Calcium Transient and Sodium‐Calcium Exchange Current in Human versus Rabbit Sinoatrial Node Pacemaker Cells

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.

A novel computational model of the human sinoatrial action potential

“…AP waveforms and Ca i transient are close to experimental traces reported by Verkerk et al [7,12]. In particular the model well describes AP morphology, both during the upstroke and during the diastolic depolarization phase.…”

“…In order to mimic the experimental [Ca 2+ ] i data recorded by Verkerk et al [12] (transient range and amplitude) the following changes have been applied: I NaCa. We reduced the maximal I NaCa activity by 60% to increase diastolic Ca 2+ level.…”

“…Comparison between intracellular Ca 2+ transient generated by the model (black line) and experimental data (red line) recorded by Verkerk et al[12].…”

“…AP features APA: action potential amplitude; MDP: maximum diastolic potential; CL: cycle length; V max : maximum upstroke velocity; APD 20,50,90 : action potential duration at 20, 50, and 90% repolarization; OS: overshoot; DDR 100 : diastolic depolarization rate in the first 100 ms of DD.Ca i transient measurements on human SAN refer to a unique SAN single cell[12]. The Ca i transient generated by the model is close to experimental traces.…”

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…These variations result from notable interspecies differences in the dynamics and contributions of the calcium handling proteins, in the density of each current, and their regulation. Very few studies, however, have reported data from single cells that were dissociated from an excised human SAN [42,110] . Each of the studies was performed with isolated cells from a single SAN, but it was possible to compare a few electrophysiological parameters with rabbit cells.…”