Sudden cardiac episodes could be caused by ‘deadly cocktail’

When international top footballer Christian Eriksen fell to the ground during the European Championships, the world was suddenly and abruptly made aware of such sudden, unexplainable cardiac episodes.

While Eriksen was stabilised, he is not the only one to have experienced such an episode. Sudden cardiac episodes account for at least 15 percent of all deaths in Western societies. But it largely remains a mystery why some people live a perfectly normal life until suddenly experiencing a cardiac episode.

In a new study, researchers from the Department of Drug Design and Pharmacology provide insight to the phenomenon using a new technology.

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“We know that some of these episodes happen due to a malfunction in a certain protein in the cell membrane of heart cells. The protein is called the cardiac sodium channel, which is basically responsible for keeping our heart beating. But we did not know why the protein suddenly stops functioning correctly after working seemingly normal for years. In our study, we demonstrate that some cases of sudden cardiac episodes are caused not by the originally suspected genetic mutation within this membrane protein alone, but may rather require the presences of both the mutation and a nearby phosphorylation” says Professor and Group Leader Stephan Pless.

Phosphorylation is a process that modifies the protein and can change its function. It happens all the time, explains Stephan Pless, since every protein is constantly modified and unmodified with a variety of chemical entities. The phosphorylation process can for example be triggered by stress or disease and the group found this modification to also affect the response to clinically used drugs.

The combination of the genetic mutation and chemical modification can render the protein non-functional, which causes the heart to stop functioning.

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Engineering a protein

To test their hypothesis, the researchers used a new technology to manipulate the protein with chemical modifications, in this case phosphorylation. To build up the protein from scratch, would be “a massive task and impossible to achieve with today’s technology,” explains Stephan Pless.

Instead, the researchers are able to insert short synthetic amino acid sequences containing mutations and or modifications into the protein. This allowed them to investigate the function of phosphorylation in combination with the mutation on the protein.

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“Before, the problem was that we couldn’t experimentally control how much phosphorylation there is because it is the cell containing the protein that will regulate the phosphorylation level at any given time. But with this new technology, we can decide if we want to have 0 percent or 100 percent phosphorylation, allowing us to study the effects of this particular modification with and without the mutation,” explains Ph.D. student Hendrik Harms.

“The technology enables us for the first time to actually study a mutation with an adjacent phosphorylation, which is either there or not. It couldn’t be done before, and certainly not without help from Professor Lucie Delemotte at the Royal Institute of Technology in Stockholm, who used computer simulations to observe the details of the structure of the protein in the presence and absence of the mutation with or without the phosphorylation,” says Postdoc Iacopo Galleano.

The insight could provide a foundation for more research into what role modifications play for the proteins in heart cells and how they respond to drugs.

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