Mechanisms of spontaneous pacing: sinoatrial nodal cells, neonatal cardiomyocytes, and human stem cell derived cardiomyocytes.

The sinoatrial (SA) node is the primary site from which the mammalian heart is paced, but the mechanisms underlying the pacemaking still remain clouded. It is generally believed that the hyperpolarization-activated current If, encoded by hyperpolarization-activated cyclic nucleotide-gated (HCN) genes, contributes significantly to pacing, which in tandem with inward current generated by efflux of Ca2+ via the Na+-Ca2+ exchanger (NCX), resulting from the released Ca2+, mediates the diastolic depolarization. Here, we review the data that implicate If as the "pacemaker current" and conclude that there is not only a significant discrepancy between the range of diastolic depolarization potential (-60 to -40 mV) and the activation potential of If (negative to -70 mV), but that also the kinetics of If and its pharmacology are incompatible with the frequency of a heartbeat in rodents and humans. We propose that If serves as a functional insulator, which protects the SA-nodal cells against the large negative electrical sink of atrial tissue connected to it with connexins. We also evaluate the role of If and calcium signaling in mediating the diastolic depolarization in rat neonatal cardiomyocytes (rN-CM), and human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CM), and provide evidence for a possible involvement of mitochondrial Ca2+ in initiating the oscillatory events required for the spontaneous pacing.