Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The voltage-gated potassium channels and their relatives

Abstract

The voltage-gated potassium channels are the prototypical members of a family of membrane signalling proteins. These protein-based machines have pores that pass millions of ions per second across the membrane with astonishing selectivity, and their gates snap open and shut in milliseconds as they sense changes in voltage or ligand concentration. The architectural modules and functional components of these sophisticated signalling molecules are becoming clear, but some important links remain to be elucidated.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Architectural features of K+ channels important for ion permeation.
Figure 2: The conformational changes that gate the K+ channel pore.
Figure 3: Two sensor domains that govern gating in the K+ channel family.

Similar content being viewed by others

References

  1. Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (Lond.) 117, 500–544 (1952)

    Article  CAS  Google Scholar 

  2. Latorre, R. & Miller, C. Conduction and selectivity in potassium channels. J. Membr. Biol. 71, 11–30 (1983)

    Article  CAS  PubMed  Google Scholar 

  3. Doyle, D. A. et al. The structure of the potassium channel: molecular basis of potassium conduction and selectivity. Science 280, 69–77 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Zhou, Y., Morais Cabral, J. H., Kaufman, A. & MacKinnon, R. Chemistry of ion hydration and coordination revealed by a K+ channel-Fab complex at 2.0 Å resolution. Nature 414, 43–48 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Morais-Cabral, J. H., Zhou, Y. & MacKinnon, R. Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature 414, 37–42 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Jiang, Y. et al. The open pore conformation of potassium channels. Nature 417, 523–526 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Roux, B. & MacKinnon, R. The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science 285, 100–102 (1999)

    Article  CAS  PubMed  Google Scholar 

  8. Dutzler, R., Campbell, E. B., Cadene, M., Chait, B. T. & MacKinnon, R. X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415, 287–294 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  9. Armstrong, C. M. Ionic pores, gates, and gating currents. Q. Rev. Biophys. 7, 179–210 (1975)

    Article  Google Scholar 

  10. Hodgkin, A. L. & Keynes, R. D. The potassium permeability of a giant nerve fibre. J. Physiol. (Lond.) 128, 61–88 (1955)

    Article  CAS  Google Scholar 

  11. Hille, B. & Schwarz, W. Potassium channels as multi-ion single-file pores. J. Gen. Physiol. 72, 409–442 (1978)

    Article  CAS  PubMed  Google Scholar 

  12. Spassova, M. & Lu, Z. Coupled ion movement underlies rectification in an inward-rectifier K+ channel. J. Gen. Physiol. 112, 211–221 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu, Y., Holmgren, M., Jurman, M. E. & Yellen, G. Gated access to the pore of a voltage-dependent K+ channel. Neuron 19, 175–184 (1997)

    Article  PubMed  Google Scholar 

  14. del Camino, D. & Yellen, G. Tight steric closure at the intracellular activation gate of a voltage-gated K+ channel. Neuron 32, 649–656 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. del Camino, D., Holmgren, M., Liu, Y. & Yellen, G. Blocker protection in the pore of a voltage-gated K+ channel and its structural implications. Nature 403, 321–325 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Holmgren, M., Shin, K. S. & Yellen, G. The activation gate of a voltage-gated K+ channel can be trapped in the open state by an intersubunit metal bridge. Neuron 21, 617–621 (1998)

    Article  CAS  PubMed  Google Scholar 

  17. Perozo, E., Cortes, D. M. & Cuello, L. G. Structural rearrangements underlying K+-channel activation gating. Science 285, 73–78 (1999)

    Article  CAS  PubMed  Google Scholar 

  18. Armstrong, C. M. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axon. J. Gen. Physiol. 58, 413–437 (1971)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Holmgren, M., Smith, P. L. & Yellen, G. Trapping of organic blockers by closing of voltage-dependent K+ channels: evidence for a trap door mechanism of activation gating. J. Gen. Physiol. 109, 527–535 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hoshi, T., Zagotta, W. N. & Aldrich, R. W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science 250, 533–538 (1990)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Rettig, J. et al. Inactivation properties of voltage-gated K+ channels altered by presence of β-subunit. Nature 369, 289–294 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Zagotta, W. N., Hoshi, T. & Aldrich, R. W. Restoration of inactivation in mutants of Shaker K+ channels by a peptide derived from ShB. Science 250, 568–571 (1990)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Murrell-Lagnado, R. D. & Aldrich, R. W. Interactions of amino terminal domains of Shaker K channels with a pore blocking site studied with synthetic peptides. J. Gen. Physiol. 102, 949–975 (1993)

    Article  CAS  PubMed  Google Scholar 

  24. Murrell-Lagnado, R. D. & Aldrich, R. W. Energetics of Shaker K channels block by inactivation peptides. J. Gen. Physiol. 102, 977–1003 (1993)

    Article  CAS  PubMed  Google Scholar 

  25. Choi, K. L., Aldrich, R. W. & Yellen, G. Tetraethylammonium blockade distinguishes two inactivation mechanisms in voltage-activated K+ channels. Proc. Natl Acad. Sci. USA 88, 5092–5095 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Demo, S. D. & Yellen, G. The inactivation gate of the Shaker K+ channel behaves like an open-channel blocker. Neuron 7, 743–753 (1991)

    Article  CAS  PubMed  Google Scholar 

  27. Zhou, M., Morais-Cabral, J. H., Mann, S. & MacKinnon, R. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature 411, 657–661 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  28. Ruppersberg, J. P. et al. Regulation of fast inactivation of cloned mammalian IK(A) channels by cysteine oxidation. Nature 352, 711–714 (1991)

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Roeper, J. et al. NIP domain prevents N-type inactivation in voltage-gated potassium channels. Nature 391, 390–393 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Gulbis, J. M., Mann, S. & MacKinnon, R. Structure of a voltage-dependent K+ channel beta subunit. Cell 97, 943–952 (1999)

    Article  CAS  PubMed  Google Scholar 

  31. Kobertz, W. R., Williams, C. & Miller, C. Hanging gondola structure of the T1 domain in a voltage-gated K+ channel. Biochemisty 39, 10347–10352 (2000)

    Article  CAS  Google Scholar 

  32. Sokolova, O., Kolmakova-Partensky, L. & Grigorieff, N. Three-dimensional structure of a voltage-gated potassium channel at 2.5 nm resolution. Structure (Camb.) 9, 215–220 (2001)

    Article  CAS  Google Scholar 

  33. Hoshi, T., Zagotta, W. N. & Aldrich, R. W. Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region. Neuron 7, 547–556 (1991)

    Article  CAS  PubMed  Google Scholar 

  34. López-Barneo, J., Hoshi, T., Heinemann, S. H. & Aldrich, R. W. Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels. Recept. Channels 1, 61–71 (1993)

    PubMed  Google Scholar 

  35. Yellen, G., Sodickson, D., Chen, T.-Y. & Jurman, M. E. An engineered cysteine in the external mouth of a K+ channel allows inactivation to be modulated by metal binding. Biophys. J. 66, 1068–1075 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu, Y., Jurman, M. E. & Yellen, G. Dynamic rearrangement of the outer mouth of a K+ channel during gating. Neuron 16, 859–867 (1996)

    Article  CAS  PubMed  Google Scholar 

  37. Pardo, L. A. et al. Extracellular K+ specifically modulates a rat brain K+ channel. Proc. Natl Acad. Sci. USA 89, 2466–2470 (1992)

    Article  ADS  CAS  PubMed  Google Scholar 

  38. Baukrowitz, T. & Yellen, G. Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms. Neuron 15, 951–960 (1995)

    Article  CAS  PubMed  Google Scholar 

  39. Kiss, L., LoTurco, J. & Korn, S. J. Contribution of the selectivity filter to inactivation in potassium channels. Biophys. J. 76, 253–263 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chapman, M. L., VanDongen, H. M. & VanDongen, A. M. Activation-dependent subconductance levels in the drk1 K+ channel suggest a subunit basis for ion permeation and gating. Biophys. J. 72, 708–719 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zheng, J. & Sigworth, F. J. Selectivity changes during activation of mutant Shaker potassium channels. J. Gen. Physiol. 110, 101–117 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Flynn, G. E. & Zagotta, W. N. Conformational changes in S6 coupled to the opening of cyclic nucleotide-gated channels. Neuron 30, 689–698 (2001)

    Article  CAS  PubMed  Google Scholar 

  43. Rothberg, B. S., Shin, K. S., Phale, P. S. & Yellen, G. Voltage-controlled gating at the intracellular entrance to a hyperpolarization-activated cation channel. J. Gen. Physiol. 119, 83–91 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Johnson, J. P. Jr & Zagotta, W. N. Rotational movement during cyclic nucleotide-gated channel opening. Nature 412, 917–921 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Jiang, Y., Pico, A., Cadene, M., Chait, B. T. & MacKinnon, R. Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel. Neuron 29, 593–601 (2001)

    Article  CAS  PubMed  Google Scholar 

  46. Liu, D. T., Tibbs, G. R., Paoletti, P. & Siegelbaum, S. A. Constraining ligand-binding site stoichiometry suggests that a cyclic nucleotide-gated channel is composed of two functional dimers. Neuron 21, 235–248 (1998)

    Article  CAS  PubMed  Google Scholar 

  47. Jiang, Y. et al. Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515–522 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  48. Weber, I. T. & Steitz, T. A. Structure of a complex of catabolite gene activator protein and cyclic AMP refined at 2.5 Å resolution. J. Mol. Biol. 198, 311–326 (1987)

    Article  CAS  PubMed  Google Scholar 

  49. Chen, G. Q., Cui, C., Mayer, M. L. & Gouaux, E. Functional characterization of a potassium-selective prokaryotic glutamate receptor. Nature 402, 817–821 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  50. Sun, Y. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Xia, X. M. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  52. Schumacher, M. A., Rivard, A. F., Bachinger, H. P. & Adelman, J. P. Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 410, 1120–1124 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Sigworth, F. J. Voltage gating of ion channels. Q. Rev. Biophys. 27, 1–40 (1994)

    Article  CAS  PubMed  Google Scholar 

  54. Noda, M. et al. Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 312, 121–127 (1984)

    Article  ADS  CAS  PubMed  Google Scholar 

  55. Seoh, S. A., Sigg, D., Papazian, D. M. & Bezanilla, F. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16, 1159–1167 (1996)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Tiwari-Woodruff, S. K., Lin, M. A., Schulteis, C. T. & Papazian, D. M. Voltage-dependent structural interactions in the Shaker K+ channel. J. Gen. Physiol. 115, 123–138 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Islas, L. D. & Sigworth, F. J. Electrostatics and the gating pore of Shaker potassium channels. J. Gen. Physiol. 117, 69–89 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  61. Durell, S. R., Hao, Y. & Guy, H. R. Structural models of the transmembrane region of voltage-gated and other K+ channels in open, closed, and inactivated conformations. J. Struct. Biol. 121, 263–284 (1998)

    Article  CAS  PubMed  Google Scholar 

  62. Monks, S. A., Needleman, D. J. & Miller, C. Helical structure and packing orientation of the S2 segment in the Shaker K+ channel. J. Gen. Physiol. 113, 415–423 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li-Smerin, Y., Hackos, D. H. & Swartz, K. J. alpha-helical structural elements within the voltage-sensing domains of a K+ channel. J. Gen. Physiol. 115, 33–50 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hong, K. H. & Miller, C. The lipid-protein interface of a Shaker K+ channel. J. Gen. Physiol. 115, 51–58 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Guy, H. R. & Seetharamulu, P. Molecular model of the action potential sodium channel. Proc. Natl Acad. Sci. USA 83, 508–512 (1986)

    Article  ADS  CAS  PubMed  Google Scholar 

  66. Catterall, W. A. Voltage-dependent gating of sodium channels: correlating structure and function. Trends Neurosci. 9, 7–10 (1986)

    Article  CAS  Google Scholar 

  67. Glauner, K. S., Mannuzzu, L. M., Gandhi, C. S. & Isacoff, E. Y. Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel. Nature 402, 813–817 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  68. Cha, A., Snyder, G. E., Selvin, P. R. & Bezanilla, F. Atomic scale movement of the voltage-sensing region in a potassium channel measured via spectroscopy. Nature 402, 809–813 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  69. Elinder, F., Mannikko, R. & Larsson, H. P. S4 charges move close to residues in the pore domain during activation in a K channel. J. Gen. Physiol. 118, 1–10 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tristani-Firouzi, M., Chen, J. & Sanguinetti, M. C. Interactions between S4-S5 linker and S6 transmembrane domain modulate gating of HERG K+ channels. J. Biol. Chem. 277, 18994–19000 (2002)

    Article  CAS  PubMed  Google Scholar 

  71. Heginbotham, L., Abramson, T. & MacKinnon, R. A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels. Science 258, 1152–1155 (1992)

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Ren, D. et al. A prokaryotic voltage-gated sodium channel. Science 294, 2372–2375 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  73. Kreusch, A., Pfaffinger, P. J., Stevens, C. F. & Choe, S. Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392, 945–948 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  74. Gulbis, J. M., Zhou, M., Mann, S. & MacKinnon, R. Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K+ channels. Science 289, 123–127 (2000)

    Article  ADS  CAS  PubMed  Google Scholar 

  75. Shen, N. V. & Pfaffinger, P. J. Molecular recognition and assembly sequences involved in the subfamily-specific assembly of voltage-gated K+ channel subunit proteins. Neuron 14, 625–633 (1995)

    Article  CAS  PubMed  Google Scholar 

  76. Holmes, T. C., Fadool, D. A., Ren, R. & Levitan, I. B. Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science 274, 2089–2091 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  77. Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996)

    Article  CAS  PubMed  Google Scholar 

  78. Wallner, M., Meera, P. & Toro, L. Determinant for β-subunit regulation in high-conductance voltage-activated and Ca2+-sensitive K+ channels: an additional transmembrane region at the N terminus. Proc. Natl Acad. Sci. USA 93, 14922–14927 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  79. Morais, C. J. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)

    Article  Google Scholar 

  80. Knaus, H. G., Eberhart, A., Kaczorowski, G. J. & Garcia, M. L. Covalent attachment of charybdotoxin to the β-subunit of the high conductance Ca2+-activated K+ channel. Identification of the site of incorporation and implications for channel topology. J. Biol. Chem. 269, 23336–23341 (1994)

    CAS  PubMed  Google Scholar 

  81. Tapper, A. R. & George, A. L. Jr Location and orientation of minK within the I(Ks) potassium channel complex. J. Biol. Chem. 276, 38249–38254 (2001)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank members of my laboratory and B. Bean for many discussions and for suggestions about the manuscript, and R. MacKinnon for advice about timing. My research was supported by the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary Yellen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yellen, G. The voltage-gated potassium channels and their relatives. Nature 419, 35–42 (2002). https://doi.org/10.1038/nature00978

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00978

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing