealed the presence of a fast large
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