Dynorphin A induces membrane permeabilization by formation of proteolipidic pores. Insights from electrophysiology and computational simulations

Abstract

Graphical abstract

Surface-Functionalized Polystyrene Nanoparticles Alter the Transmembrane Potential via Ion-Selective Pores Maintaining Global Bilayer Integrity

“…The upper limit of our conductance measurements ( G ∼ 1 nS) would correspond to r ≥ 1 nm. Such scattered values in pore dimensions are characteristic of systems forming disordered channel structures where there is not a unique pore configuration but rather a variety of arrangements, as seen for viral proteins − cell-penetrating peptides, and other small charged peptides. ,, Note that the myriad of pore configurations, as opposed to that of well-defined canonical ion channels, is seen in a dual way: as a static disorder (existence of different conductive levels in the traces) but also as a dynamic disorder (variation of current levels with time, shown in Figure A–C) …”

“…Importantly, experiments with PS-NH 2 NPs display scattered values that range from anionic selectivity to cationic one (Figure B). Positively charged PS-NH 2 NPs alone cannot account for a cation-selective pore, indicating that the negatively charged lipids present in the membrane must participate in the pore structure similar to membrane proteins that assemble with lipids to form joint proteolipidic structures. − …”

“…Such scattered values in pore dimensions are characteristic of systems forming disordered channel structures where there is not a unique pore configuration but rather a variety of arrangements, as seen for viral proteins 43−51 cell-penetrating peptides, 99 and other small charged peptides. 42,52,100 Note that the myriad of pore configurations, as opposed to that of well-defined canonical ion channels, 96 is seen in a dual way: as a static disorder (existence of different conductive levels in the traces) but also as a dynamic disorder (variation of current levels with time, shown in Figure 6A−C). 101 A combined measurement of the membrane-disrupting activity of PS NPs could come from the transferred charge Q calculated as the integral of the current over time as shown in Figure 7.…”

“…We observe that under physiological conditions, the studied NPs attach to the lipid surface and form disordered conductive pores that resemble proteolipid pores formed by association of membrane proteins and lipid molecules. 42 − 52 By using a combination of different electrophysiological parameters, we elucidate the conductive nature of the observed pores, the participation of PS NPs in their structure, and the role of NP charge and functionalization. Based on this, we discuss the possible role of NP-induced pores and their role for membrane organization in nanoplastic toxicology.…”

Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

“…It is processed into shorter intermediates, such as big dynorphin (BigDyn, 32 residues), which is further processed into dynorphin A (DynA, 17 residues) and dynorphin B (DynB, 13 residues) [13] . Dynorphins are some of the most positively charged peptides found in our body [15] ( Table 1 ), which makes them highly prone to interact with negatively charged molecules, such as the negatively charged polar head groups of phospholipids [16] and also other molecules, e.g. the Aβ ( Table 1 ).…”