Selective transport of Li+ across lipid bilayer membranes mediated by an ionophore of novel design (ETH1644)

Abstract

The neutral noncyclic, lithium-selective ionophore ETH1644, which is structurally different from previously available ionophores of this type, is a selective carrier of Li+ in lipid bilayer membranes of various lipid composition. The ionophore forms a 2:1 carrier/cation complex, and the rate-limiting step in the overall transport process is the diffusion of the carrier/ion complex across the membrane. The selectivity sequence for lithium vs. other ions normally found in biological systems is: Li+ (1) greater than Na+ (0.017) greater than or equal to K+ (0.017) greater than Cl- (0.001), Ca2+ and Mg2+ are impermeant. At neutral pH protons do not interfere with the Li+-carrying ability of this ionophore. On the basis of structural differences and supported by conductance data, it is argued that the improved selectivity of Li+ over the other alkali cations is due more to a decrease in the affinities of the ionophore for the latter cations that to an increase of its affinity to Li+. This ionophore can also act as a carrier of biogenic amines (catecholes, indoles and derivatives), with the structure of the permeant species and mechanism of permeation similar to that observed with the alkali cations. The selectivity sequence is: tryptamine (18.1) greater than phenylethylamine (11.6) greater than tyramine (2.4) greater than Li+ (1) greater than serotonin (0.34) greater than epinephrine (0.09) greater than dopamine (0.05) greater than norepinephrine (0.02), showing the ionophore to be more selective to Li+ than to any of the neurotransmitters studied.

Lithium-selective permeation through lipid bilayer membranes mediated by a di-imide ionophore with nonsymmetrical imide substituents (ETH1810)

“…Taking the ion and ionophore concentration dependences together indicates a 2:1 ionophore : ion stoichiometry for the membrane-permeating species. This is similar to the stoichiometries found for previously studied ionophores [20,40].…”

“…The major difference among members of group I are in the magnitudes of ionic selectivity. While all select lithium over sodium, even the best of them (AST01) does not show high selectivity, giving a lithium/sodium permeability ratio of 13 [19, 201. ETH1644 (of group II) did not show any significant improvement in potency (compared to AS701, the best of group I) but has been found to induce better selectivity, giving a lithium/sodium permeability ratio of 60 in lipid bilayer membranes [40]. Yet, considering the levels of sodium concentration in biological fluids [5], even this fivefold increase in…”

“…We have previously investigated lithium-selective permeation of lipid bilayer membranes, mediated by ionophores listed in group I and by ETHI644 (of group II) [17][18][19][20][21]40]. All molecules were found to act as lithium carriers in these membrane systems [18][19][20]40].…”

“…All molecules were found to act as lithium carriers in these membrane systems [18][19][20]40]. The major difference among members of group I are in the magnitudes of ionic selectivity.…”

“…Steady-state electrical properties of the membranes and the pH of the bathing solutions were measured using previously described methods [17,19,20,40].…”