The Journal of Membrane Biology

, Volume 61, Issue 3, pp 209–219 | Cite as

Ionic permeation of lipid bilayer membranes mediated by a neutral, noncyclic Li+-selective carrier having imide and ether ligands. I. Selectivity among monovalent cations

  • Rimona Margalit
  • George Eisenman


We have found that Simon's neutral, noncyclic, Li+-selective complexone, which has imide and ether ligands, renders lipid bilayer membranes selectively permeable to certain cations and anions. The present paper characterizes the ability of this molecule to carry monovalent cations; and we show it to be most selective for Li+ among the alkali cations, the first reconstitution of Li+-selective permeation in lipid bilayer membranes. This complexone acts as an “equilibrium-domain” carrier for Ag+> Li+>Tl+>Na+>NH 4 + >Rb+>Cs+ over a wide range of experimental conditions. The major type of membrane-permeating species formed is a 2∶1 carrier/cation complex dominant except at the lowest salt and carrier concentrations where a 1∶1 carrier/cation, with a similar selectivity sequence, can be detected. Among the groupIa cations the selectivity sequence in bilayers, Li+>Na+>K+>Rb+>Cs+, is similar to that previously found for this molecule in thick solvent-polymer membrane electrodes. We find this carrier to be more selective to Ag+ than to any other monovalent cation yet studied. This high Ag+ selectivity is used, together with the dependence of the selectivity on the nature of the N-amide substitutents, to argue that the imide oxygens play a major role as ligands.

Key words

Lithium carrier selectivity bilayers membrane electrodes Li selectivity Ag selectivity amide ligands 


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  1. 1.
    Amdisen, A., Schou, M. 1978. Lithium.In: Side Effects of Drugs Annual 2, M.N.G. Dukes, editor, pp. 17–29. Excerpta Medica, Amsterdam-OxfordGoogle Scholar
  2. 2.
    Ammann, D., Bissig, R., Cimerman, Z., Fiedler, V., Guggi, M., Morf, W.E., Oehme, M., Osswald, H., Pretsch, E., Simon, W. 1976. Synthetic neutral carriers for cations.In: Ion and Enzyme Electrodes in Biology and Medicine. M. Kessler, L.C. Clark, Jr., D.W. Lubbers, I.A. Silver, and W. Simon, editors. pp. 22–37. Urban and Schwarzenberg, Munchen-Berlin-WienGoogle Scholar
  3. 3.
    Ammann, D., Pretsch, E., Simon, W., 1974. A sodium ion-selective electrode based on a neutral carrier.Anal Lett. 7:23–32Google Scholar
  4. 4.
    Andersen, O.S. 1978. Ion transport across simple lipid membranes.In: Renal Functions. G.E. Giebisch and E.F. Purcell, editors, pp. 71–99. J. Macy, Jr. Foundation, New YorkGoogle Scholar
  5. 5.
    Andersen, O.S., Feldberg, S., Nakadomari, H., Levy, S., McLaughlin, S. 1978. Electrostatic interactions among hydrophobic ions in lipid bilayer membranes.Biophys. J. 21:35–77PubMedGoogle Scholar
  6. 6.
    Andreoli, T.E., Tieffenberg, M., Tosteson, D.C. 1967. The effects of valinomycin on the ionic permeability of thin lipid membranes.J. Gen. Physiol. 50:2527–2545PubMedGoogle Scholar
  7. 7.
    Ciani, S. 1976. Influence of molecular variations of ionophore and lipid on the selective ion permeability of membranes: A theoretical model.J. Membrane Biol. 30:45–63Google Scholar
  8. 8.
    Ciani, S., Eisenman, G., Szabo, G. 1969. A theory for the effects of neutral carriers such as the macrotetralide actin antibiotics on the electrical properties of bilayer membranes.J. Membrane Biol. 1:346–382Google Scholar
  9. 9.
    Duhm, J., Becker, B.F. 1977. Studies of the lithium transport across the red cell membrane.Pfluegers Arch. Eur. J. Physiol. 367:211–219;370:211–219Google Scholar
  10. 10.
    Ehrlich, B.E., Diamond, J.M., Clausen, C., Gosenfeld, L., Kaufman-Diamond, S. 1979. The red cell membrane as a model for studying lithium's therapeutic action.In: Lithium: Unresolved Issues and Controversies. Excerpta Medica, Amsterdam (in press)Google Scholar
  11. 11.
    Eisenman, G. 1961. On the elementary atomic origin of equilibrium ionic specificity.In: Symposium on Membrane Transport. A. Kleinzeller and A. Kotyk, editors, pp. 163–179. Academic press, New YorkGoogle Scholar
  12. 12.
    Eisenman, G. 1969. Theory of membrane electrode potentials: An examination of the parameters determining the selectivity of solid and liquid ion exchangers and of neutral ion-sequestering molecules.In: Ion Selective Electrodes, R.A. Durst, editor. pp. 1–56. Natl. Bureau of Standards Special Publication No. 314Google Scholar
  13. 13.
    Eisenman, G. 1978.In: Advances in Chemical Physics. R. Lefever and A. Goldbeter, editors, Vol. 39, pp. 316–318. Interscience, New YorkGoogle Scholar
  14. 14.
    Eisenman, G., Ciani, S., Szabo, G. 1968. Some theoretically expected and experimentally observed properties of lipid bilayer membranes containign neutral molecular carriers of ions.Fed. Proc. 27:1289–1304PubMedGoogle Scholar
  15. 15.
    Eisenman, G., Krasne, S. 1975. The ion selectivity of carrier molecules, membranes and enzymes.In: MTP International Review of Science Biochemistry Series. C.F. Fox, editor. Vol. 2, pp. 27–59. Butterworths, LondonGoogle Scholar
  16. 16.
    Eisenman, G., Krasne, S., Ciani, S. 1975. The kinetic and equilibrium components of selective ionic permeability mediated by nactin and valinomycin-like carriers having systematically varied degrees of methylation.Ann. N.Y. Acad. Sci. 254:34–60Google Scholar
  17. 17.
    Eisenman, G., Margalit, R. 1978. Amphoteric complexes of a neutral ionophore having tertiary amide ligands—a model for anion binding to the polypeptide backbone.In: Frontiers of Biological Energetics: Electron to Tissue. J.S. Leigh, P.L. Dutton, and A. Scarpa, editors. Vol. II, pp. 1215–1225. Academic Press, New YorkGoogle Scholar
  18. 18.
    Eisenman, G., Sandblom, J., Neher, E. 1977. Ionic selectivity, saturation, binding and block in the gramicidin A channel: A preliminary report.In: Metal-Ligand Interactions in Organic Chemistry and Biochemistry B. Pullman and N. Goldblum, editors. Vol. 2, pp. 1–36. D. Reidel, DordrechtGoogle Scholar
  19. 19.
    Eisenman, G., Sandblom, J., Neher, E. 1978. Interactions in cation permeation through the gramicidin channel: Ca, Rb, K, Na, Li, Tl, H, and effects of anion binding.Biophys. J. 22:307–340PubMedGoogle Scholar
  20. 20.
    Eisenman, G., Szabo, G., Ciani, S., McLaughlin, S., Krasne, S. 1973. Ion binding and ion transport produced by neutral lipid-soluble molecules.Prog. Surf. Memb. Sci. 6:139–241Google Scholar
  21. 21.
    Guggi, M. 1977. Ph.D. Thesis. Swiss Federal Institute of Technology. ZürichGoogle Scholar
  22. 22.
    Guggi, M., Fiedler, V., Pretsch, E., Simon, W. 1975. A lithium ion-selective electrode based on a neutral carrier.Anal Lett. 8:857–866Google Scholar
  23. 23.
    Hille, B. 1975. Ionic selectivity of the Na+ and K+ channels of nerve membranes.In: Membranes—A Series of Advances. G. Eisenman, editor, Vol. 3, pp. 255–323. Marcel Dekker, New YorkGoogle Scholar
  24. 24.
    Hladky, S.B., Haydon, D.A. 1973. Membrane conductance and surface potential.Biochim. Biophys. Acta 318:464–468Google Scholar
  25. 25.
    Kirsh, N.N.L., Funck, R.J.J., Pretsch, E., Simon, W. 1977. Membrane selectivity and synthesis of ionophores for Li+. Stability constants in ethanol.Helv. Chim. Acta 60:2326–2333PubMedGoogle Scholar
  26. 26.
    Krasne, S., Eisenman, G. 1976. Influence of molecular variations of ionophore and lipid on the selective ion permeability of membranes. I. Tetranactin and the methylation of nonactintype carriers.J. Membrane Biol. 30:1–44Google Scholar
  27. 27.
    Krasne, S., Eisenman, G., Szabo, G. 1971. Freezing and melting of lipid bilayers and the mode of action of nonactin, vallinomycin and gramicidin A.Science 174:412–415PubMedGoogle Scholar
  28. 28.
    Kuo, K.H., Eisenman, G. 1977. Na+-selective permeation of lipid bilayers mediated by a neutral ionophore.Biophys. J. 17:212aGoogle Scholar
  29. 29.
    Kuo, K.H., Eisenman, G. 1978. Mode of action of Simon's non-cyclic Na+-selective ligand on bilayers.Arzneimittel-Forschung (Drug Research),28(1):707Google Scholar
  30. 30.
    Laprade, R., Ciani, S., Eisenman, G., Szabo, G. 1975. The kinetics of carrier-mediated ion permeation in lipid bilayers and its theoretical interpretation.In: Membranes—A Series of Advances. G. Eisenman, editor. Vol. 3, pp. 127–214. Marcel Dekker, New YorkGoogle Scholar
  31. 31.
    Läuger, P. 1972. Carrier-mediated ion transport.Science 178:23–30Google Scholar
  32. 32.
    Lehn, J.M., Savage, J.R. 1971. Cation and cavity selectivities of alkali and alkaline earth “cryptates.”Chem. Commun. 197:440–441Google Scholar
  33. 33.
    Margalit, R., Eisenman, G. 1978a. Mode of action of Simon's noncyclic Li+-selective molecule on bilayers including its ability to carry anions selectively.Arzneimittel-Forschung (Drug Research)28(1):707–708Google Scholar
  34. 34.
    Margalit, R., Eisenman, G. 1978b. Anion selective permeation of lipid bilayers mediated by a neutral carrier with only oxygen ligands.Biophys. J. 21:26aGoogle Scholar
  35. 35.
    Margalit, R., Eisenman, G. 1979a. Co-transport of cations and anions across lipid bilayers mediated by a neutral carrier —a model for biological symport systems.Biophys. J. 26:260aGoogle Scholar
  36. 36.
    Margalit, R., Eisenman G. 1979b. Some binding properties of the peptide backbone inferred from studies of a neutral non-cyclic carrier having imide ligands.In: Peptides: Structure and Biological Functions. E. Gross and J. Meienhofer, editors. pp. 665–679. Pierce, Rockford (Illinois)Google Scholar
  37. 37.
    McBride, D., Szabo, G. 1978. Blocking of gramidcin channel conductance by Ag+.Biophys. J. 21:25aGoogle Scholar
  38. 38.
    McLaughlin, S.G.A., Szabo, G., Ciani, S., Eisenman, G. 1972. The effects of a cyclic polyether on the electrical properties of phospholipid bilayer membranes.J. Membrane Biol. 9:3–36Google Scholar
  39. 39.
    Mueller, P., Ruding, D.O. 1967. Development of K+−Na+ discrimination in experimental bimolecular lipid membranes by macrocyclic antibiotics. B.B.R.C.26:398–404Google Scholar
  40. 40.
    Ovchinnikov, Y.A., Ivanov V.T., Shkrov, A.M. 1974. Membrane Active Complexones. B.B.A. Library, Vol. 12, Elsevier Scientific, New YorkGoogle Scholar
  41. 41.
    Pandey, G.N., Dorus, E., Davis, J.M., Tosteson, D.C. 1979. Lithium transport in red blood cells, genetic and clinical aspects.In: The Li+ Ion Impact on Treatment and Research, F.K. Goodwin, editor.Arch. Gen. Psychiat. Special Issue: 902–908Google Scholar
  42. 42.
    Szabo, G., Eisenman, G. 1973b. Enhanced cation permeability in glyceryl oleate bilayers.Biophys. J. 13:173aGoogle Scholar
  43. 43.
    Szabo, G., Eisenman, G., Ciani, S. 1969. The effects of macrotetralide actin antibiotics on the electrical properties of phospholipid bilayer membranes.J. Membrane. Biol. 1:346–382Google Scholar
  44. 44.
    Szabo, G., Eisenman, G., Laprade, R., Ciani, S., Krasne, S. 1973a. Experimentally observed effects of carriers on the electrical properties of bilayer membranes-equilibrium domain.In: Membranes—A Series of Advances. G. Eisenman, editor. Vol. 2, pp. 179–328. Marcel Dekker, New YorkGoogle Scholar
  45. 45.
    Szabo, G., McBride, D. 1978. Influence of double-layer and dipolar surface potentials on ionic conductance of gramicidin channels.Biophys. J. 21:25aGoogle Scholar
  46. 46.
    Wieland, T., Faulstich, H., Burgermeister, W., Otting, W., Mohle, W., Shemyakin, M.M., Ovchinnikov, Y.A., Ivanov, V.T., Malenkov, G.G. 1970. Affinity of antamanide for sodium ions.FEBS. Lett. 9:89–92PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1981

Authors and Affiliations

  • Rimona Margalit
    • 1
  • George Eisenman
    • 1
  1. 1.Department of PhysiologyUniversity of California School of MedicineLos Angeles

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