Lea Rems

The impact of high-intensity pulsed electric fields on cellular excitability

The impact of high-intensity pulsed electric fields on cellular excitability

assistant prof. Lea Rems
University of Ljubljana, Faculty of Electrical Engineering,
Tržaška 25, 1000 Ljubljana
Slovenia

Multiple types of cells of the human body, including neurons, muscle and neuroendocrine cells, have the ability to generate and propagate intrinsic electrical signals called action potentials. This electrical cellular excitability is essential for various physiological processes, such as brain activity, periodic beating of the heart, and contraction of skeletal muscles during movements. Using external pulsed electric fields, we can stimulate excitable cells to trigger action potentials on demand, which is readily used in deep brain stimulation, artificial cardiac pacing, and functional electrical stimulation. For such electrostimulation, low-intensity pulsed electric fields are used that elicit normal electrophysiological response of the cells, i.e. physiological action potential. However, when increasing the intensity of applied electric field, additional effects begin to take place, which are associated with changes in the structural organization of the cell membrane – a phenomenon termed electroporation [1]. Various molecular mechanisms have been found to participate in electroporation, including formation of aqueous pores in the lipid domains of the cell membrane and oxidative damage of polyunsaturated lipids. Recent studies suggest that high-intensity electric fields resulting in electroporation can also lead to alteration of voltage-gated ion channels, which are specialized membrane proteins that play the key role in generation and propagation of action potentials [2]. High-intensity pulsed electric fields can thus dramatically change the electrical properties of the cell membrane, and consequently cellular excitability [3, 4]. Nevertheless, the underlying molecular mechanisms remain poorly understood. The lecture will present our recent findings on how electroporation affects action potential generation in a genetically engineered minimal model of excitable cells. The experimental results will be complemented by insights from molecular dynamics simulations of model lipid membranes with voltage-gated ion channels under electric field, as well as mathematical models describing cellular electrophysiology. These results have broad application and are relevant for electroporation-based treatments targeting excitable cells, including gene delivery in skeletal muscles, neuronal stimulation, ablation of brain tumors and epileptogenic zones, and ablation of the heart muscle for treatment of cardiac arrhythmias.

References

1. Kotnik T, Rems L, Tarek M, Miklavčič D. Membrane electroporation and electropermeabilization: Mechanisms and models. Ann Rev. Biophys. 48:63-91, 2019. https://doi.org/10.1146/annurev-biophys-052118-115451
2. Rems L, Kasimova MA, Testa I, Delemotte L. Pulsed electric fields can create pores in the voltage sensors of voltage-gated ion channels. Biophys. J. 119:190-205, https://doi.org/10.1016/j.bpj.2020.05.030
3. Tung L, Tovar O, Neunlist M, Jain SK, O’Neill RJ. Effects of strong electrical shock on cardiac muscle tissue. Annals New York Academy of Sciences 720: 160-17, 1994.
4. Chaigne S, Sigg DC, Stewart MT, Hocini M, Batista Napotnik T, Miklavčič D, Bernus O, Benoist D. Reversible and irreversible effects of electroporation on contractility and calcium homeostasis in isolated cardiac ventricular myocytes. Arrhythm. Electrophysiol. 15: e011131, 2022. https://doi.org/10.1161/CIRCEP.122.011131

Webpage: https://lbk.fe.uni-lj.si/en/

Lea Rems

Lea Rems obtained her PhD in electrical engineering from the University of Ljubljana in Slovenia in 2016. After postdoctoral trainings at the Delft University of Technology in the Netherlands and KTH Royal Institute of Technology in Sweden, she returned to the University of Ljubljana as Marie Skłodowska-Curie fellow and assistant professor. Her research has continuously been focused on deciphering the fundamental mechanisms of how pulsed electric fields perturb biological cells, especially in the context of cell membrane electroporation. In recent years, she has been especially interested in understanding the coupling between electroporation and electrophysiology of excitable cells – knowledge that is needed in development of electroporation-based treatments targeting excitable cells, including cardiac and brain tissue ablation, as well as gene therapy. Dr. Rems received several national and international awards for her work, including the Vodovnik award for doctoral thesis and the Chiabrera award for excellence in the field of Bioelectromagnetics.