The Journal of Membrane Biology

, Volume 25, Issue 1, pp 361–380 | Cite as

Mitochondrial uncoupling agents

Effects on membrane permeability of molluscan neurons
  • Jeffery L. Barker
  • Herbert Levitan
Article

Summary

Agents which uncouple oxidative phosphorylation in mitochondria were applied to identified neurons in an isolated ganglion of the marine molluscNavanax inermis. Aromatic monocarboxylic acids, acetanilides, benzamides, benzaldehydes and phenols all caused a rapid, reversible, dose-dependent increase in the membrane potential and conductance of the neurons tested. These events were due primarily to an increase in the membrane's conductance to potassium, relative to chloride. All active compounds also produced a reversible, dose-dependent decrease in the permeability of alkali-cations relative to potassium. The relative activity of congeners in each group of substances was directly correlated with the octanol-water partition coefficients of the various compounds, indicating that hydrophobicity was important in determining drug effect and suggesting that steric requirements were minimal. The results suggest that the observed changes in membrane electrical properties and cation selectivity are due to an increase in the membrane's anionic field strength caused by the hydrophobic interaction of anionic and nonionic agents with the neuronal membrane.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Barker, J.L., Levitan, H. 1971. Salicylate: Effects on membrane permeability of molluscan neurons.Science 172:1245PubMedGoogle Scholar
  2. Barker, J.L., Levitan, H. 1974. Phenols: Effects on invertebrate membrane permeability related to uncoupling activity in mitochondria.Brain Res. 67:555PubMedGoogle Scholar
  3. Barker, J.L., Levitan, H. 1975. Acetanilides: Effects on invertebrate neurons correlated with analgesic activity in vertebrates.J. Pharmacol. Exp. Ther. 193:892PubMedGoogle Scholar
  4. Bryant, S.H., Morales-Aguilera, O. 1971. Chloride conductance in normal and mytonic muscle fibres and the action of monocarboxylic aromatic acids.J. Physiol. (Lond.) 219:367Google Scholar
  5. Caswell, A.H. 1969. Proton permeability and the regulation of potassium permeability in mitochondria by uncoupling agents.J. Membrane Biol. 1:53Google Scholar
  6. Diamond, J.M., Wright, E.M. 1969. Biological membranes: The physical basis of ion and nonelectrolyte selectivity.Annu. Rev. Physiol. 31:581PubMedGoogle Scholar
  7. Eisenman, G. 1961. On the elementary atomic origin of equilibrium ion specificity.In: Symposium on Membrane Transport and Metabolism. A. Kleinzeller and K.A. Kotyk, editors. p. 163. Academic Press, New YorkGoogle Scholar
  8. Eisenman, G. 1963. The influence of Na, K, Li, Rb, and Cs on cellular potentials and related phenomena.Bol. Inst. Estud. Med. Bio. (Univ. Nac. Auton. Mex.) 21:155Google Scholar
  9. Eisenman, G. Some elementary factors involved in specific ion permeation.Proc. 23rd Int. Cong. Physiol. Sci. (Tokyo), p. 489Google Scholar
  10. Fujita, T. 1966. The analysis of physiological activity of substituted phenols with substituent constants.J. Med. Chem. 9:797PubMedGoogle Scholar
  11. Fujita, T., Iwasa, J., Hansch, C. 1964. A new substituent, constant, π, derived from partition coefficients.J. Amer. Chem. Soc. 86:5175Google Scholar
  12. Godfraind, J.M., Kawamura, H., Krnjević, K., Pumain, R. 1971. Actions of dinitrophenol and some other metabolic inhibitors on cortical neurones.J. Physiol. (London) 215:199Google Scholar
  13. Gorman, A.L.F., McReynolds, J.S. 1974. COntrol of membrane K+ permeability in a hyperpolarizing photoreceptor: Similar effects of light and metabolic inhibitors.Science 185:620PubMedGoogle Scholar
  14. Haas, H.G., Kern, R., Einwächter, H.M. 1970. Electrical activity and metabolism in cardiac tissue: An experimental and theoretical study.J. Membrane Biol. 3:180Google Scholar
  15. Hagiwara, S., Toyama, K., Hayashi, H. 1971. Mechanism of anion and cation permeations in the resting membrane of a barnacle muscle fiber.J. Gen. Physiol. 57:408PubMedGoogle Scholar
  16. Hansch, C. 1971. Quantitative structure-activity relationships in drug design.In: Drug Design. E.J. Ariens, editor. Vol. 1, p. 271. Academic Press, New YorkGoogle Scholar
  17. Hansch, C. 1975. Biosterism. Intra-Science Chem. Reports (in press)Google Scholar
  18. Hansch, C., Anderson, S. 1967 The effect of intramolecular hydrophobic bonding on partition coefficients.J. Org. Chem. 32:2583Google Scholar
  19. Hansch, C., Glave, W.R. 1971. Structure-activity relationships in membrane-perturbing agents.Mol. Pharmacol. 7:337PubMedGoogle Scholar
  20. Hansch, C., Helmer, F. 1968. Extrathermodynamic approach to the study of the adsorption of organic compounds by macromolecules.J. Polymer Sci.: Part A-1 6:3295Google Scholar
  21. Hansch, G., Kiehs, K., Lawrence, G.L. 1965. The role of substituents in the hydrophobic bonding of phenols by serum and mitochondrial proteins.J. Amer. Chem. Soc. 87:5570Google Scholar
  22. Hansch, C., Kim, K.H., Sarma, R.H. 1973. Structure-activity relationship in benzamides inhibiting alcohol dehydrogenase.J. Amer. Chem. Soc. 95:6447Google Scholar
  23. Hansch, C., Leo, A., Unger, S.H., Kim, K.H., Nikaitani, D., Lien, E.J. 1973. “Aromatic” substituent constants for structure-activity correlations.J. Med. Chem. 16:1207PubMedGoogle Scholar
  24. Hicklin, J.A. 1959. Salicylate and potassium fluxes of rat diaphragm.Nature 184:2029PubMedGoogle Scholar
  25. Jaffé, H.H. 1953. A re-examination of the Hammett equation.Chem. Rev. 53:191Google Scholar
  26. Lehninger, A.L., Carafoli, E., Rossi, C.S. 1967. Energy-linked ion movements in mitochondrial systems.Adv. Enzymol. 29:259PubMedGoogle Scholar
  27. Leo, A., Hansch, C., Elkins, D. 1971. Partition coefficients and their uses.Chem. Rev. 71:525Google Scholar
  28. Levitan, H., Barker, J.L. 1972a. Salicylate: A structure-activity study of its effects on membrane permeability.Science 176:1423PubMedGoogle Scholar
  29. Levitan, H., Barker, J.L. 1972b. Membrane permeability: Cation selectivity reversibly altered by salicylate.Science 178:63PubMedGoogle Scholar
  30. Levitan, H., Tauc, L., Segundo, J.P. 1970. Electrical transmission among neurons in the buccal ganglion of a mollusc,Navanax inermis.J. Gen. Physiol. 55:484PubMedGoogle Scholar
  31. Machleidt, H., Roth, S., Seeman, P. 1972. The hydrophobic expansion of erythrocyte membranes by the phenol anesthetics.Biochim. Biophys. Acta 255:178PubMedGoogle Scholar
  32. Manchester, K.L., Randle, P.J., Smith, G.H. 1958. Some effects of sodium salicylate on muscle metabolism.Brit. Med. J. 1:1028Google Scholar
  33. McDonald, T.F., Macleod, D.P. 1972. The effect of 2,4-dinitrophenol on electrical and mechanical activity, metabolism and ion movements in guinea-pig ventricular muscle.Brit. J. Pharmacol. 44:711Google Scholar
  34. McLaughlin, S.G.A. 1972. The mechanism of action of DNP on phospholipid bilayer membranes.J. Membrane Biol. 9:361Google Scholar
  35. McLaughlin, S.G.A. 1973. Salicylates and phospholipid bilayer membranes.Nature 243:234PubMedGoogle Scholar
  36. Meech, R.W. 1972. Intracellular calcium injection causes increased potassium conductance inAplysia nerve cells.Comp. Biochem. Physiol. 42 A:493Google Scholar
  37. Meech, R.W. 1974a. Prolonged action potentials inAplysia neurones injected with EGTA.Comp. Biochem. Physiol. 48 A:397Google Scholar
  38. Meech, R.W. 1974b. The sensitivity ofHelix aspersa neurones to injected calcium ions.J. Physiol. (London) 237:259Google Scholar
  39. Mitchell, P. 1966. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation.Biol. Rev. 41:445PubMedGoogle Scholar
  40. Mitchell, P., Moyle, J. 1967. Acid-base titration across the membrane system of rat-liver mitochondria.Biochem. J. 104:588PubMedGoogle Scholar
  41. Mitchell, P., Moyle, J. 1969. Estimation of membrane potential and pH difference across the cristae membrane of rat liver mitochondria.Europ. J. Biochem. 7:471PubMedGoogle Scholar
  42. Omachi, A. 1964. Sulfate transport in human red cells: Inhibition by some uncouplers of oxidative phosphorylation.Science 145:1449PubMedGoogle Scholar
  43. Strickholm, A., Wallin, B.G. 1967. Relative ion permeabilities in the crayfish giant axon determined from rapid external ion changes.J. Gen. Physiol. 50:1929PubMedGoogle Scholar
  44. Vasington, F.D., Murphy, J.V. 1962. Ca++ uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation.J. Biol. Chem. 237:2670PubMedGoogle Scholar
  45. Weast, R.C. (editor). 1971. Handbook of Chemistry and Physics. Chemical Rubber Co., Cleveland, OhioGoogle Scholar
  46. Webb, J.L., Hollander, P.B. 1956. Metabolic aspects of the relationship between the contractility and membrane potential of the rat atrium.Circ. Res. 4:618PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York Inc 1975

Authors and Affiliations

  • Jeffery L. Barker
    • 1
    • 2
  • Herbert Levitan
    • 1
    • 2
  1. 1.Behavioral Biology Branch, National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesda
  2. 2.Department of ZoologyUniversity of MarylandCollege Park

Personalised recommendations