Biological Membranes as Bilayer Couples. A Molecular Mechanism of Drug-Erythrocyte Interactions

TLDR

The bilayer couple hypothesis may explain many membrane‑mediated phenomena in cell biology. The study proposes that asymmetrically distributed proteins and lipids in membrane bilayers enable the two halves to act as bilayer couples. The authors model amphipathic drug interactions with erythrocytes, showing that anionic drugs preferentially insert into the outer leaflet, expanding it and inducing crenation, while cationic drugs insert into the inner leaflet, causing cup‑shaped deformation, with impermeable drugs acting only on the outer leaflet. Experimental tests with erythrocytes and ghosts confirmed several predictions of the bilayer‑couple hypothesis.

Abstract

We propose that membranes whose proteins and polar lipids are distributed asymmetrically in the two halves of the membrane bilayer can act as bilayer couples, i.e., the two halves can respond differently to a perturbation. This hypothesis is applied to the interactions of amphipathic drugs with human erythrocytes. It is proposed that anionic drugs intercalate mainly into the lipid in the exterior half of the bilayer, expand that layer relative to the cytoplasmic half, and thereby induce the cell to crenate, while permeable cationic drugs do the opposite and cause the cell to form cup-shapes. This differential distribution of the drugs is attributed to interactions with the phosphatidylserine that is concentrated in the cytoplasmic half of the membrane. Impermeable amphipathic drugs intercalate only into the exterior half of the bilayer, and therefore are crenators of the intact cell. Several predictions of this hypothesis have been confirmed experimentally with erythrocytes and erythrocyte ghosts. The bilayer couple hypothesis may contribute to the explanation of many membrane-mediated phenomena in cell biology.