The effect of the neurotoxic cations aluminum, cadmium and manganese on membranes was examined in sonicated unilamellar vesicles containing phosphatidylserine and compared to the effect of Ca2+. Fusion of membranes was monitored by assessing the resonance energy transfer between N-(7-nitrobenz-2-oxa-1,3-diazol-4-y)phosphatidylethanolamine and N-(lissamine-rhodamine B-sulfonyl)phosphatidylethanolamine. Self-quenching of high concentrations of carboxyfluorescein in liposomes was used to demonstrate the release of molecules entrapped in liposomes to compare the kinetics of leakage and intermixing of lipid. Rigidification of membranes was evaluated by monitoring the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene embedded in membranes containing phosphatidylserine and dipalmitoylphosphatidylcholine. Cation-induced lipid intermixing of vesicles membranes and release of dye from the vesicles occurred in the same concentration range. With aluminum, these effects were observed with concentrations less than 25 microM. Significant rigidification of vesicle membranes was apparent with less than 25 microM of Al3+. Similar effects could only be observed with concentrations of Cd2+ and Mn2+ at least one order of magnitude higher (200 and 400 microM, respectively).