Skip to main content
SpringerLink
Log in

Normal mode dynamics of voltage-gated K+ channels: gating principle, opening mechanism, and inhibition

  • Published:
Journal of Computational Neuroscience Aims and scope Submit manuscript

Abstract

Voltage-dependent potassium channels open in response to changes in membrane potential and become partially inactivated upon binding of inhibitors. Here we calculate normal mode motion of two voltage-dependent K+ channels, KvAP and Shaker, and their complexes with inhibitors and address the gating principle, opening mechanism, and inhibition. The normal modes indicate that pore expansion and channel opening is correlated with a displacement of the arginine gating charges and a tilting of the voltage-sensor paddles. Normal modes of Shaker in complex with agitoxin, which blocks the central pore, do not display significantly altered paddle tilting and pore expansion. In contrast, normal modes of Shaker in complex with hanatoxin, which binds to the voltage sensor paddle, display decreased paddle tilting and pore expansion. This study presents a unified motion for the gating principle and channel opening, and offers insight into the voltage sensor paddle motion and its inhibition.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

KvAP:

Archaeal voltage-dependent potassium channel (derived from the extremophile Aeropyrum Pernix living at a temperature of 95 °C)

Shaker:

Mammalian voltage-dependent potassium channel (derived from Rattus Norvegicus)

RMSD:

Root mean square deviation

References

  • Aggarwal, S. K., & MacKinnon, R. (1996). Contribution of the S4 segment to gating charge in the Shaker K+ channel. Neuron, 16, 1169–1177.

    Article  CAS  PubMed  Google Scholar 

  • Ahern, C. A., & Horn, R. (2004). Stirring up controversy with a voltage sensor paddle. Trends in Neurosciences, 27, 303–307.

    Article  CAS  PubMed  Google Scholar 

  • Armstrong, C. M., & Bezanilla, F. (1974). Charge movement associated with the opening and closing of the activation gates of the Na channels. Journal of General Physiology, 63, 533–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atilgan, A. R., Durell, S. R., Jernigan, R. L., Demirel, M. C., Keskin, O., & Bahar, I. (2001). Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophysical Journal, 80, 505–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bahar, I., Lezon, T. R., Yang, L. W., & Eyal, E. (2010). Global dynamics of proteins: bridging between structure and function. Annual Review of Biophysics, 39, 23–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bezanilla, F. (2000). The voltage sensor in voltage-dependent ion channels. Physiological Reviews, 80, 555–592.

    CAS  PubMed  Google Scholar 

  • Brooks, B., & Karplus, M. (1983). Harmonic dynamics of proteins: normal modes and fluctuations in bovine pancreatic trypsin inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 80, 6571–6575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chanda, B., Asamoah, O. K., Blunck, R., Roux, B., & Bezanilla, F. (2005). Gating charge displacement in voltage-gated ion channels involves limited transmembrane movement. Nature, 436, 852–856.

    Article  CAS  PubMed  Google Scholar 

  • Chen, X., Wang, Q., Ni, F., & Ma, J. (2010). Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement. Proc Natl Acad Sci U S A, 107, 11352–11357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delarue, M., & Sanejouand, Y. H. (2002). Simplified normal mode analysis of conformational transitions in DNA-dependent polymerases: the elastic network model. Journal of Molecular Biology, 320, 1011–1024.

    Article  CAS  PubMed  Google Scholar 

  • Durell, S. R., Shrivastava, I. H., & Guy, H. R. (2004). Models of the structure and voltage-gating mechanism of the shaker K+ channel. Biophysical Journal, 87, 2116–2130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eriksson, M. A., & Roux, B. (2002). Modeling the structure of agitoxin in complex with the Shaker K+ channel: a computational approach based on experimental distance restraints extracted from thermodynamic mutant cycles. Biophysical Journal, 83, 2595–2609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Go, N., Noguti, T., & Nishikawa, T. (1983). Dynamics of a small globular protein in terms of low-frequency vibrational modes. Proceedings of the National Academy of Sciences of the United States of America, 80, 3696–3700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen, M. Ø., Jogini, V., Borhani, D. W., Leffler, A. E., Dror, R. O., & Shaw, D. E. (2012). Mechanism of voltage gating in potassium channels. Science, 336, 229–233.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, Y., Lee, A., Chen, J., Ruta, V., Cadene, M., Chait, B. T., & MacKinnon, R. (2003a). X-ray structure of a voltage-dependent K+ channel. Nature, 423, 33–41.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, Y., Ruta, V., Chen, J., Lee, A., & MacKinnon, R. (2003b). The principle of gating charge movement in a voltage-dependent K+ channel. Nature, 423, 42–48.

    Article  CAS  PubMed  Google Scholar 

  • Khalili-Araghi, F., Jogini, V., Yarov-Yarovoy, V., Tajkhorshid, E., Roux, B., & Schulten, K. (2010). Calculation of the gating charge for the Kv1.2 voltage-activated potassium channel. Biophysical Journal, 98, 2189–2198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krebs, W. G., Alexandrov, V., Wilson, C. A., Echols, N., Yu, H., & Gerstein, M. (2002). Normal mode analysis of macromolecular motions in a database framework: developing mode concentration as a useful classifying statistic. Proteins, 48, 682–695.

    Article  CAS  PubMed  Google Scholar 

  • Krezel, A. M., Kasibhatla, C., Hidalgo, P., MacKinnon, R., & Wagner, G. (1995). Solution structure of the potassium channel inhibitor agitoxin 2: caliper for probing channel geometry. Protein Science, 4, 1478–1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larsson, H. P., Baker, O. S., Dhillon, D. S., & Isacoff, E. Y. (1996). Transmembrane movement of the shaker K+ channel S4. Neuron, 16, 387–397.

    Article  CAS  PubMed  Google Scholar 

  • Levitt, M., Sander, C., & Stern, P. S. (1985). Protein normal-mode dynamics: trypsin inhibitor, crambin, ribonuclease and lysozyme. Journal of Molecular Biology, 181, 423–447.

    Article  CAS  PubMed  Google Scholar 

  • Lindahl, E., Azuara, C., Koehl, P., & Delarue, M. (2006). NOMAD-Ref: visualization, deformation and refinement of macromolecular structures based on all-atom normal mode analysis. Nucleic Acids Research, 34, W52–W56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Long, S. B., Campbell, E. B., & Mackinnon, R. (2005a). Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science, 309, 897–903.

    Article  CAS  PubMed  Google Scholar 

  • Long, S. B., Campbell, E. B., & Mackinnon, R. (2005b). Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science, 309, 903–908.

    Article  CAS  PubMed  Google Scholar 

  • Long, S. B., Tao, X., Campbell, E. B., & MacKinnon, R. (2007). Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature, 450, 376–382.

    Article  CAS  PubMed  Google Scholar 

  • Lou, K. L., Huang, P. T., Shiau, Y. S., Liaw, Y. C., Shiau, Y. Y., & Liou, H. H. (2003). A possible molecular mechanism of hanatoxin binding-modified gating in voltage-gated K + −channels. Journal of Molecular Recognition, 16, 392–395.

    Article  CAS  PubMed  Google Scholar 

  • Pathak, M. M., Yarov-Yarovoy, V., Agarwal, G., Roux, B., Barth, P., Kohout, S., Tombola, F., & Isacoff, E. Y. (2007). Closing in on the resting state of the Shaker K(+) channel. Neuron, 56, 124–140.

    Article  CAS  PubMed  Google Scholar 

  • Ruta, V., Chen, J., & MacKinnon, R. (2005). Calibrated measurement of gating-charge arginine displacement in the KvAP voltage-dependent K+ channel. Cell, 123, 463–475.

    Article  CAS  PubMed  Google Scholar 

  • Samson, A. O., & Levitt, M. (2008). Inhibition mechanism of the acetylcholine receptor by alpha-neurotoxins as revealed by normal-mode dynamics. Biochemistry, 47, 4065–4070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samson, A. O., & Levitt, M. (2011). Normal modes of prion proteins: from native to infectious particle. Biochemistry, 50, 2243-2248.

  • Schmidt, D., Jiang, Q. X., & MacKinnon, R. (2006). Phospholipids and the origin of cationic gating charges in voltage sensors. Nature, 444, 775–779.

    Article  CAS  PubMed  Google Scholar 

  • Shenkarev, Z. O., Paramonov, A. S., Lyukmanova, E. N., Shingarova, L. N., Yakimov, S. A., Dubinnyi, M. A., Chupin, V. V., Kirpichnikov, M. P., Blommers, M. J. J., & Arseniev, A. S. (2010). NMR structural and dynamical investigation of the isolated voltage-sensing domain of the potassium channel KvAP: implications for voltage gating. Journal of the American Chemical Society, 132, 5630–5637.

    Article  CAS  PubMed  Google Scholar 

  • Shrivastava, I. H., & Bahar, I. (2006). Common mechanism of pore opening shared by five different potassium channels. Biophysical Journal, 90, 3929–3940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shrivastava, I. H., Durell, S. R., & Guy, H. R. (2004). A model of voltage gating developed using the KvAP channel crystal structure. Biophysical Journal, 87, 2255–2270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sigworth, F. J. (1994). Voltage gating of ion channels. Quarterly Reviews of Biophysics, 27, 1–40.

    Article  CAS  PubMed  Google Scholar 

  • Suhre, K., & Sanejouand, Y. H. (2004). ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement. Nucleic Acids Research, 32, W610–W614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swartz, K. J., & MacKinnon, R. (1997a). Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels. Neuron, 18, 675–682.

    Article  CAS  PubMed  Google Scholar 

  • Swartz, K. J., & MacKinnon, R. (1997b). Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites. Neuron, 18, 665–673.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi, H., Kim, J. I., Min, H. J., Sato, K., Swartz, K. J., & Shimada, I. (2000). Solution structure of hanatoxin1, a gating modifier of voltage-dependent K(+) channels: common surface features of gating modifier toxins. Journal of Molecular Biology, 297, 771–780.

    Article  CAS  PubMed  Google Scholar 

  • Taly, A., Corringer, P. J., Grutter, T., Prado de Carvalho, L., Karplus, M., & Changeux, J. P. (2006). Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors. Proceedings of the National Academy of Sciences of the United States of America, 103, 16965–16970.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tama, F., & Sanejouand, Y. H. (2001). Conformational change of proteins arising from normal mode calculations. Protein Engineering, 14, 1–6.

    Article  CAS  PubMed  Google Scholar 

  • Tirion, M. M. (1996). Large amplitude elastic motions in proteins from a single-parameter. Atomic Analysis Physical Review Letters, 77, 1905–1908.

    Article  CAS  Google Scholar 

  • Tombola, F., Pathak, M. M., & Isacoff, E. Y. (2005). How far will you go to sense voltage? Neuron, 48, 719–725.

    Article  CAS  PubMed  Google Scholar 

  • Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., & Berendsen, H. J. (2005). GROMACS: fast, flexible, and free. Journal of Computational Chemistry, 26, 1701–1718.

    Article  Google Scholar 

  • Yang, N., George, A. L., Jr., & Horn, R. (1996). Molecular basis of charge movement in voltage-gated sodium channels. Neuron, 16, 113–122.

    Article  PubMed  Google Scholar 

  • Yang, Y.-C., Lin, S., Chang, P.-C., Lin, H.-C., & Kuo, C.-C. (2011). Functional extension of amino acid triads from the fourth transmembrane Segment (S4) into its external linker in Shaker K Channels. The Journal of Biological Chemistry, 286, 37503–37514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yanping, X., Ramu, Y., & Zhe, L. (2010). A Shaker K+ channel with a miniature engineered voltage sensor. Cell, 142, 580–589.

    Article  Google Scholar 

  • Yeheskel, A., Haliloglu, T., & Ben Tal, N. (2010). Independent and cooperative motions of the Kv1.2 channel: voltage sensing and gating. Biophysical Journal, 98, 2179–2188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Dr. Dahlia Weiss for careful reading of this manuscript, and helpful comments.

This research was supported by CIG award 322113 to A.O.S.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Faculty of Medicine in the Galilee, Bar Ilan University, 14100, Safed, Israel

    Moshe M. Greenberger & Abraham O. Samson

Authors
  1. Moshe M. Greenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abraham O. Samson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abraham O. Samson.

Additional information

Action Editor: John Huguenard

Supporting information

STAND movie of the lowest frequency mode of Shaker is available free of charge via the internet at http://pubs.acs.org

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Greenberger, M.M., Samson, A.O. Normal mode dynamics of voltage-gated K+ channels: gating principle, opening mechanism, and inhibition. J Comput Neurosci 38, 83–88 (2015). https://doi.org/10.1007/s10827-014-0527-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10827-014-0527-3

Keywords

Search

Navigation