Skip to main content
Log in

Multi-ion versus single-ion conduction mechanisms can yield current rectification in biological ion channels

  • Original Paper
  • Published:
Journal of Biological Physics Aims and scope Submit manuscript

Abstract

There is clear evidence that the net magnitude of negative charge at the intracellular end of inwardly rectifying potassium channels helps to generate an asymmetry in the magnitude of the current that will pass in each direction. However, a complete understanding of the physical mechanism that links these charges to current rectification has yet to be obtained. Using Brownian dynamics, we compare the conduction mechanism and binding sites in rectifying and non-rectifying channel models. We find that in our models, rectification is a consequence of asymmetry in the hydrophobicity and charge of the pore lining. As a consequence, inward conduction can occur by a multi-ion conduction mechanism. However, outward conduction is restricted, since there are fewer ions at the intracellular entrance and outwardly moving ions must cross the pore on their own. We pose the question as to whether the same mechanism could be at play in inwardly rectifying potassium channels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hibino, H., Inanobe, A., Furutani, K., Murakami, S., Findlay, I., Kurachi, Y.: Inwardly rectifying potassium channels: their structure, function and physiological roles. Physiol. Rev. 90, 291–366 (2010)

    Article  Google Scholar 

  2. Reimann, F., Ashcroft, F.M.: Inwardly rectifying potassium channels. Curr. Opin. Cell Biol. 11, 503–508 (1999)

    Article  Google Scholar 

  3. Neusch, C., Weishaupt, J.H., Bähr, M.: Kir channels in the CNS: emerging new roles and implications for neurological diseases. Cell Tissue Res. 311, 131–138 (2003)

    Google Scholar 

  4. Yang, J., Jan, Y.N., Jan, L.Y.: Control of rectification and permeation by residues in two distinct domains in an inward rectifier K\(^{+}\) channel. Neuron 14, 1047–1054 (1995)

    Article  Google Scholar 

  5. Xie, L.H., John, S.A., Ribalet, B., Weiss, J.N.: Regulation of gating by negative charges in the cytoplasmic pore in the Kir2.1 channel. J. Physiol. 561, 159–168 (2004)

    Article  Google Scholar 

  6. Matsuda, H., Saigusa, A., Irisawa, H.: Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg\(^{2+}\). Nature 325, 156–159 (1987)

    Article  ADS  Google Scholar 

  7. Guo, D., Ramu, Y., Klem, A.M., Lu, Z.: Mechanism of rectification in inward-rectifier K\(^{+}\) channels. J. Gen. Physiol. 121, 261–275 (2003)

    Article  Google Scholar 

  8. Robertson, J.L., Palmer, L.G., Roux, B.: Long-pore electrostatics in inward rectifier potassium channels. J. Gen. Physiol. 132, 613–632 (2008)

    Article  Google Scholar 

  9. Robertson, J.L., Palmer, L.G., Roux, B.: Multi-ion distributions in the cytoplasmic domain of inward rectifier potassium channels. Biophys. J. 103, 434–443 (2012)

    Article  ADS  Google Scholar 

  10. Yeh, S.H., Chang, H.K., Shieh, R.C.: Electrostatics in the cytoplasmic pore produce intrinsic inward rectification in Kir2.1 channels. J. Gen. Physiol. 126, 551–562 (2005)

    Article  Google Scholar 

  11. Clarke, O.B., Caputo, A.T., Hill, A.P., Vandenberg, J.I., Smith, B.J., Gulbis, J.M.: Domain reorientation and rotation of an intracellular assembly regulate conduction in Kir potassium channels. Cell 141, 1018–1029 (2010)

    Article  Google Scholar 

  12. Fujiwara, Y., Kubo, Y.: Functional roles of charged amino acid residues on the wall of the cytoplasmic pore of Kir2.1. J. Gen. Physiol. 127, 401–419 (2006)

    Article  Google Scholar 

  13. Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P.A., Choe, S.: Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat. Neurosci. 8, 279–287 (2005)

    Article  Google Scholar 

  14. Guo, D., Lu, Z.: Interaction mechanisms between polyamines and IRK1 inward rectifier K\(^{+}\) channels. J. Gen. Physiol. 122, 485–500 (2003)

    Article  Google Scholar 

  15. Silver, M.R., DeCoursey, T.E.: Intrinsic gating of inward rectifier in bovine pulmonary artery endothelial cells in the presence or absence of internal Mg\(^{2+}\). J. Gen. Physiol. 96, 109–133 (1990)

    Article  Google Scholar 

  16. Nichols, C.G., Lopatin, A.N.: Inward rectifier potassium channels. Annu. Rev. Physiol. 59, 171–191 (1997)

    Article  Google Scholar 

  17. Aleksandrov, A., Velimirovic, B., Clapham, D.E.: Inward rectification of the IRK1 K\(^{+}\) channel reconstituted in lipid bilayers. Biophys. J. 70, 2680–2687 (1996)

    Article  ADS  Google Scholar 

  18. Stanfield, P.R., Davies, N.W., Shelton, P.A., Sutcliffe, M.J., Khan, I.A., Brammer, W.J., Conley, E.C.: A single aspartate residue is involved in both intrinsic gating and blockage by Mg\(^{2+}\) of the inward rectifier, IRK1. J. Physiol. 478, 1–6 (1994)

    Google Scholar 

  19. Lopatin, A.N., Nichols, C.G.: [K\(^{+}\)] dependence of open-channel conductance in cloned inward rectifier potassium channels (IRK1, Kir2.1). Biophys. J. 71, 682–694 (1996)

    Article  ADS  Google Scholar 

  20. Guo, D., Lu, Z.: IRK1 inward rectifier K\(^{+}\) channels exhibit no intrinsic rectification. J. Gen. Physiol. 120, 539–551 (2002)

    Article  Google Scholar 

  21. Hilder, T.A., Chung, S.H.: Conductance properties of the inwardly rectifying channel, Kir3.2: molecular and Brownian dynamics study. Biochim. Biophys. Acta. 1828, 471–478 (2013)

    Article  Google Scholar 

  22. Hilder, T.A., Chung, S.H.: Conduction and block of inward rectifier K\(^{+}\) channels: predicted structure of a potent blocker of Kir2.1. Biochem. 52, 967–974 (2013)

    Article  Google Scholar 

  23. Chung, S.H., Allen, T.W., Kuyucak, S.: Modeling diverse range of potassium channels with Brownian dynamics. Biophys. J. 83, 263–277 (2002)

    Article  ADS  Google Scholar 

  24. Hoyles, M., Kuyucak, S., Chung, S.H.: Computer simulation of ion conductance in membrane channels. Phys. Rev. E 58, 3654–3661 (1998)

    Article  ADS  Google Scholar 

  25. Whorton, M.R., MacKinnon, R.: Crystal structure of the mammalian GIRK2 K\(^{+}\) channel and gating regulation by G proteins, PIP\(_{2}\), and sodium. Cell 147, 199–208 (2011)

    Article  Google Scholar 

  26. Tao, X., Avalos, J.L., Chen, J., MacKinnon, R.: Crystal structure of the eukaryotic strong inward-rectifier K\(^{+}\) channel Kir2.2 at 3.1 Å resolution. Science 326, 1668–1674 (2009)

    Article  ADS  Google Scholar 

  27. Hansen, S.B., Tao, X., MacKinnon, R.: Structural basis of PIP\(_{2}\) activation of the classical inward rectifier K\(^{+}\) channel Kir2.2. Nature 477, 495–498 (2011)

    Article  ADS  Google Scholar 

  28. Chung, S.H., Corry, B.: Conduction properties of KcsA measured using Brownian dynamics with flexible carbonyl groups in the selectivity filter. Biophys. J. 93, 44–53 (2007)

    Article  ADS  Google Scholar 

  29. Gordon, D., Krishnamurthy, V., Chung, S.H.: Generalized Langevin models of molecular dynamics simulations with applications to ion channels. J. Chem. Phys. 131, 134102–1–134102-13 (2009)

    Article  Google Scholar 

  30. Allen, T.W., Kuyucak, S., Chung, S.H.: Molecular dynamics study of the KcsA potassium channel. Biophys. J. 77, 2502–2516 (1999)

    Article  Google Scholar 

  31. Chung, S.H., Allen, T.W., Hoyles, M., Kuyucak, S.: Permeation of ions across the potassium channel: Brownian dynamics studies. Biophys. J. 77, 2517–2533 (1999)

    Article  Google Scholar 

  32. Brelidze, T.I., Niu, X., Magelby, K.L.: A ring of eight negatively charged amino acids doubles the conductance of BK channels and prevents inward rectification. Proc. Natl. Acad. Sci. USA 100, 9017–9022 (2003)

    Article  ADS  Google Scholar 

  33. Nishida, M., MacKinnon, R.: Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 Å resolution. Cell 111, 957–965 (2002)

    Article  Google Scholar 

  34. Xie, L.H., John, S.A., Weiss, J.N.: Spermine block of the strong inward rectifier potassium channel Kir2.1: dual roles of surface charge screening and pore block. J. Gen. Physiol. 120, 53–66 (2002)

    Article  Google Scholar 

Download references

Acknowledgments

Silvie Ngo provided excellent technical assistance, for which we are grateful. We thank Michael Thomas for his scientific advice. This work was supported by the NCI National Facility at the Australian National University. We gratefully acknowledge the support from the Australian Research Council through a Discovery Early Career Researcher Award, and the National Health and Medical Council.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tamsyn A. Hilder.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 1.08 MB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hilder, T.A., Corry, B. & Chung, SH. Multi-ion versus single-ion conduction mechanisms can yield current rectification in biological ion channels. J Biol Phys 40, 109–119 (2014). https://doi.org/10.1007/s10867-013-9338-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10867-013-9338-4

Keywords

Navigation