The rhythm of the heartbeat is regulated by the function of a particular type of ion channel in the heart tissue. Hyperpolarization-activated cyclic nucleotide–gated channels, in short HCN channels, control the frequency of electrical oscillations in our cells. In particular, they are responsible for the frequency of the heartbeat and also for electrical processes in nerve cells. Despite their huge importance in controlling such key processes in human physiology, there is currently only one single approved medicine – ivabradine – for correcting dysfunction of the HCN channels and thus treating certain illnesses. Ivabradine acts as a blocker for a HCN channel subtype, which is primarily found in the sinus nodes in the heart. As a result, it is frequently used to treat with good success illnesses such as angina pectoris or chronic heart insufficiency. The problem is that there are other HCN channel subtypes in the brain that are also blocked by ivabradine. This means that the medicine causes unwanted side effects. Researchers have thus long been searching for blockers that can specifically block the precise form of the HCN subtype found in the heart, without affecting the channels in the brain.

A group of researchers headed by Professor Anna Moroni and Professor Andrea Saponaro from the University of Milan and Professor Gerhard Thiel from the Department of Biology at TU Darmstadt has now used cryogenic electron microscopy (cryo-EM) to decipher the structure of the HCN4 channel in complex with the blocker ivabradine in the open pore Their research results have now been published in the journal “Proceedings of the National Academy of Sciences” (PNAS).

“The results enable us to understand where precisely the blocker binds in the channel and how this mechanism actually works”, explains Thiel. “The most important and key contribution made by TU Darmstadt was to use molecular-dynamic simulations on the Lichtenberg high-performance computer to trace how the blocker moves into the channel and how it inhibits the flow of ions.

Jan Krumbach and Professor Kay Hamacher (Department of Biology) at TU Darmstadt used these molecular-dynamic simulations on the Lichtenberg high-performance computer to follow the dynamics of the blocker in the channel protein. This enabled them to develop a detailed picture of how ivabradine binds in the pore and how it blocks the flow of ions through the channel pore by electrostatic repulsion. Alongside these detailed insights, the researchers also found evidence of the contribution made by previously unknown binding sites. These research results open up new perspectives in the search for HCN blockers that can better differentiate between HCN subtypes. As a result, it may be possible to minimise the possible side effects of medicines in the future.

This current collaboration is just one element of the successful cooperation between the research group at the University of Milan and the Centre for Synthetic Biology at TU Darmstadt with the aim of developing a better understanding of the function of HCN channels: In another recently published article, doctoral students from the group headed by Professor Hamacher, with assistance from their colleagues in Milan, were able to show how the activity of the HCN channels is controlled by a cellular ligand.