Abstract
The effects of dipole modifiers and their structural analogs on the single channel activity of amphotericin B in sterol-containing planar phosphocholine membranes are studied. It is shown that the addition of phloretin in solutions bathing membranes containing cholesterol or ergosterol decreases the conductance of single amphotericin B channels. Quercetin decreases the channel conductance in cholesterol-containing bilayers while it does not affect the channel conductance in ergosterol-containing membranes. It is demonstrated that the insertion of styryl dyes, such as RH 421, RH 237 or RH 160, in bilayers with either cholesterol or ergosterol leads to the increase of the current amplitude of amphotericin B pores. Introduction of 5α-androstan-3β-ol into a membrane-forming solution increases the amphotericin B channel conductance in a concentration-dependent manner. All the effects are likely to be attributed to the influence of the membrane dipole potential on the conductance of single amphotericin B channels. However, specific interactions of some dipole modifiers with polyene-sterol complexes might also contribute to the activity of single amphotericin B pores. It has been shown that the channel dwell time increases with increasing sterol concentration, and it is higher for cholesterol-containing membranes than for bilayers including ergosterol, 6-ketocholestanol, 7-ketocholestanol or 5α-androstan-3β-ol. These findings suggest that the processes of association/dissociation of channel forming molecules depend on the membrane fluidity.
Highlights
The structure of polyene antibiotic amphotericin B (AmB) comprises two rigid fragments, a macrolide ring and a mycosamine sugar moiety, which are linked by a b-glycosidic bond
The exact molecular architecture of the AmB channel is under debate; different models for the formation and structure of the AmB channel have been proposed
The most popular is the steroldependent double-pore model: the two-sided effect of polyene antibiotic results from the association of AmB with sterol molecules and the formation of anion-selective symmetric barrel stave pores made from two ‘‘half-pores’’ in opposite monolayers [3,4,5,6]
Summary
The structure of polyene antibiotic amphotericin B (AmB) comprises two rigid fragments, a macrolide ring and a mycosamine sugar moiety, which are linked by a b-glycosidic bond. Since a sterol concentration and a phase separation in the membrane (the presence of lipid rafts, which are able to cumulate sterols and AmB), may affect the parameters of AmB-channels, we compared the conductance-voltage characteristics of single pores at different concentrations of cholesterol or ergosterol in the membrane forming solutions: 5 mol%, 33 mol% and 67 mol%.
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