The dipole potential of lipid membranes determines the mechanism of ion permeability mediated by ester-stabilized phosphonium ylides

Ester-stabilized phosphonium ylides are able to selectively transfer protons across lipid membranes, which serve as protonophores that exist in both a positively charged form and a zwitterionic neutral form. The protonophoric activity of three phosphonium ylide precursors with different numbers of methyl groups in their phenyl rings on liposomes loaded with the fluorescent pH-sensitive probe 8-hydroxypyrene-1,3,6-trisulfonic acid was studied. The mechanism of proton permeability of phosphonium ylide precursors changed from protonophoric, in the case of liposomes formed from lipids with ether linkages, to non-specific leakage, in the case of lipids with ester linkages and cholesterol. It has been reported previously that ester carbonyls contribute significantly to the magnitude of the dipole potential of the lipid membrane, and without them (<i>i.e.</i> with ether lipids) the magnitude is about 100 mV lower. Tetraphenylborate (TPB) at nanomolar concentrations enhanced proton transport by phosphonium ylide precursors on liposomes and planar bilayer lipid membranes formed from ester lipids by tens of times due to ion pair formation of TPB and phosphonium cations. Our work shows for the first time that the mode of action of ionophores depends on the dipole potential of the lipid membrane and, therefore, may vary for membranes of various cells and their organelles having different lipid compositions.