The voltage-gated potassium channels and their relatives

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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.

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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.

References

  1. 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)

  2. 2

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

  3. 3

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

  4. 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)

  5. 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)

  6. 6

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

  7. 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)

  8. 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)

  9. 9

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

  10. 10

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

  11. 11

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

  12. 12

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

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 17

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

  18. 18

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

  19. 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)

  20. 20

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

  21. 21

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

  22. 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)

  23. 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)

  24. 24

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

  25. 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)

  26. 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)

  27. 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)

  28. 28

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

  29. 29

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

  30. 30

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

  31. 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)

  32. 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)

  33. 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)

  34. 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)

  35. 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)

  36. 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)

  37. 37

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

  38. 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)

  39. 39

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

  40. 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)

  41. 41

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

  42. 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)

  43. 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)

  44. 44

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

  45. 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)

  46. 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)

  47. 47

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

  48. 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)

  49. 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)

  50. 50

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

  51. 51

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

  52. 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)

  53. 53

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

  54. 54

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

  55. 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)

  56. 56

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

  57. 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)

  58. 58

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

  59. 59

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

  60. 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)

  61. 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)

  62. 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)

  63. 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)

  64. 64

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

  65. 65

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

  66. 66

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

  67. 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)

  68. 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)

  69. 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)

  70. 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)

  71. 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)

  72. 72

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

  73. 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)

  74. 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)

  75. 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)

  76. 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)

  77. 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)

  78. 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)

  79. 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)

  80. 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)

  81. 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)

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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.

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Correspondence to Gary Yellen.

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

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