A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family

What is it about?

Hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channels are unique because they are activated upon membrane hyperpolarization instead depolarization. They generate a K+ current named funny (If) that is responsible for the automatic activity of several cells types including those of the sinoatrial node, which is the physiological pacemaker of the heart. We identified a Spanish family with inappropriate sinus tachycardia (IST), which is a syndrome characterized by unexplained sinus tachycardia at rest and an exaggerated chronotropic response to physical activity. The affected individuals carry a mutation in the gene encoding HCN4 channels, which substitutes a residue (p.V240M) within the HCN domain (HCND). This domain is common to the four channels belonging to the HCN family. Using of a multidisciplinary approach including electrophysiological and biochemical techniques, as well as molecular and mathematical modeling, we demonstrate that the biophysical alterations produced by the mutation markedly increased the current density and the ultimate mechanisms responsible for this gain-of-function effect. The results also allow us to use ivabradine, a selective If inhibitor as the drug of choice, because mutated channels are sensitive to it.

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Photo by Robina Weermeijer on Unsplash

Photo by Robina Weermeijer on Unsplash

Why is it important?

Previous work on HCN1 and HCN2 channels suggested that the HCND would act as a sliding crank that couples the C-terminal cyclic nucleotide–binding (CNBD) and voltage-sensor domains (VSD) stabilizing them in a position that closes the channel pore at depolarizing membrane potentials. Our work identifies that in HCN4 channels, valine at position 240 is critical for this stabilization. Moreover, we demonstrate that some alterations in the HCND structural conformation may selectively affect the VSD but not the CNBD. Thus, the mutation increases the If density without modifying the channel sensitivity to cyclic nucleotides or the level of HCN4 channel expression at the cell membrane. Many HCN4 loss-of-function mutations are responsible for arrhythmogenic syndromes, conversely, gain-of-function disease-causing mutations are extremely infrequent. Our results support the view that IST can be considered an inherited arrhythmogenic syndrome being HCN4 a major candidate gene. Furthermore, our results strongly support the contention that HCN4 channels critically determine If density in sinoatrial cells and, thus, heart rate.

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