Skip to main content

Thank you for visiting 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.

hERG potassium channels and cardiac arrhythmia


hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Multiple ion channel currents shape the cardiac action potential.
Figure 2: Conformation of a single hERG channel is voltage dependent.
Figure 3: Reduced hERG current delays ventricular repolarization and can induce arrhythmia.
Figure 4: Structural features of voltage-gated K+ channels.
Figure 5: Model of the hERG drug-binding site.


  1. 1

    Warmke, J. W. & Ganetzky, B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl Acad. Sci. USA 91, 3438–3442 (1994).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Curran, M. E. et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80, 795–803 (1995).

    CAS  Google Scholar 

  3. 3

    Haverkamp, W. et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur. Heart J. 21, 1216–1231 (2000).

    CAS  Google Scholar 

  4. 4

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

    ADS  CAS  Google Scholar 

  5. 5

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

    ADS  CAS  Google Scholar 

  6. 6

    Jiang, Y. et al. X-ray structure of a voltage-dependent K+ channel. Nature 423, 33–41 (2003).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

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

    ADS  CAS  Google Scholar 

  8. 8

    Farrelly, A. M. et al. Expression and function of KCNH2 (HERG) in the human jejunum. Am. J. Physiol. 284, G883–G895 (2003).

    CAS  Google Scholar 

  9. 9

    Chiesa, N., Rosati, B., Arcangeli, A., Olivotto, M. & Wanke, E. A novel role for HERG K+ channels: spike-frequency adaptation. J. Physiol. (Lond.) 501, 313–318 (1997).

    CAS  Google Scholar 

  10. 10

    Smith, G. A. et al. Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells. J. Biol. Chem. 277, 18528–18534 (2002).

  11. 11

    Shi, W. et al. Identification of two nervous system-specific members of the erg potassium channel gene family. J. Neurosci. 17, 9423–9432 (1997).

    CAS  Google Scholar 

  12. 12

    Wimmers, S., Wulfsen, I., Bauer, C. K. & Schwarz, J. R. Erg1, erg2 and erg3 K channel subunits are able to form heteromultimers. Pflugers Arch. 441, 450–455 (2001).

    CAS  Google Scholar 

  13. 13

    Sanguinetti, M. C., Jiang, C., Curran, M. E. & Keating, M. T. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81, 299–307 (1995).

    CAS  Google Scholar 

  14. 14

    Trudeau, M., Warmke, J. W., Ganetzky, B. & Robertson, G. A. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269, 92–95 (1995).

    ADS  CAS  Google Scholar 

  15. 15

    Bennett, P. B., Yazawa, K., Makita, N. & George, A. L. Molecular mechanism for an inherited cardiac arrhythmia. Nature 376, 683–685 (1995).

    ADS  CAS  Google Scholar 

  16. 16

    Plaster, N. M. et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105, 511–519 (2001).

    CAS  Google Scholar 

  17. 17

    Splawski, I. et al. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).

    CAS  Google Scholar 

  18. 18

    Furutani, M. et al. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation 99, 2290–2294 (1999).

    CAS  Google Scholar 

  19. 19

    Delisle, B. P., Anson, B. D., Rajamani, S. & January, C. T. Biology of cardiac arrhythmias: ion channel protein trafficking. Circ. Res. 94, 1418–1428 (2004).

    CAS  Google Scholar 

  20. 20

    Gong, Q., Keeney, D. R., Molinari, M. & Zhou, Z. Degradation of trafficking-defective long QT syndrome type II mutant channels by the ubiquitin–proteasome pathway. J. Biol. Chem. 280, 19419–19425 (2005).

    CAS  Google Scholar 

  21. 21

    Sanguinetti, M. C., Curran, M. E., Spector, P. S. & Keating, M. T. Spectrum of HERG K+ channel dysfunction in an inherited cardiac arrhythmia. Proc. Natl Acad. Sci. USA 93, 2208–2212 (1996).

    ADS  CAS  Google Scholar 

  22. 22

    Kagan, A., Yu, Z., Fishman, G. I. & McDonald, T. V. The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. J. Biol. Chem. 275, 11241–11248 (2000).

    CAS  Google Scholar 

  23. 23

    Nakajima, T. et al. Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ. Res. 83, 415–422 (1998).

    CAS  Google Scholar 

  24. 24

    Brugada, R. et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109, 30–35 (2004).

    CAS  Google Scholar 

  25. 25

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Jiang, Y., Lee, A., Cadene, M., Chait, B. T. & MacKinnon, R. The open pore conformation of potassium channels. Nature 417, 523–526 (2002).

    ADS  CAS  Google Scholar 

  27. 27

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

    ADS  CAS  Google Scholar 

  28. 28

    Mitcheson, J. S., Chen, J., Lin, M., Culberson, C. & Sanguinetti, M. C. A structural basis for drug-induced long QT syndrome. Proc. Natl Acad. Sci. USA 97, 12329–12333 (2000).

    ADS  CAS  Google Scholar 

  29. 29

    Webster, S. M., Del Camino, D., Dekker, J. P. & Yellen, G. Intracellular gate opening in Shaker K+ channels defined by high-affinity metal bridges. Nature 428, 864–868 (2004).

    ADS  CAS  Google Scholar 

  30. 30

    Fernandez, D., Ghanta, A., Kauffman, G. W. & Sanguinetti, M. C. Physicochemical features of the hERG channel drug binding site. J. Biol. Chem. 279, 10120–10127 (2004).

    CAS  Google Scholar 

  31. 31

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

    CAS  Google Scholar 

  32. 32

    Taylor, B. L. & Zhulin, I. B. PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol. Mol. Biol. Rev. 63, 479–506 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    London, B. et al. Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current. Circ. Res. 81, 870–878 (1997).

    CAS  Google Scholar 

  34. 34

    Cui, J., Melman, Y., Palma, E., Fishman, G. I. & McDonald, T. V. Cyclic AMP regulates the HERG K+ channel by dual pathways. Curr. Biol. 10, 671–674 (2000).

    CAS  Google Scholar 

  35. 35

    Akhavan, A. et al. Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization. J. Cell Sci. 118, 2803–2812 (2005).

    CAS  Google Scholar 

  36. 36

    Barhanin, J. et al. KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium channel. Nature 384, 78–80 (1996).

    ADS  CAS  Google Scholar 

  37. 37

    Sanguinetti, M. C. et al. Coassembly of KvLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 384, 80–83 (1996).

    ADS  CAS  Google Scholar 

  38. 38

    Abbott, G. W. et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175–187 (1999).

    CAS  Google Scholar 

  39. 39

    Pourrier, M., Zicha, S., Ehrlich, J., Han, W. & Nattel, S. Canine ventricular KCNE2 expression resides predominantly in Purkinje fibers. Circ. Res. 93, 189–191 (2003).

    CAS  Google Scholar 

  40. 40

    Lundquist, A. L. et al. Expression of multiple KCNE genes in human heart may enable variable modulation of IKs . J. Mol. Cell. Cardiol. 38, 277–287 (2005).

    CAS  Google Scholar 

  41. 41

    Weerapura, M., Nattel, S., Chartier, D., Caballero, R. & Hebert, T. E. A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J. Physiol. (Lond.) 540, 15–27. (2002).

    CAS  Google Scholar 

  42. 42

    Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl Acad. Sci. USA 97, 10613–10618 (2000).

    ADS  CAS  Google Scholar 

  43. 43

    Noble, D. & Tsien, R. W. Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J. Physiol. (Lond.) 200, 205–231 (1969).

    CAS  Google Scholar 

  44. 44

    Shibasaki, T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J. Physiol. (Lond.) 387, 227–250 (1987).

    CAS  Google Scholar 

  45. 45

    Clay, J. R., Hill, C. E., Roitman, D. & Shrier, A. Repolarization current in embryonic chick atrial heart cells. J. Physiol. (Lond.) 403, 525–537 (1988).

    CAS  Google Scholar 

  46. 46

    Sanguinetti, M. C. & Jurkiewicz, N. K. Two components of cardiac delayed rectifier K+ current: Differential sensitivity to block by class III antiarrhythmic agents. J. Gen. Physiol. 96, 195–215 (1990).

    CAS  Google Scholar 

  47. 47

    Piper, D. R., Varghese, A., Sanguinetti, M. C. & Tristani-Firouzi, M. Gating currents associated with intramembrane charge displacement in HERG potassium channels. Proc. Natl Acad. Sci. USA 100, 10534–10539 (2003).

    ADS  CAS  Google Scholar 

  48. 48

    Smith, P. L. & Yellen, G. Fast and slow voltage sensor movements in HERG potassium channels. J. Gen. Physiol. 119, 275–293 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Subbiah, R. N., Kondo, M., Campbell, T. J. & Vandenberg, J. I. Tryptophan scanning mutagenesis of the HERG K+ channel: The S4 domain is loosely packed and likely to be lipid exposed. J. Physiol. (Lond.) 569, 367–379 (2005).

    CAS  Google Scholar 

  50. 50

    Piper, D. R., Hinz, W. A., Tallurri, C. K., Sanguinetti, M. C. & Tristani-Firouzi, M. Regional specificity of human ether-a'-go-go-related gene channel activation and inactivation gating. J. Biol. Chem. 280, 7206–7217 (2005).

    CAS  Google Scholar 

  51. 51

    Zhang, M., Liu, J. & Tseng, G. N. Gating charges in the activation and inactivation processes of the HERG channel. J. Gen. Physiol. 124, 703–718 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Silverman, W. R., Roux, B. & Papazian, D. M. Structural basis of two-stage voltage-dependent activation in K+ channels. Proc. Natl Acad. Sci. USA 100, 2935–2940 (2003).

    ADS  CAS  Google Scholar 

  54. 54

    Liu, J., Zhang, M., Jiang, M. & Tseng, G. N. Negative charges in the transmembrane domains of the HERG K channel are involved in the activation- and deactivation-gating processes. J. Gen. Physiol. 121, 599–614 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Fernandez, D., Ghanta, A., Kinard, K. I. & Sanguinetti, M. C. Molecular mapping of a site for Cd2+-induced modification of human ether-a-go-go-related gene (hERG) channel activation. J. Physiol. (Lond.) 567, 737–755 (2005).

    CAS  Google Scholar 

  56. 56

    Laine, M., Papazian, D. M. & Roux, B. Critical assessment of a proposed model of Shaker. FEBS Lett. 564, 257–263 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Posson, D. J., Ge, P., Miller, C., Bezanilla, F. & Selvin, P. R. Small vertical movement of a K+ channel voltage sensor measured with luminescence energy transfer. Nature 436, 848–851 (2005).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

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

    CAS  Google Scholar 

  60. 60

    Lu, Z., Klem, A. M. & Ramu, Y. Coupling between voltage sensors and activation gate in voltage-gated K+ channels. J. Gen. Physiol. 120, 663–676. (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    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).

    CAS  Google Scholar 

  62. 62

    Spector, P. S., Curran, M. E., Zou, A., Keating, M. T. & Sanguinetti, M. C. Fast inactivation causes rectification of the IKr channel. J. Gen. Physiol. 107, 611–619 (1996).

    CAS  Google Scholar 

  63. 63

    Smith, P. L., Baukrowitz, T. & Yellen, G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379, 833–836 (1996).

    ADS  CAS  Google Scholar 

  64. 64

    Fan, J.-S., Jinag, M., Dun, W., McDonald, T. V. & Tseng, G.-N. Effects of outer mouth mutations on hERG channel function: A comparison with similar mutations in the Shaker channel. Biophys. J. 76, 3128–3140 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    CAS  Google Scholar 

  66. 66

    Kiss, L. & Korn, S. J. Modulation of C-type inactivation by K+ at the potassium channel selectivity filter. Biophys. J. 74, 1840–1849 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    De Bruin, M. L., Pettersson, M., Meyboom, R. H., Hoes, A. W. & Leufkens, H. G. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death. Eur. Heart J. 26, 590–597 (2005).

    CAS  Google Scholar 

  68. 68

    Vitola, J., Vukanovic, J. & Roden, D. M. Cisapride-induced torsades de pointes. J. Cardiovasc. Electrophysiol. 9, 1109–1113 (1998).

    CAS  Google Scholar 

  69. 69

    Recanatini, M., Poluzzi, E., Masetti, M., Cavalli, A. & De Ponti, F. QT prolongation through hERG K+ channel blockade: current knowledge and strategies for the early prediction during drug development. Med. Res. Rev. 25, 133–166 (2005).

    CAS  Google Scholar 

  70. 70

    Kuryshev, Y. A. et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J. Pharmacol. Exp. Ther. 312, 316–323 (2005).

    CAS  Google Scholar 

  71. 71

    Cavalli, A., Poluzzi, E., De Ponti, F. & Recanatini, M. Toward a pharmacophore for drugs inducing the long QT syndrome: Insights from a CoMFA study of HERG K+ channel blockers. J. Med. Chem. 45, 3844–3853 (2002).

    CAS  Google Scholar 

  72. 72

    Ekins, S., Crumb, W. J., Sarazan, R. D., Wikel, J. H. & Wrighton, S. A. Three-dimensional quantitative structure–activity relationship for inhibition of human ether-a-go-go-related gene potassium channel. J. Pharmacol. Exp. Ther. 301, 427–434 (2002).

    CAS  Google Scholar 

  73. 73

    Pearlstein, R. A. et al. Characterization of HERG potassium channel inhibition using CoMSiA 3D QSAR and homology modeling approaches. Bioorg. Med. Chem. Lett. 13, 1829–1835 (2003).

    CAS  Google Scholar 

  74. 74

    Sanguinetti, M. C. & Mitcheson, J. S. Predicting drug-hERG channel interactions that cause acquired long QT syndrome. Trends Pharmacol. Sci. 26, 119–124 (2005).

    CAS  Google Scholar 

  75. 75

    Dubin, A. E. et al. Identifying modulators of hERG channel activity using the PatchXpress planar patch clamp. J. Biomol. Screen. 10, 168–181 (2005).

    CAS  Google Scholar 

  76. 76

    Pearlstein, R., Vaz, R. & Rampe, D. Understanding the structure-activity relationship of the human ether-a-go-go-related gene cardiac K+ channel. A model for bad behavior. J. Med. Chem. 46, 2017–2022 (2003).

    CAS  Google Scholar 

  77. 77

    Rajamani, R., Tounge, B. A., Li, J. & Reynolds, C. H. A two-state homology model of the hERG K+ channel: application to ligand binding. Bioorg. Med. Chem. Lett. 15, 1737–1741 (2005).

    CAS  Google Scholar 

  78. 78

    Osterberg, F. & Aqvist, J. Exploring blocker binding to a homology model of the open hERG K+ channel using docking and molecular dynamics methods. FEBS Lett. 579, 2939–2944 (2005).

    Google Scholar 

  79. 79

    Lastraioli, E. et al. herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res. 64, 606–611 (2004).

    CAS  Google Scholar 

  80. 80

    Kang, J. et al. Discovery of a small molecule activator of the Human Ether-a-go-go-Related Gene (HERG) cardiac K+ channel. Mol. Pharmacol. 67, 827–836 (2005).

    CAS  Google Scholar 

  81. 81

    Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genetics 12, 17–23 (1996).

    Google Scholar 

  82. 82

    Splawski, I., Tristani-Firouzi, M., Lehmann, M. H., Sanguinetti, M. C. & Keating, M. T. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nature Genet. 17, 338–340 (1997).

    CAS  Google Scholar 

  83. 83

    Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).

    CAS  Google Scholar 

  84. 84

    Chen, Q. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293–296 (1998).

    ADS  CAS  Google Scholar 

  85. 85

    Priori, S. G. et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103, 196–200 (2001).

    CAS  Google Scholar 

  86. 86

    Priebe, L. & Beuckelmann, D. J. Simulation study of cellular electric properties in heart failure. Circ. Res. 82, 1206–1223 (1998).

    CAS  Google Scholar 

  87. 87

    Priori, S. G. et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ. Res. 96, 800–807 (2005).

    CAS  Google Scholar 

  88. 88

    Schott, J.-J. et al. Cardiac conduction defects associate with mutations in SCN5A. Nature Genet. 23, 20–21 (1999).

    CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Michael C. Sanguinetti.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and permissions information is available at

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sanguinetti, M., Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).

Download citation

Further reading


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.


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