First person – Kateryna Demydenko

Kateryna Demydenko

How would you explain the main findings of your paper in lay terms?

The majority of the heart is made up of cardiac myocytes, which are the cells that are responsible for the pumping of the heart. Pump function is driven by electrical signals that excite the myocytes and Ca²⁺ is a key mediator of this process. Under healthy conditions, strong contraction of the heart is ensured by homogeneous and synchronized Ca²⁺ release from intracellular stores through RyR Ca²⁺ channels across the cell. Acting via InsP₃R Ca²⁺ channels on the intracellular store, hormones that are increased in disease, such as endothelin-1, can increase the strength of contractions to meet the needs of the body. By inducing extra Ca²⁺ release events, these hormones can also cause arrhythmia. Using a specifically designed reporter of Ca²⁺ changes localized to Ca²⁺ release sites next to the channels, we have shown that endothelin-1 elicits its effects by harmonizing Ca²⁺ release site activation and, in doing so, augments Ca²⁺ release. This effect of endothelin-1 is brought about by inducing Ca²⁺ release via InsP₃R channels in the dyad, which then facilitates the activation of nearby RyRs, thereby generating a synchronized Ca²⁺ elevation in the cell.

Were there any specific challenges associated with this project? If so, how did you overcome them?

To study and identify mechanistic insights into the actions of endothelin-1, it is necessary to selectively measure local Ca²⁺ dynamics in dyadic structures of the cardiac myocytes. To do this, I used a genetically encoded spatially restricted Ca²⁺ biosensor that allowed me to directly analyze Ca²⁺ release kinetics at individual dyads in intact cardiac myocytes during electrically evoked Ca²⁺ transients. Together with a large amount of data came a burden to develop an automated and reliable pipeline for the analysis. I spent many hours learning to write scripts in analytical software and optimizing the analysis pipeline to run smoothly over the whole dataset. This pipeline required a lot of bug fixing and trial-and-error, but ultimately, I was successful and this allowed us to provide for the first time a detailed analysis of the modulation of dyadic Ca²⁺ by neurohormonal agents in intact cells and how this relates to global Ca²⁺ changes underlying cardiac myocyte contraction.

When doing the research, did you have a particular result or ‘eureka’ moment that has stuck with you?

There were many fascinating things during the course of this project, but the most striking moment for me was seeing the heterogeneity in Ca²⁺ release process between the different dyads as well as in the same dyad between the consecutive beats in healthy cells. I really did not expect to see this variability when knowing that spatially uniform synchronous Ca²⁺ elevations are central to the efficient contraction of cardiac myocytes. It is even more amazing that by manipulating the differences in local Ca²⁺ release properties, it is possible to modulate the strength of cardiac myocyte contraction or the likelihood of pathological arrhythmogenesis.

Why did you choose Journal of Cell Science for your paper?

I think Journal of Cell Science, with its wide scope in the field of cell biology, was the best fit for our research, providing the possibility to share our mechanistic insights by which InsP₃ generated downstream of endothelin-1 fine-tunes Ca²⁺ transient properties by signaling to RyRs. The microdomain Ca²⁺ signaling that I studied is also relevant to the growing body of scientists who are interested in membrane contact sites and microdomains. Besides that, I deeply appreciate the efforts of the journal in supporting scientific communication with a broad audience and dissemination of data and technical approaches within the research community.

Have you had any significant mentors who have helped you beyond supervision in the lab? How was their guidance special?

I've been lucky to have a mentor at each stage of my research career who has been extremely generous with time and advice. Dr Cristian Gurgui and Prof. Karel Talavera introduced me to the world of professional research when I did an internship as a master's student under their supervision. Enjoyment of the challenge and excitement of experimentation in the supportive environment convinced me to pursue a career in science and go for a PhD. My PhD mentor, Prof. Llewelyn Roderick has been very supportive through all the years I have spent in his lab. He taught me how to transform my curiosity into testable hypotheses and to develop research questions to guide the project. He provided me also with opportunities for networking and for sharing my findings with other researchers by encouraging me to take part in several national and international research conferences and workshops. All the advice and guidance from the aforementioned people helped me to become a better scientist and significantly contributed to my professional development.

What motivated you to pursue a career in science, and what have been the most interesting moments on the path that led you to where you are now?

My professional goal is to contribute to the development of life-improving solutions. This ambition determined the direction of my studies and training. During my undergraduate studies, I learnt that it is essential to have an extensive knowledge in molecular and cellular biology for understanding the cause–consequence chain in physiological function and malfunction. I am especially fascinated by how Ca²⁺ signaling can control simultaneously, yet selectively, a myriad of metabolic and physiological functions in the cell. The disturbances in its homeostasis are frequently associated with the development of pathologies in many organs of our body, including the heart. I was extremely curious to learn more about the role Ca²⁺ plays in adapting pump function of the heart to changing environments and how it can be manipulated to harness beneficial effects at the expense of that which are adverse.

Who are your role models in science? Why?

In science as in life, I do not have a role model as there is no ‘one size fits all’ experience that brings you to success. However, I have always tried to learn from my fellow PhD students and postdocs, as much as from the established scientists I had a chance to meet. The fruitful discussions and late evening chats that we had have broadened my horizons and taught me to persevere in challenging situations.

What's next for you?

I am about to submit my thesis and complete my PhD. I am also currently looking for a position where I can add value to the development of novel therapeutics for patients with heart failure.

Tell us something interesting about yourself that wouldn't be on your CV

If I were not a scientist, I would probably became a historian. In my free time, I love to read historical books authored by both experts and witnesses of certain periods in the past. Our perception of past events is usually subjective, and the same facts can be interpreted from a different angle. Studying history gives me a deeper understanding of some of the most important events and social movements that contributed to the world we live in today.