Abstract
A persistent challenge in membrane biophysics has been to quantitatively predict how membrane physical properties change upon addition of new amphiphiles (e.g., lipids, alcohols, peptides, or proteins) in order to assess whether the changes are large enough to plausibly result in biological ramifications. Because of their roles as general anesthetics, n-alcohols are perhaps the best-studied amphiphiles of this class. When n-alcohols are added to model and cell membranes, changes in membrane parameters tend to be modest. One striking exception is found in the large decrease in liquid-liquid miscibility transition temperatures (Tmix) observed when short-chain n-alcohols are incorporated into giant plasma membrane vesicles (GPMVs). Coexisting liquid-ordered and liquid-disordered phases are observed at temperatures below Tmix in GPMVs as well as in giant unilamellar vesicles (GUVs) composed of ternary mixtures of a lipid with a low melting temperature, a lipid with a high melting temperature, and cholesterol. Here, we find that when GUVs of canonical ternary mixtures are formed in aqueous solutions of short-chain n-alcohols (n ≤ 10), Tmix increases relative to GUVs in water. This shift is in the opposite direction from that reported for cell-derived GPMVs. The increase in Tmix is robust across GUVs of several types of lipids, ratios of lipids, types of short-chain n-alcohols, and concentrations of n-alcohols. However, as chain lengths of n-alcohols increase, nonmonotonic shifts in Tmix are observed. Alcohols with chain lengths of 10–14 carbons decrease Tmix in ternary GUVs of dioleoyl-PC/dipalmitoyl-PC/cholesterol, whereas 16 carbons increase Tmix again. Gray et al. observed a similar influence of the length of n-alcohols on the direction of the shift in Tmix. These results are consistent with a scenario in which the relative partitioning of n-alcohols between liquid-ordered and liquid-disordered phases evolves as the chain length of the n-alcohol increases.
Highlights
Scientists have invested decades of research into understanding how n-alcohols affect model lipid membranes, largely with the goal of clarifying mechanisms by which ethanol consumption perturbs mammalian cell membranes
When ternary giant unilamellar vesicles (GUVs) are formed in aqueous solutions of short-chain n-alcohols, the temperatures at which the vesicles demix into coexisting Lo and Ld phases increase relative to GUVs in water
Tmix increases by 1.9C for vesicles of 35/35/30 DOPC/DPPC/cholesterol in 100 mM butanol. This shift is in the opposite direction to that observed in cell-derived giant plasma membrane vesicles (GPMVs) [13]
Summary
Scientists have invested decades of research into understanding how n-alcohols affect model lipid membranes, largely with the goal of clarifying mechanisms by which ethanol consumption perturbs mammalian cell membranes. N-alcohols alter physical properties of liquid-phase membranes: lipid lateral mobilities increase [4,5,6], ion channel cation permeabilities increase [7], membrane areas increase [8], thicknesses decrease [9], bending moduli decrease [8], area compressibilities decrease [8], interfacial tensions decrease [8], gel-liquid transition temperatures. Using cell-derived giant plasma membrane vesicles (GPMVs), they found that short-chain n-alcohols dramatically decreased miscibility transition temperatures (Tmix). The shift in Tmix ($4C for 120 mM ethanol) is more than an order of magnitude larger than ethanol’s effect on membrane melting temperatures [10,13]. The result that short-chain n-alcohols decrease Tmix of GPMVs by $4C holds well for ethanol, propanol, octanol, and decanol at the AC50 concentration [13]
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