Skip to main content
Biophysical Journal logoLink to Biophysical Journal
. 1999 Jan;76(1 Pt 1):129–148. doi: 10.1016/S0006-3495(99)77184-5

Physical origin of selectivity in ionic channels of biological membranes.

A Laio 1, V Torre 1
PMCID: PMC1302506  PMID: 9876129

Abstract

This paper shows that the selectivity properties of monovalent cation channels found in biological membranes can originate simply from geometrical properties of the inner core of the channel without any critical contribution from electrostatic interactions between the permeating ions and charged or polar groups. By using well-known techniques of statistical mechanics, such as the Langevin equations and Kramer theory of reaction rates, a theoretical equation is provided relating the permeability ratio PB/PA between ions A and B to simple physical properties, such as channel geometry, thermodynamics of ion hydration, and electrostatic interactions between the ion and charged (or polar) groups. Diffusive corrections and recrossing rates are also considered and evaluated. It is shown that the selectivity found in usual K+, gramicidin, Na+, cyclic nucleotide gated, and end plate channels can be explained also in the absence of any charged or polar group. If these groups are present, they significantly change the permeability ratio only if the ion at the selectivity filter is in van der Waals contact with them, otherwise these groups simply affect the channel conductance, lowering the free energy barrier of the same amount for the two ions, thus explaining why single channel conductance, as it is experimentally observed, can be very different in channels sharing the same selectivity sequence. The proposed theory also provides an estimate of channel minimum radius for K+, gramicidin, Na+, and cyclic nucleotide gated channels.

Full Text

The Full Text of this article is available as a PDF (218.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen O. S. Kinetics of ion movement mediated by carriers and channels. Methods Enzymol. 1989;171:62–112. doi: 10.1016/s0076-6879(89)71007-7. [DOI] [PubMed] [Google Scholar]
  2. Andersen O. S., Koeppe R. E., 2nd Molecular determinants of channel function. Physiol Rev. 1992 Oct;72(4 Suppl):S89–158. doi: 10.1152/physrev.1992.72.suppl_4.S89. [DOI] [PubMed] [Google Scholar]
  3. Bek S., Jakobsson E. Brownian dynamics study of a multiply-occupied cation channel: application to understanding permeation in potassium channels. Biophys J. 1994 Apr;66(4):1028–1038. doi: 10.1016/S0006-3495(94)80884-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chiamvimonvat N., Pérez-García M. T., Tomaselli G. F., Marban E. Control of ion flux and selectivity by negatively charged residues in the outer mouth of rat sodium channels. J Physiol. 1996 Feb 15;491(Pt 1):51–59. doi: 10.1113/jphysiol.1996.sp021195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cooper K. E., Gates P. Y., Eisenberg R. S. Diffusion theory and discrete rate constants in ion permeation. J Membr Biol. 1988 Dec;106(2):95–105. doi: 10.1007/BF01871391. [DOI] [PubMed] [Google Scholar]
  6. Cooper K. E., Gates P. Y., Eisenberg R. S. Surmounting barriers in ionic channels. Q Rev Biophys. 1988 Aug;21(3):331–364. doi: 10.1017/s0033583500004480. [DOI] [PubMed] [Google Scholar]
  7. Cooper K., Jakobsson E., Wolynes P. The theory of ion transport through membrane channels. Prog Biophys Mol Biol. 1985;46(1):51–96. doi: 10.1016/0079-6107(85)90012-4. [DOI] [PubMed] [Google Scholar]
  8. Dorman V., Partenskii M. B., Jordan P. C. A semi-microscopic Monte Carlo study of permeation energetics in a gramicidin-like channel: the origin of cation selectivity. Biophys J. 1996 Jan;70(1):121–134. doi: 10.1016/S0006-3495(96)79554-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doyle D. A., Morais Cabral J., Pfuetzner R. A., Kuo A., Gulbis J. M., Cohen S. L., Chait B. T., MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998 Apr 3;280(5360):69–77. doi: 10.1126/science.280.5360.69. [DOI] [PubMed] [Google Scholar]
  10. Dwyer T. M., Adams D. J., Hille B. The permeability of the endplate channel to organic cations in frog muscle. J Gen Physiol. 1980 May;75(5):469–492. doi: 10.1085/jgp.75.5.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. EISENMAN G. Cation selective glass electrodes and their mode of operation. Biophys J. 1962 Mar;2(2 Pt 2):259–323. doi: 10.1016/s0006-3495(62)86959-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. EISENMAN G. THE INFLUENCE OF NA, K LI, RB, AND CS ON CELLULAR POTENTIALS AND RELATED PHENOMENA. Bol Inst Estud Med Biol Univ Nac Auton Mex. 1963 Aug;21:155–183. [PubMed] [Google Scholar]
  13. Eisenman G., Horn R. Ionic selectivity revisited: the role of kinetic and equilibrium processes in ion permeation through channels. J Membr Biol. 1983;76(3):197–225. doi: 10.1007/BF01870364. [DOI] [PubMed] [Google Scholar]
  14. Eismann E., Müller F., Heinemann S. H., Kaupp U. B. A single negative charge within the pore region of a cGMP-gated channel controls rectification, Ca2+ blockage, and ionic selectivity. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1109–1113. doi: 10.1073/pnas.91.3.1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Favre I., Moczydlowski E., Schild L. On the structural basis for ionic selectivity among Na+, K+, and Ca2+ in the voltage-gated sodium channel. Biophys J. 1996 Dec;71(6):3110–3125. doi: 10.1016/S0006-3495(96)79505-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fuller C. M., Berdiev B. K., Shlyonsky V. G., Ismailov I. I., Benos D. J. Point mutations in alpha bENaC regulate channel gating, ion selectivity, and sensitivity to amiloride. Biophys J. 1997 Apr;72(4):1622–1632. doi: 10.1016/S0006-3495(97)78808-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Galzi J. L., Devillers-Thiéry A., Hussy N., Bertrand S., Changeux J. P., Bertrand D. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature. 1992 Oct 8;359(6395):500–505. doi: 10.1038/359500a0. [DOI] [PubMed] [Google Scholar]
  18. Hagiwara S., Takahashi K. The anomalous rectification and cation selectivity of the membrane of a starfish egg cell. J Membr Biol. 1974;18(1):61–80. doi: 10.1007/BF01870103. [DOI] [PubMed] [Google Scholar]
  19. Heginbotham L., Lu Z., Abramson T., MacKinnon R. Mutations in the K+ channel signature sequence. Biophys J. 1994 Apr;66(4):1061–1067. doi: 10.1016/S0006-3495(94)80887-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Heinemann S. H., Terlau H., Stühmer W., Imoto K., Numa S. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature. 1992 Apr 2;356(6368):441–443. doi: 10.1038/356441a0. [DOI] [PubMed] [Google Scholar]
  21. Hille B. Ionic selectivity, saturation, and block in sodium channels. A four-barrier model. J Gen Physiol. 1975 Nov;66(5):535–560. doi: 10.1085/jgp.66.5.535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Imoto K., Busch C., Sakmann B., Mishina M., Konno T., Nakai J., Bujo H., Mori Y., Fukuda K., Numa S. Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature. 1988 Oct 13;335(6191):645–648. doi: 10.1038/335645a0. [DOI] [PubMed] [Google Scholar]
  23. Kim M. S., Morii T., Sun L. X., Imoto K., Mori Y. Structural determinants of ion selectivity in brain calcium channel. FEBS Lett. 1993 Mar 1;318(2):145–148. doi: 10.1016/0014-5793(93)80009-j. [DOI] [PubMed] [Google Scholar]
  24. Kirsch G. E., Pascual J. M., Shieh C. C. Functional role of a conserved aspartate in the external mouth of voltage-gated potassium channels. Biophys J. 1995 May;68(5):1804–1813. doi: 10.1016/S0006-3495(95)80357-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kumpf R. A., Dougherty D. A. A mechanism for ion selectivity in potassium channels: computational studies of cation-pi interactions. Science. 1993 Sep 24;261(5129):1708–1710. doi: 10.1126/science.8378771. [DOI] [PubMed] [Google Scholar]
  26. Levitt D. G. General continuum theory for multiion channel. I. Theory. Biophys J. 1991 Feb;59(2):271–277. doi: 10.1016/S0006-3495(91)82220-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lipkind G. M., Hanck D. A., Fozzard H. A. A structural motif for the voltage-gated potassium channel pore. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9215–9219. doi: 10.1073/pnas.92.20.9215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Läuger P. Ion transport through pores: a rate-theory analysis. Biochim Biophys Acta. 1973 Jul 6;311(3):423–441. doi: 10.1016/0005-2736(73)90323-4. [DOI] [PubMed] [Google Scholar]
  29. Menini A. Currents carried by monovalent cations through cyclic GMP-activated channels in excised patches from salamander rods. J Physiol. 1990 May;424:167–185. doi: 10.1113/jphysiol.1990.sp018061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Myers V. B., Haydon D. A. Ion transfer across lipid membranes in the presence of gramicidin A. II. The ion selectivity. Biochim Biophys Acta. 1972 Aug 9;274(2):313–322. doi: 10.1016/0005-2736(72)90179-4. [DOI] [PubMed] [Google Scholar]
  31. Picco C., Menini A. The permeability of the cGMP-activated channel to organic cations in retinal rods of the tiger salamander. J Physiol. 1993 Jan;460:741–758. doi: 10.1113/jphysiol.1993.sp019497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pérez-Cornejo P., Begenisich T. The multi-ion nature of the pore in Shaker K+ channels. Biophys J. 1994 Jun;66(6):1929–1938. doi: 10.1016/S0006-3495(94)80986-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Reuter H., Stevens C. F. Ion conductance and ion selectivity of potassium channels in snail neurones. J Membr Biol. 1980 Dec 15;57(2):103–118. doi: 10.1007/BF01868997. [DOI] [PubMed] [Google Scholar]
  34. Roux B., Karplus M. Ion transport in a model gramicidin channel. Structure and thermodynamics. Biophys J. 1991 May;59(5):961–981. doi: 10.1016/S0006-3495(91)82311-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roux B., Karplus M. Molecular dynamics simulations of the gramicidin channel. Annu Rev Biophys Biomol Struct. 1994;23:731–761. doi: 10.1146/annurev.bb.23.060194.003503. [DOI] [PubMed] [Google Scholar]
  36. Roux B. Valence selectivity of the gramicidin channel: a molecular dynamics free energy perturbation study. Biophys J. 1996 Dec;71(6):3177–3185. doi: 10.1016/S0006-3495(96)79511-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sagnella D. E., Laasonen K., Klein M. L. Ab initio molecular dynamics study of proton transfer in a polyglycine analog of the ion channel gramicidin A. Biophys J. 1996 Sep;71(3):1172–1178. doi: 10.1016/S0006-3495(96)79321-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sesti F., Nizzari M., Torre V. Effect of changing temperature on the ionic permeation through the cyclic GMP-gated channel from vertebrate photoreceptors. Biophys J. 1996 Jun;70(6):2616–2639. doi: 10.1016/S0006-3495(96)79832-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Slesinger P. A., Jan Y. N., Jan L. Y. The S4-S5 loop contributes to the ion-selective pore of potassium channels. Neuron. 1993 Oct;11(4):739–749. doi: 10.1016/0896-6273(93)90083-4. [DOI] [PubMed] [Google Scholar]
  40. Starkus J. G., Kuschel L., Rayner M. D., Heinemann S. H. Ion conduction through C-type inactivated Shaker channels. J Gen Physiol. 1997 Nov;110(5):539–550. doi: 10.1085/jgp.110.5.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wallace B. A. Gramicidin channels and pores. Annu Rev Biophys Biophys Chem. 1990;19:127–157. doi: 10.1146/annurev.bb.19.060190.001015. [DOI] [PubMed] [Google Scholar]
  42. Wu J. Microscopic model for selective permeation in ion channels. Biophys J. 1991 Jul;60(1):238–251. doi: 10.1016/S0006-3495(91)82046-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yang J., Ellinor P. T., Sather W. A., Zhang J. F., Tsien R. W. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature. 1993 Nov 11;366(6451):158–161. doi: 10.1038/366158a0. [DOI] [PubMed] [Google Scholar]
  44. Yool A. J., Schwarz T. L. Alteration of ionic selectivity of a K+ channel by mutation of the H5 region. Nature. 1991 Feb 21;349(6311):700–704. doi: 10.1038/349700a0. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES