Loss-of-function mutations in the HCN4 gene alter the expression and kinetics of HCN4 channels, affecting the hyperpolarization-activated current during human sinoatrial node action potentials.
How do loss-of-function mutations in the HCN4 gene affect the hyperpolarization-activated current (If) and pacemaker activity in the human sinoatrial node?
This review synthesizes current knowledge on how HCN4 mutations alter pacemaker current kinetics, highlighting the gap between clinical sinus node dysfunction and experimental models.
Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated "funny" current (If), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the kinetic changes would affect If flowing during a human SAN action potential often remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on If during the time course of a human SAN action potential, as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and in silico experiments.
Verkerk et al. (Thu,) conducted a review in Sinus node dysfunction. HCN4 mutations was evaluated. Loss-of-function mutations in the HCN4 gene alter the expression and kinetics of HCN4 channels, affecting the hyperpolarization-activated current during human sinoatrial node action potentials.