Pulsed Electric Fields Can Create Pores in the Voltage Sensors of Voltage-Gated Ion Channels

Abstract

Pulsed electric fields are increasingly used in medicine to transiently increase the cell membrane permeability via electroporation to deliver therapeutic molecules into the cell. One type of event that contributes to this increase in membrane permeability is the formation of pores in the membrane lipid bilayer. However, electrophysiological measurements suggest that membrane proteins are affected as well, particularly voltage-gated ion channels (VGICs). The molecular mechanisms by which the electric field could affects these molecules remain unidentified. In this study, we used molecular dynamics simulations to unravel the molecular events that take place in different VGICs when exposing them to electric fields mimicking electroporation conditions. We show that electric fields can induce pores in the voltage-sensor domains (VSDs) of different VGICs and that these pores form more easily in some channels than in others. We demonstrate that poration is more likely in VSDs that are more hydrated and are electrostatically more favorable for the entry of ions. We further show that pores in VSDs can expand into so-called complex pores, which become stabilized by lipid headgroups. Our results suggest that such complex pores are considerably more stable than conventional lipid pores, and their formation can lead to severe unfolding of VSDs from the channel. We anticipate that such VSDs become dysfunctional and unable to respond to changes in transmembrane voltage, which is in agreement with previous electrophysiological measurements showing a decrease in the voltage-dependent transmembrane ionic currents after pulse treatment. Finally, we discuss the possibility of activation of VGICs by submicrosecond-duration pulses. Overall, our study reveals a new, to our knowledge, mechanism of electroporation through membranes containing VGICs.

PEDOT:PSS‐Coated Stimulation Electrodes Attenuate Irreversible Electrochemical Events and Reduce Cell Electropermeabilization

“…www.advmatinterfaces.de the creation of pores in voltage-gated ion channels embedded in the cell membrane. [51] Moreover, dissolved metal particles from electrodes have been shown to be harmful to cells in a concentration dependent manner. [52] Such mechanisms indicate the complexity of these chemical changes and the effect on cells.…”

Pulse Duration Dependent Asymmetry in Molecular Transmembrane Transport Due to Electroporation in H9c2 Rat Cardiac Myoblast Cells In Vitro

“…However, with the use of a cocktail of verapamil (for blocking L-type Ca 2+ channels in plasma membrane), caffeine (for depleting Ca 2+ from the ER by stimulating ryanodine receptors), and cyclopiazonic acid (for blocking re-uptake of Ca 2+ to the ER) in the paper from Semenov [22], CICR is unlikely to be responsible for symmetrical transport after nsEP. In our experiments, we also cannot rule out the possibility that nsEP affect permeability of protein ion channels directly [22,23,71], and that this may be done more uniformly across the cell, however, the direction of electric field may influence the effect of electric field on ion channels [71].…”

Advanced extraction techniques for Berberis species phytochemicals: A review

“…Pulsed electric field‐assisted extraction is a non‐thermal extraction technique in which pulsed electric‐field can penetrate the cell wall and increase cell membrane permeability causing leakage of intracellular compounds (Carullo et al ., 2020; Rems et al ., 2020). This is due to a phenomenon called electroporation in which intense electric field increases the permeability of the cell membrane in increases to allow the passage of ions and macromolecules outside the cell (Martínez et al ., 2020).…”