Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current

The hyperpolarization-activated 'funny' current, If, plays an important modulating role in the pacemaker activity of the human sinoatrial node (SAN). If is carried by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are tetramers built of four HCN subunits. In human SAN, HCN4 is the most abundant of the four isoforms of the HCN family. Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, or in the KCNE2 gene, which encodes the MiRP1 accessory β-subunit, have been associated with sinus node dysfunction. Voltage-clamp experiments on HCN4 channels expressed in COS-7 cells, Xenopus oocytes, or HEK-293 cells have revealed changes in the expression and kinetics of mutant channels, but the extent to which these changes would affect If flowing during a human SAN action potential is unresolved. Here, we review the changes in expression and kinetics of HCN4 mutant channels and provide an overview of their effects on If during the time course of a human SAN action potential, both under resting conditions and upon adrenergic stimulation. These effects are assessed in simulated action potential clamp experiments, with action potentials recorded from isolated human SAN pacemaker cells as command potential and kinetics of If based on voltage-clamp data from these cells. Results from in vitro and in silico experiments show several inconsistencies with clinical observations, pointing to challenges for future research.