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  • Review Article
  • Published:

Voltage-gated potassium channels as therapeutic targets

Nature Reviews Drug Discovery volume 8, pages 982–1001 (2009)Cite this article

Key Points

  • Voltage-gated K+ (KV) channels regulate various physiological and pathophysiological processes and offer tremendous opportunities for the development of new drugs for cancer, autoimmune disease and cardiovascular, neurological and metabolic disorders.

  • KV channels can be targeted with classical small molecules, venom peptides or antibodies.

  • KV1.1 channels play an important part in controlling neuronal excitability. KV1.1 channel 'disinactivators', which prevent β-subunit-mediated inactivation, prevent seizures in rodents and have been proposed for the treatment of epilepsy.

  • KV1.3 is overexpressed in activated effector memory T cells and constitutes a promising target for the treatment of autoimmune diseases. Several KV1.3 blockers are in preclinical development for multiple sclerosis.

  • KV1.5 is an attractive target for the treatment of atrial fibrillation, and selective KV1.5 inhibitors are in clinical trials. Vernakalant is currently in the final development stages.

  • KV7.1 underlies the cardiac slow delayed rectifier current, IKs, and several marked antiarrhythmic agents such as azimilide exert their effects at least in part through inhibition of this channel.

  • KV7.2/KV7.3 channels underlie the neuronal M-current and are attractive targets for the treatment of epilepsy, neuropathic pain and possibly neuropsychiatric disorders. The KV7 channel activator retigabine is currently awaiting approval by the US Food and Drug Administration (FDA) as a novel antiepileptic agent.

  • Based on its expression in tumour cell lines and human cancers, KV10.1 seems to be a promising oncology target.

  • KV11.1 plays a crucial part in cardiac repolarization, and channel inhibitors have become infamous as the cause of drug-induced long QT syndrome. The FDA requires that all new drug candidates are tested for potential KV11.1 inhibition. KV11.1 activators are potential antiarrhythmics.

  • The development of KV channel modulators has been difficult and continues to be challenging. However, it is expected that drugs targeting KV channels will reach the clinic within the next 10 years.

Abstract

The human genome encodes 40 voltage-gated K+ channels (KV), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca2+ signalling and cell volume, to driving cellular proliferation and migration. KV channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting KV channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the KV1 subfamily, the KV7 subfamily (also known as KCNQ), KV10.1 (also known as EAG1 and KCNH1) and KV11.1 (also known as HERG and KCNH2) channels.

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Figure 1: Theoretical effects of KV channel inhibitors and activators on pathologically altered neuronal activity.
Figure 2: Structures of unselective KV channel blockers and KV1 family channel modulators.
Figure 3: KV1.5 inhibitors as atrium-selective antiarrhythmic agents.
Figure 4: KV7.1 and KV11.1 are crucial for determining the length of the cardiac action potential.
Figure 5: Structures of KV7.2–KV7.5 channel modulators.
Figure 6: Modulators of KV10.1 and KV11.1.

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References

  1. Harmar, A. J. et al. IUPHAR-DB: the IUPHAR database of G protein-coupled receptors and ion channels. Nucleic Acids Res. 37, D680–D685 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Papazian, D. M., Schwarz, T. L., Tempel, B. L., Jan, Y. N. & Jan, L. Y. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237, 749–753 (1987). A study describing the cloning of the first K V channel.

    Article  CAS  PubMed  Google Scholar 

  3. Long, S. B., Campbell, E. B. & Mackinnon, R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309, 897–903 (2005). The first description of the crystal structure of a voltage-gated mammalian K+ channel with its associated β-subunit.

    Article  CAS  PubMed  Google Scholar 

  4. Long, S. B., Campbell, E. B. & Mackinnon, R. Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309, 903–908 (2005). A companion paper to reference 3 describing the structural basis of the coupling of the voltage sensor with the pore domain.

    Article  CAS  PubMed  Google Scholar 

  5. Swartz, K. J. Towards a structural view of gating in potassium channels. Nature Rev. Neurosci. 5, 905–916 (2004).

    Article  CAS  Google Scholar 

  6. Bezanilla, F. Ion channels: from conductance to structure. Neuron 60, 456–468 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Bezanilla, F. How membrane proteins sense voltage. Nature Rev. Mol. Cell Biol. 9, 323–332 (2008).

    Article  CAS  Google Scholar 

  8. Gutman, G. A. et al. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol. Rev. 57, 473–508 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Wulff, H. & Zhorov, B. S. K+ channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem. Rev. 108, 1744–1773 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chandy, K. G. et al. Potassium channels as targets for specific immunomodulation. Trends Pharmacol. Sci. 25, 280–289 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006). A study describing the cloning of CRAC from patients with a rare form of severe combined immunodeficiency.

    Article  CAS  PubMed  Google Scholar 

  12. Pardo, L. A. et al. Oncogenic potential of EAG K+ channels. EMBO J. 18, 5540–5547 (1999). A study showing the oncogenic potential of K V 10.1 and suggesting it as a potential target for cancer therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, S., Zhang, J. J. & Huang, X. Y. Orai1 and STIM1 are critical for breast tumour cell migration and metastasis. Cancer Cell 15, 124–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Monet, M. et al. Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim. Biophys. Acta 1793, 528–539 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Hegle, A. P., Marble, D. D. & Wilson, G. F. A voltage-driven switch for ion-independent signalling by ether-a-go-go K+ channels. Proc. Natl Acad. Sci. USA 103, 2886–2891 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Feinshreiber, L., Singer-Lahat, D., Ashery, U. & Lotan, I. Voltage-gated potassium channel as a facilitator of exocytosis. Ann. New York Acad. Sci. 1152, 87–92 (2009).

    Article  CAS  Google Scholar 

  17. Kaczmarek, L. K. Non-conducting functions of voltage-gated ion channels. Nature Rev. Neurosci. 7, 761–771 (2006).

    Article  CAS  Google Scholar 

  18. Downie, B. R. et al. Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumours. J. Biol. Chem. 283, 36234–36240 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hebert, S. C., Desir, G., Giebisch, G. & Wang, W. Molecular diversity and regulation of renal potassium channels. Physiol. Rev. 85, 319–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Zhou, B. Y., Ma, W. & Huang, X. Y. Specific antibodies to the external vestibule of voltage-gated potassium channels block current. J. Gen. Physiol. 111, 555–563 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bruhova, I. & Zhorov, B. S. Monte Carlo-energy minimization of correolide in the Kv1.3 channel: possible role of potassium ion in ligand-receptor interactions. BMC Struct. Biol. 7, 5 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sanchez-Chapula, J. A., Navarro-Polanco, R. A., Culberson, C., Chen, J. & Sanguinetti, M. C. Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block. J. Biol. Chem. 277, 23587–23595 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. 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  CAS  PubMed  Google Scholar 

  24. Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006). An excellent review describing the role of K V 11.1 in arrhythmias.

    Article  CAS  PubMed  Google Scholar 

  25. Wuttke, T. V., Seebohm, G., Bail, S., Maljevic, S. & Lerche, H. The new anticonvulsant retigabine favours voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol. Pharmacol. 67, 1009–1017 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Zhang, Z. H., Rhodes, K. J., Childers, W. E., Argentieri, T. M. & Wang, Q. Disinactivation of N-type inactivation of voltage-gated K channels by an erbstatin analogue. J. Biol. Chem. 279, 29226–29230 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Lu, Q. et al. Disruption of Kv1.1 N-type inactivation by novel small molecule inhibitors (disinactivators). Bioorg. Med. Chem. 16, 3067–3075 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Dabrowski, M. A. et al. Ion channel screening technology. CNS Neurol. Disord. Drug Targets 7, 122–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Coleman, S. K., Newcombe, J., Pryke, J. & Dolly, J. O. Subunit composition of Kv1 channels in human CNS. J. Neurochem. 73, 849–858 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Bagetta, G., Nistico, G. & Dolly, J. O. Production of seizures and brain damage in rats by α-dendrotoxin, a selective K+ channel blocker. Neurosci. Lett. 139, 34–40 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Smart, S. L. et al. Deletion of the KV1.1 potassium channel causes epilepsy in mice. Neuron 20, 809–819 (1998). A study showing that K V 1.1 knockout induces epilepsy in mice.

    Article  CAS  PubMed  Google Scholar 

  32. Brew, H. M. et al. Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J. Neurophysiol. 98, 1501–1525 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Zuberi, S. M. et al. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain 122, 817–825 (1999).

    Article  PubMed  Google Scholar 

  34. Schulte, U. et al. The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvβ1. Neuron 49, 697–706 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Hogg, D. S., Ryan, R. & Kozlowski, R. Z. Ion channels and protein-protein interactions: novel approaches to mining validated targets. Drug Discov. Int. 2007, 20–22 (2007).

    Google Scholar 

  36. Lawton, G. Potassium channel modulators and uses thereof. WO 2008149163 (2008).

  37. Nashmi, R. & Fehlings, M. G. Mechanisms of axonal dysfunction after spinal cord injury: with an emphasis on the role of voltage-gated potassium channels. Brain Res. 38, 165–191 (2001).

    CAS  Google Scholar 

  38. Hayes, K. C. The use of 4-aminopyridine (fampridine) in demyelinating disorders. CNS Drug Rev. 10, 295–316 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Karimi-Abdolrezaee, S., Eftekharpour, E. & Fehlings, M. G. Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma. Eur. J. Neurosci. 19, 577–589 (2004).

    Article  PubMed  Google Scholar 

  40. Korenke, A. R., Rivey, M. P. & Allington, D. R. Sustained-release fampridine for symptomatic treatment of multiple sclerosis. Ann. Pharmacother. 42, 1458–1465 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Goodman, A. D. et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 373, 732–738 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Browne, D. L. et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature Genet. 8, 136–140 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Glaudemans, B. et al. A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. J. Clin. Invest. 19, 936–942 (2009). A study linking K V 1.1 mutations to human hypomagnesaemia.

    Article  CAS  Google Scholar 

  44. DeCoursey, T. E., Chandy, K. G., Gupta, S. & Cahalan, M. D. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature 307, 465–468 (1984).

    Article  CAS  PubMed  Google Scholar 

  45. Matteson, D. R. & Deutsch, C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature 307, 468–471 (1984).

    Article  CAS  PubMed  Google Scholar 

  46. Lin, C. S. et al. Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J. Exp. Med. 177, 637–645 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Koo, G. C. et al. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J. Immunol. 158, 5120–5128 (1997).

    CAS  PubMed  Google Scholar 

  48. Zhang, S. L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Feske, S. Calcium signalling in lymphocyte activation and disease. Nature Rev. Immunol. 7, 690–702 (2007).

    Article  CAS  Google Scholar 

  51. Wulff, H., Beeton, C. & Chandy, K. G. Potassium channels as therapeutic targets for autoimmune disorders. Curr. Opin. Drug Discov. Devel. 6, 640–647 (2003).

    CAS  PubMed  Google Scholar 

  52. Liu, Q.-H. et al. Modulation of Kv channel expression and function by TCR and co-stimulatory signals during peripheral CD4+ lymphocyte differentiation. J. Exp. Med. 196, 897–909 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Beeton, C. & Chandy, K. G. Potassium channels, memory T cells and multiple sclerosis. Neuroscientist 11, 550–562 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Wulff, H. et al. The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS. J. Clin. Invest. 111, 1703–1713 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Beeton, C. et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc. Natl Acad. Sci. USA 103, 17414–17419 (2006). A study validating K V 1.3 as a target for the treatment of multiple sclerosis, rheumatoid arthritis and type 1 diabetes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Matheu, M. P. et al. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity 29, 602–614 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wulff, H. & Pennington, M. Targeting effector memory T-cells with Kv1.3 blockers. Curr. Opin. Drug Discov. Devel. 10, 438–445 (2007).

    CAS  PubMed  Google Scholar 

  58. Markovic-Plese, S., Cortese, I., Wandinger, K. P., McFarland, H. F. & Martin, R. CD4+CD28− co-stimulation-independent T cells in multiple sclerosis. J. Clin. Invest. 108, 1185–1194 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Viglietta, V., Kent, S. C., Orban, T. & Hafler, D. A. GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. J. Clin. Invest. 109, 895–903 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kivisakk, P. et al. Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann. Neurol. 55, 627–638 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Rus, H. et al. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proc. Natl Acad. Sci. USA 102, 11094–11099 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Beeton, C. et al. Selective blockade of T lymphocyte K+ channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Proc. Natl Acad. Sci. USA 98, 13942–13947 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Beeton, C. et al. Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases. Mol. Pharmacol. 67, 1369–1381 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Sullivan, J. K. et al. Fusion proteins of toxin peptides with linkers and IgG and their use as therapeutic agents. WO 2006116156 (2006).

  65. Schmitz, A. et al. Design of PAP-1, a selective small molecule Kv1.3 blocker, for the suppression of effector memory T cells in autoimmune diseases. Mol. Pharmacol. 68, 1254–1270 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Baell, J. B. et al. Khellinone derivatives as blockers of the voltage-gated potassium channel Kv1.3: synthesis and immunosuppressive activity. J. Med. Chem. 47, 2326–2336 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Harvey, A. J., Baell, J. B., Toovey, N., Homerick, D. & Wulff, H. A new class of blockers of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-position of khellinone. J. Med. Chem. 49, 1433–1441 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Azam, P., Sankaranarayanan, A., Homerick, D., Griffey, S. & Wulff, H. Targeting effector memory T cells with the small molecule Kv1.3 blocker PAP-1 suppresses allergic contact dermatitis. J. Invest. Dermatol. 127, 1419–1429 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ren, Y. R. et al. Clofazimine inhibits human Kv1.3 potassium channel by perturbing calcium oscillation in T lymphocytes. PLoS ONE 3, e4009 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu, J. et al. The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight. Hum. Mol. Gen. 12, 551–559 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, J. et al. The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity. Proc. Natl Acad. Sci. USA 101, 3112–3117 (2004). A study suggesting that K V 1.3 is involved in determining peripheral insulin sensitivity and proposing K V 1.3 as a target for the treatment of obesity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tucker, K., Overton, J. M. & Fadool, D. A. Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice. Int. J. Obes. 32, 1222–1232 (2008).

    Article  CAS  Google Scholar 

  73. Lucero, M. T. & Pappone, P. A. Voltage-gated potassium channels in brown fat cells. J. Gen. Physiol. 93, 451–472 (1989).

    Article  CAS  PubMed  Google Scholar 

  74. Pappone, P. A. & Ortiz-Miranda, S. I. Blockers of voltage-gated K channels inhibit proliferation of cultured brown fat cells. Am. J. Physiol. 264, C1014–C1019 (1993).

    Article  CAS  PubMed  Google Scholar 

  75. Ramirez-Ponce, M. P., Mateos, J. C., Carrion, N. & Bellido, J. A. Voltage-dependent potassium channels in white adipocytes. Biochem. Biophys. Res. Commun. 223, 250–256 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Ramirez-Ponce, M. P., Mateos, J. C. & Bellido, J. A. Human adipose cells have voltage-dependent potassium currents. J. Membr. Biol. 196, 129–134 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Tamkun, M. M. et al. Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle. FASEB J. 5, 331–337 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Overturf, K. E. et al. Cloning and characterization of a Kv1.5 delayed rectifier K+ channel from vascular and visceral smooth muscles. Am. J. Physiol. 267, C1231–C1238 (1994).

    Article  CAS  PubMed  Google Scholar 

  79. Archer, S. L. et al. Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J. Clin. Invest. 101, 2319–2330 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wang, Z., Fermini, B. & Nattel, S. Sustained depolarization-induced outward current in human atrial myocytes: evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents. Cir. Res. 73, 1061–1076 (1993).

    Article  CAS  Google Scholar 

  81. Fedida, D. et al. Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current. Cir. Res. 73, 210–216 (1993). Reference 80 and reference 81 demonstrated that K V 1.5 underlies the atrium-specific ultra-rapid delayed rectifier current.

    Article  CAS  Google Scholar 

  82. Wettwer, E. et al. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation 110, 2299–2306 (2004).

    Article  PubMed  Google Scholar 

  83. Brendel, J. & Peukert, S. Blockers of the Kv1.5 channel for the treatment of atrial arrhythmias. Curr. Med. Chem. 1, 273–287 (2003).

    CAS  Google Scholar 

  84. Tamargo, J., Caballero, R., Gomez, R. & Delpon, E. IKur/Kv1.5 channel blockers for the treatment of atrial fibrillation. Expert Opin. Investig. Drugs 18, 399–416 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Ford, J. W. & Milnes, J. T. New drugs targeting the cardiac ultra-rapid delayed-rectifier current (I Kur): rationale, pharmacology and evidence for potential therapeutic value. J. Cardiovas. Pharmacol. 52, 105–120 (2008).

    Article  CAS  Google Scholar 

  86. Gross, M. F. et al. Aryl sulphonamido indane inhibitors of the Kv1.5 ion channel. Bioorg. Med. Chem. Lett. 17, 2849–2853 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lloyd, J. et al. Benzopyran sulphonamides as KV1.5 potassium channel blockers. Bioorg. Med. Chem. Lett. 17, 3271–3275 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Knobloch, K. et al. Electrophysiological and antiarrhythmic effects of the novel IKur channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the IKr blockers dofetilide, azimilide, d, l-sotalol and ibutilide. Naunyn-Schmiedeberg. Arch. Pharmacol. 366, 482–487 (2002).

    Article  CAS  Google Scholar 

  89. Wirth, K. J. et al. Atrial effects of the novel K+-channel-blocker AVE0118 in anesthetized pigs. Cardiovasc. Res. 60, 298–306 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Gogelein, H. et al. Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels. Naunyn-Schmiedeberg. Arch. Pharmacol. 370, 183–192 (2004).

    Article  CAS  Google Scholar 

  91. Trotter, B. W. et al. Design and synthesis of novel isoquinoline-3-nitriles as orally bioavailable Kv1.5 antagonists for the treatment of atrial fibrillation. J. Med. Chem. 49, 6954–6957 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Lagrutta, A., Wang, J., Fermini, B. & Salata, J. J. Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current. J. Pharmacol. Exp. Ther. 317, 1054–1063 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Regan, C. P. et al. Atrial antifibrillatory effects of structurally distinct IKur blockers 3-[(dimethylamino)methyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one and 2-phenyl-1, 1-dipyridin-3-yl-2-pyrrolidin-1-yl-ethanol in dogs with underlying heart failure. J. Pharmacol. Exp. Ther. 324, 322–330 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Fluxe, A. et al. Discovery and synthesis of tetrahydroindolone-derived carbamates as Kv1.5 blockers. Bioorg. Med. Chem. Lett. 16, 5855–5858 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Wu, S. et al. Discovery and in vitro/in vivo studies of tetrazole derivatives as Kv1.5 blockers. Bioorg. Med. Chem. Lett. 16, 6213–6218 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Eldstrom, J. et al. The molecular basis of high-affinity binding of the antiarrhythmic compound vernakalant (RSD1235) to Kv1.5 channels. Mol. Pharmacol. 72, 1522–1534 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Fedida, D. Vernakalant (RSD1235): a novel, atrial-selective antifibrillatory agent. Expert. Opin. Investig. Drugs 16, 519–532 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Naccarelli, G. V. et al. Vernakalant: pharmacology electrophysiology, safety and efficacy. Drugs Today 44, 325–329 (2008).

    Article  CAS  Google Scholar 

  99. Janusz, J. M. et al. Kv1.5 potassium channel inhibitors. WO 2007149873 (2009).

  100. Wirth, K. J. et al. In vitro and in vivo effects of the atrial selective antiarrhythmic compound AVE1231. J. Cardiovasc. Pharmacol. 49, 197–206 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Ehrlich, J. R. et al. Characterization of human cardiac Kv1.5 inhibition by the novel atrial-selective antiarrhythmic compound AVE1231. J. Cardiovasc. Pharmacol. 51, 380–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Rivard, L. et al. Electrophysiological and atrial antiarrhythmic effects of a novel IKur/Kv1.5 blocker in dogs. Heart Rhythm 2, S180 (2005).

    Article  Google Scholar 

  103. Shiroshita-Takeshita, A., Maltais, C., Ford, J., Madge, D. & Nattel, S. Electrophysiological and atrial antiarrhythmic effects of a novel IKUR/Kv1.5 blocker in dogs with atrial tachycardia remodeling. Heart Rhythm 3, S183–S183 (2005).

    Article  Google Scholar 

  104. Salinas, M., Duprat, F., Heurteaux, C., Hugnot, J. P. & Lazdunski, M. New modulatory alpha subunits for mammalian Shab K+ channels. J. Biol. Chem. 272, 24371–24379 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. Ottschytsch, N., Raes, A., Van Hoorick, D. & Snyders, D. J. Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome. Proc. Natl Acad. Sci. USA 99, 7986–7991 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Jacobson, D. A. et al. Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion. Cell Metabol. 6, 229–235 (2007).

    Article  CAS  Google Scholar 

  107. Dai, X. Q., Kolic, J., Marchi, P., Sipione, S. & Macdonald, P. E. SUMOylation regulates Kv2.1 and modulates pancreatic β-cell excitability. J. Cell Sci. 122, 775–779 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Leung, Y. M., Kwan, E. P., Ng, B., Kang, Y. & Gaisano, H. Y. SNAREing voltage-gated K+ and ATP-sensitive K+ channels: tuning beta-cell excitability with syntaxin-1A and other exocytotic proteins. Endocr. Rev. 28, 653–663 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Zhuang, G. Q. et al. SNAP-25(1–180) enhances insulin secretion by blocking Kv2.1 channels in rat pancreatic islet beta-cells. Biochem. Biophys. Res. Commun. 379, 812–816 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Veh, R. W. et al. Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur. J. Neurosci. 7, 2189–2205 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Abbott, G. W. et al. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104, 217–231 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Angulo, E. et al. Upregulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease. J. Neurochem. 91, 547–557 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Pannaccione, A. et al. Upregulation and increased activity of KV3.4 channels and their accessory subunit MinK-related peptide 2 induced by amyloid peptide are involved in apoptotic neuronal death. Mol. Pharmacol. 72, 665–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Yu, H. B., Li, Z. B., Zhang, H. X. & Wang, X. L. Role of potassium channels in Aβ (1–40)-activated apoptotic pathway in cultured cortical neurons. J. Neurosci. Res. 84, 1475–1484 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Ogita, K. et al. In vivo treatment with the K+ channel blocker 4-aminopyridine protects against kainate-induced neuronal cell death through activation of NMDA receptors in murine hippocampus. Neuropharmacology 48, 810–821 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Birnbaum, S. G. et al. Structure and function of Kv4-family transient potassium channels. Physiol. Rev. 84, 803–833 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Dixon, J. E. et al. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ. Res. 79, 659–668 (1996).

    Article  CAS  PubMed  Google Scholar 

  118. Hohnloser, S. H., Dorian, P., Straub, M., Beckmann, K. & Kowey, P. Safety and efficacy of intravenously administered tedisamil for rapid conversion of recent-onset atrial fibrillation or atrial flutter. J. Am. Col. Cardiol. 44, 99–104 (2004).

    Article  CAS  Google Scholar 

  119. Hu, H. J. et al. The Kv4.2 potassium channel subunit is required for pain plasticity. Neuron 50, 89–100 (2006). A study showing that K V 4.2 channels are important for pain plasticity.

    Article  CAS  PubMed  Google Scholar 

  120. Jespersen, T., Grunnet, M. & Olesen, S. P. The KCNQ1 potassium channel: from gene to physiological function. Physiology 20, 408–416 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Brown, D. A. & Passmore, G. M. Neural KCNQ (Kv7) channels. Br. J. Pharmacol. 156, 1185–1195 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sanguinetti, M. C. et al. Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature 384, 80–83 (1996). A study showing that K V 7.1 and KCNE1 underlie I Ks.

    Article  CAS  PubMed  Google Scholar 

  123. Peroz, D. et al. Kv7.1 (KCNQ1) properties and channelopathies. J. Physiol. (Lond). 586, 1785–1789 (2008).

    Article  CAS  Google Scholar 

  124. Duggal, P. et al. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation 97, 142–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Bellocq, C. et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109, 2394–2397 (2004).

    Article  PubMed  Google Scholar 

  126. Chen, Y. H. et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 299, 251–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Lai, L., Su, M., Tseng, Y. & Lien, W. Sensitivity of the slow component of the delayed rectifier potassium current (IKs) to potassium channel blockers: implications for clinical reverse use-dependent effects. J. Biomed. Sci. 6, 251–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  128. Nattel, S., Liu, L. & St-Georges, D. Effects of the novel antiarrhythmic agent azimilide on experimental atrial fibrillation and atrial electrophysiologic properties. Cardiovasc. Res. 37, 627–635 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Gerlach, U. Blockers of the slowly delayed rectifier potassium IKs channel: potential antiarrhythmic agents. Curr. Med. Chem. 1, 243–252 (2003).

    CAS  Google Scholar 

  130. Pritchett, E. L. & Marcello, S. R. Azimilide for atrial fibrillation: clinical trial results and implications. Card. Electrophysiol. Rev. 7, 215–219 (2003).

    Article  PubMed  Google Scholar 

  131. Pritchett, E. L. et al. Antiarrhythmic efficacy of azimilide in patients with atrial fibrillation. Maintenance of sinus rhythm after conversion to sinus rhythm. Am. Heart J. 151, 1043–1049 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Viswanathan, M. N. & Page, R. L. Pharmacological therapy for atrial fibrillation: current options and new agents. Expert Opin. Investig. Drugs 18, 417–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Gogelein, H., Bruggemann, A., Gerlach, U., Brendel, J. & Busch, A. E. Inhibition of IKs channels by HMR 1556. Naunyn-Schmiedeberg. Arch. Pharmacol. 362, 480–488 (2000).

    Article  CAS  Google Scholar 

  134. Thomas, G. P., Gerlach, U. & Antzelevitch, C. HMR 1556, a potent and selective blocker of slowly activating delayed rectifier potassium current. J. Cardiovasc. Pharmacol. 41, 140–147 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. So, P. P., Hu, X. D., Backx, P. H., Puglisi, J. L. & Dorian, P. Blockade of IKs by HMR 1556 increases the reverse rate-dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles. Br. J. Pharmacol. 148, 255–263 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Bauer, A. et al. The new selective IKs-blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation. Basic Res. Cardiol. 100, 270–278 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Nakashima, H., Gerlach, U., Schmidt, D. & Nattel, S. In vivo electrophysiological effects of a selective slow delayed-rectifier potassium channel blocker in anesthetized dogs: potential insights into class III actions. Cardiovasc. Res. 61, 705–714 (2004).

    Article  CAS  PubMed  Google Scholar 

  138. Lynch, J. J. Jr et al. Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, IKs, in canine models of malignant ischemic ventricular arrhythmia. Circulation 100, 1917–1922 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Busch, A. E. et al. Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes. Mol. Pharmacol. 46, 750–753 (1994).

    CAS  PubMed  Google Scholar 

  140. Magyar, J. et al. L-364, 373 fails to activate the slow delayed rectifier K+ current in canine ventricular cardiomyocytes. Naunyn-Schmiedeberg. Arch. Pharmacol. 373, 85–89 (2006).

    Article  CAS  Google Scholar 

  141. Salata, J. J. et al. A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol. Pharmacol. 54, 220–230 (1998).

    Article  CAS  PubMed  Google Scholar 

  142. Schroeder, B. C. et al. A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403, 196–199 (2000).

    Article  CAS  PubMed  Google Scholar 

  143. Bleich, M. & Warth, R. The very small-conductance K+ channel KvLQT1 and epithelial function. Pflugers Arch. 440, 202–206 (2000).

    CAS  PubMed  Google Scholar 

  144. Mall, M. et al. Role of KVLQT1 in cyclic adenosine monophosphate-mediated Cl- secretion in human airway epithelia. Am. J. Respir. Cell. Mol. Biol. 23, 283–289 (2000).

    Article  CAS  PubMed  Google Scholar 

  145. Vallon, V. et al. KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc. Natl Acad. Sci. USA 102, 17864–17869 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Yasuda, K. et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature Genet. 40, 1092–1097 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Boini, K. M. et al. Enhanced insulin sensitivity of gene targeted mice lacking functional KCNQ1. Am. J. Physiol. 296, R1695–R1701 (2009).

    CAS  Google Scholar 

  148. Marrion, N. V. Control of M-current. Ann. Rev. Physiol. 59, 483–504 (1997).

    Article  CAS  Google Scholar 

  149. Biervert, C. et al. A potassium channel mutation in neonatal human epilepsy. Science 279, 403–406 (1998). A study demonstrating that K V 7.2 mutations cause neonatal epilepsy.

    Article  CAS  PubMed  Google Scholar 

  150. Wang, H. S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893 (1998). A study showing that K V 7.2/K V 7.3 heteromultimers underlie the neuronal M-current.

    Article  CAS  PubMed  Google Scholar 

  151. Schroeder, B. C., Hechenberger, M., Weinreich, F., Kubisch, C. & Jentsch, T. J. KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J. Biol. Chem. 275, 24089–24095 (2000).

    Article  CAS  PubMed  Google Scholar 

  152. Kubisch, C. et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96, 437–446 (1999).

    Article  CAS  PubMed  Google Scholar 

  153. Van Eyken, E. et al. KCNQ4: a gene for age-related hearing impairment? Hum. Mutat. 27, 1007–1016 (2006).

    Article  CAS  PubMed  Google Scholar 

  154. Fontana, D. J., Inouye, G. T. & Johnson, R. M. Linopirdine (DuP 996) improves performance in several tests of learning and memory by modulation of cholinergic neurotransmission. Pharmacol. Biochem. Behav. 49, 1075–1082 (1994).

    Article  CAS  PubMed  Google Scholar 

  155. Borjesson, A., Karlsson, T., Adolfsson, R., Ronnlund, M. & Nilsson, L. Linopirdine (DUP 996): cholinergic treatment of older adults using successive and non-successive tests. Neuropsychobiology 40, 78–85 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Zaczek, R. et al. Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine. J. Pharmacol. Exp. Ther. 285, 724–730 (1998).

    CAS  PubMed  Google Scholar 

  157. Wickenden, A. D., Yu, W., Zou, A., Jegla, T. & Wagoner, P. K. Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol. Pharmacol. 58, 591–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Rundfeldt, C. & Netzer, R. The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits. Neurosci. Lett. 282, 73–76 (2000).

    Article  CAS  PubMed  Google Scholar 

  159. Main, M. J. et al. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol. Pharmacol. 58, 253–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Blackburn-Munro, G., Dalby-Brown, W., Mirza, N. R., Mikkelsen, J. D. & Blackburn-Munro, R. E. Retigabine: chemical synthesis to clinical application. CNS Drug Rev. 11, 1–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  161. Plosker, G. L. & Scott, L. J. Retigabine: in partial seizures. CNS Drugs 20, 601–610 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Porter, R. J., Nohria, V. & Rundfeldt, C. Retigabine. Neurotherapeutics 4, 149–154 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. French, J. & Mansbach, H. 1200 mg/day retigabine as adjunctive therapy in adults with refractory partial-onset seizures. American Epilepsy Society Meeting (Seattle, Washington, 2008).

    Google Scholar 

  164. Brodie, M. & Mansbach, H. Retigabine 600 or 900 mg/day as adjunctive therapy in adults with partial-onset seizures. American Epilepsy Society Meeting (Seattle, Washington, 2008).

    Google Scholar 

  165. Wickenden, A. D. et al. N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator. Mol. Pharmacol. 73, 977–986 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Roeloffs, R. et al. In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7.2/Kv7.3) activator in rodent anticonvulsant models. J. Pharmacol. Exp. Ther. 326, 818–828 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Rigdon, G. C. Results of phase 1 program for ICA-105665, drug candidate for the treatment of epilepsy and neuropathic pain. Antiepileptic Drug Trials X Conference (Coral Gables, Florida, 2009).

    Google Scholar 

  168. Passmore, G. M. et al. KCNQ/M currents in sensory neurons: significance for pain therapy. J. Neurosci. 23, 7227–7236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Gerlach, A., Stoehr, S. J. & Rigdon, G. C. Sub-type selective activation of KCNQ2/3 channels modulates the excitability of nociceptive dorsal root ganglion neurons. Society of Neuroscience Meeting (San Diego, California, 2007).

    Google Scholar 

  170. Munro, G. & Dalby-Brown, W. Kv7 (KCNQ) channel modulators and neuropathic pain. J. Med. Chem. 50, 2576–2582 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Wickenden, A. D. & McNaughton-Smith, G. Kv7 channels as targets for the treatment of pain. Curr. Pharm. Des. 15, 1773–1798 (2009).

    Article  CAS  PubMed  Google Scholar 

  172. Ilyin, V., Carlin, K. P., Hodges, D. D., Robeldo, S. & Woodward, R. M. Flupirtine: A positive modulator of heteromeric KCNQ2/Q3 channels. Society of Neuroscience Meeting (Orlando, Florida, 2002).

    Google Scholar 

  173. Blackburn-Munro, G. & Jensen, B. S. The anticonvulsant retigabine attenuates nociceptive behaviours in rat models of persistent and neuropathic pain. Eur. J. Pharmacol. 460, 109–116 (2003).

    Article  CAS  PubMed  Google Scholar 

  174. Hirano, K. et al. Kv7.2–7.5 voltage-gated potassium channel (KCNQ2–5) opener, retigabine, reduces capsaicin-induced visceral pain in mice. Neurosci. Lett. 413, 159–162 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Leventhal, L. et al. Activity of a KCNQ2/3 opener in rat models of inflammatory pain. Society of Neuroscience Meeting (San Diego, California, 2007).

    Google Scholar 

  176. Mark, L. et al. Activity of a KCNQ2/3 opener in rat models of neuropathic pain. Society of Neuroscience Meeting (San Diego, California, 2007).

    Google Scholar 

  177. Wickenden, A. D., Roeloffs, R., McNaughton-Smith, G. & Rigdon, G. C. KCNQ potassium channels: drug targets for the treatment of epilepsy and pain. Expert Opin. Ther. Pat. 14, 1–13 (2004).

    Article  Google Scholar 

  178. Wua, Y. J. & Dworetzky, S. I. Recent developments on KCNQ potassium channel openers. Curr. Med. Chem. 12, 453–460 (2005).

    Article  PubMed  Google Scholar 

  179. Dworetzky, S. I., Gribkoff, V. K., Kinney, G. G. & Hewawasam, P. 3-Fluoro-2-oxindole modulators of KCNQ potassium channels and use thereof in treating migraine and mechanistically related disease. US 6855829 (2005).

  180. Peretz, A. et al. Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties. Mol. Pharmacol. 67, 1053–1066 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Peretz, A. et al. A tale of switched functions: from cyclooxygenase inhibition to M-channel modulation in new diphenylamine derivatives. PLoS ONE 2, e1332 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hansen, H. H. et al. Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS. J. Physiol. (Lond). 586, 1823–1832 (2008).

    Article  CAS  Google Scholar 

  183. Redrobe, J. P. & Nielsen, A. N. Effects of neuronal Kv7 potassium channel activators on hyperactivity in a rodent model of mania. Behav. Brain Res. 198, 481–485 (2009).

    Article  CAS  PubMed  Google Scholar 

  184. Sotty, F. et al. Antipsychotic-like effect of retigabine [N-(2-amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ potassium channel opener, via modulation of mesolimbic dopaminergic neurotransmission. J. Pharmacol. Exp. Ther. 328, 951–962 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Husum Bak-Jensen, H. et al. Use of KCNQ-openers for treating or reducing the symptoms of schizophrenia. WO 2007090409 (2007).

  186. Bak-Jensen, H. H. & Hertel, K. P. Use of KCNQ potassium channel openers for reducing symptoms or treating disorders or conditions wherein the dopaminergic system is disrupted. WO 2009015667 (2009).

  187. Argentieri, T. M. & Sheldon, J. H. Methods of selecting compounds for modulation of bladder function. US 7160684 (2007).

  188. Haemmerlein, B. et al. Overexpression of Eag1 potassium channels in clinical tumours. Mol. Can. 5, 41 (2006).

    Article  CAS  Google Scholar 

  189. Occhiodoro, T. et al. Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett. 434, 177–182 (1998).

    Article  CAS  PubMed  Google Scholar 

  190. Martin, S. et al. Eag1 potassium channel immunohistochemistry in the CNS of adult rat and selected regions of human brain. Neurosci. 155, 833–844 (2008).

    Article  CAS  Google Scholar 

  191. Bijlenga, P. et al. An ether-a-go-go K+ current, ih-eag, contributes to the hyperpolarization of human fusion-competent myoblasts. J. Physiol. (Lond.) 512, 317–323 (1998).

    Article  CAS  Google Scholar 

  192. Ousingsawat, J. et al. Expression of voltage-gated potassium channels in human and mouse colonic carcinoma. Clin. Cancer Res. 13, 824–831 (2007).

    Article  CAS  PubMed  Google Scholar 

  193. Ding, X. W., Yan, J. J., An, P., Lu, P. & Luo, H. S. Aberrant expression of ether a go-go potassium channel in colorectal cancer patients and cell lines. World J. Gastroenterol. 13, 1257–1261 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ding, X. W., Luo, H. S., Jin, X., Yan, J. J. & Ai, Y. W. Aberrant expression of Eag1 potassium channels in gastric cancer patients and cell lines. Med. Oncol. 24, 345–350 (2007).

    Article  CAS  PubMed  Google Scholar 

  195. Mello de Queiroz, F., Suarez-Kurtz, G., Stuhmer, W. & Pardo, L. A. Ether a go-go potassium channel expression in soft tissue sarcoma patients. Mol. Cancer 5, 42 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Diaz, L. et al. Estrogens and human papilloma virus oncogenes regulate human ether-a-go-go-1 potassium channel expression. Cancer Res. 69, 3300–3307 (2009).

    Article  CAS  PubMed  Google Scholar 

  197. Weber, C. et al. Silencing the activity and proliferative properties of the human Eag1 potassium channel by RNAi. J. Biol. Chem. 281, 13033–13037 (2006).

    Article  CAS  Google Scholar 

  198. Toral, C. et al. Effect of extracellular matrix on adhesion, viability, actin cytoskeleton and K+ currents of cells expressing human ether a go-go channels. Life Sci. 81, 255–265 (2007).

    Article  CAS  PubMed  Google Scholar 

  199. Gavrilova-Ruch, O. et al. Effects of imipramine on ion channels and proliferation of IGR1 melanoma cells. J. Membr. Biol. 188, 137–149 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Ouadid-Ahidouch, H. et al. Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether-a-gogo K+ channel. Recept. Channels 7, 345–356 (2001).

    CAS  PubMed  Google Scholar 

  201. Roy, J., Vantol, B., Cowley, E. A., Blay, J. & Linsdell, P. Pharmacological separation of hEAG and hERG K+ channel function in the human mammary carcinoma cell line MCF-7. Oncol. Rep. 19, 1511–1516 (2008).

    CAS  PubMed  Google Scholar 

  202. Hancox, J. C., McPate, M. J., El Harchi, A. & Zhang, Y. H. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacol. Ther. 119, 118–132 (2008).

    Article  CAS  PubMed  Google Scholar 

  203. Gomez-Varela, D. et al. Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide. FEBS Lett. 580, 5059–5066 (2006).

    Article  CAS  PubMed  Google Scholar 

  204. Gomez-Varela, D. et al. Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumour activity. Cancer Res. 67, 7343–7349 (2007).

    Article  CAS  PubMed  Google Scholar 

  205. Grunnet, M., Hansen, R. S. & Olesen, S. P. hERG1 channel activators: a new anti-arrhythmic principle. Prog. Biophys. Mol. Biol. 98, 347–362 (2008).

    Article  CAS  PubMed  Google Scholar 

  206. 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).

    Article  CAS  PubMed  Google Scholar 

  207. Kamath, G. S. & Mittal, S. The role of antiarrhythmic drug therapy for the prevention of sudden cardiac death. Prog. Cardiovasc. Dis. 50, 439–448 (2008).

    Article  CAS  PubMed  Google Scholar 

  208. Hansen, R. S. et al. Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643). Mol Pharmacol. 69, 266–277 (2006).

    CAS  PubMed  Google Scholar 

  209. Hansen, R. S. et al. Biophysical characterization of the new human ether-a-go-go-related gene channel opener NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea]. Mol. Pharmacol. 70, 1319–1329 (2006).

    Article  CAS  PubMed  Google Scholar 

  210. 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).

    Article  CAS  PubMed  Google Scholar 

  211. Zhou, J. et al. Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity. Mol. Pharmacol. 68, 876–884 (2005).

    CAS  PubMed  Google Scholar 

  212. Su, Z. et al. Electrophysiologic characterization of a novel hERG channel activator. Biochem. Pharmacol. 77, 1383–1390 (2009).

    Article  CAS  PubMed  Google Scholar 

  213. Zeng, H. et al. Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator. J. Pharmacol. Exp. Ther. 319, 957–962 (2006).

    Article  CAS  PubMed  Google Scholar 

  214. Gussak, I. & Antzelevitch, C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J. Electrocardiol. 33, 299–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  215. Anderson, C. L. et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation 113, 365–373 (2006).

    Article  CAS  PubMed  Google Scholar 

  216. Zhou, Z., Gong, Q. & January, C. T. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. J. Biol. Chem. 274, 31123–31126 (1999).

    Article  CAS  PubMed  Google Scholar 

  217. Dennis, A., Wang, L., Wan, X. & Ficker, E. hERG channel trafficking: novel targets in drug-induced long QT syndrome. Biochem. Soc. Trans. 35, 1060–1063 (2007).

    Article  CAS  PubMed  Google Scholar 

  218. Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009). A study showing that overexpression of a primate-specific splice variant of K V 11.1 is associated with an increased risk of schizophrenia.

    Article  CAS  PubMed  Google Scholar 

  219. Arcangeli, A. Expression and role of hERG channels in cancer cells. Novartis Found. Symp. 266, 225–232 (2005).

    CAS  PubMed  Google Scholar 

  220. Bianchi, L. et al. HERG encodes a K+ current highly conserved in tumours of different histogenesis — a selective advantage for cancer cells? Cancer Res. 58, 815–822 (1998).

    CAS  PubMed  Google Scholar 

  221. Cherubini, A. et al. HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium. Br. J. Cancer 83, 1722–1729 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Pillozzi, S. et al. HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic haemopoietic progenitors. Leukemia 16, 1791–1798 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  224. Masi, A. et al. hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines. Br. J. Cancer 93, 781–792 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Lastraioli, E. et al. hERG1 channels in human esophagus: evidence for their aberrant expression in the malignant progression of Barrett's esophagus. J. Cell. Physiol. 209, 398–404 (2006).

    Article  CAS  PubMed  Google Scholar 

  226. Pillozzi, S. et al. VEGFR-1 (FLT-1), beta1 integrin, and hERG K+ channel form a macromolecular signalling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 110, 1238–1250 (2007).

    Article  CAS  PubMed  Google Scholar 

  227. Crociani, O. et al. Cell cycle-dependent expression of HERG1 and HERG1B isoforms in tumour cells. J. Biol. Chem. 278, 2947–2955 (2003).

    Article  CAS  PubMed  Google Scholar 

  228. Guasti, L. et al. Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumour cells. Mol. Cell. Biol. 28, 5043–5060 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ganapathi, S. B., Kester, M. & Elmslie, K. S. State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy. Am. J. Physiol. Cell. Physiol. 296, C701–C710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Wang, X. et al. Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway. FASEB J. 20, 1531–1533 (2006).

    Article  CAS  PubMed  Google Scholar 

  231. Watanabe, H. et al. Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J. Neurochem. 75, 28–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  232. Peters, H. C., Hu, H., Pongs, O., Storm, J. F. & Isbrandt, D. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behaviour. Nature Neurosci. 8, 51–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  233. Nerbonne, J. M. Studying cardiac arrhythmias in the mouse — a reasonable model for probing mechanisms? Trends Cardiovasc. Med. 14, 83–93 (2004).

    Article  PubMed  Google Scholar 

  234. Tytgat, J. et al. A unified nomenclature for short-chain peptides isolated from scorpion venoms: alpha-KTx molecular subfamilies. Trends Pharmacol. Sci. 20, 444–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  235. MacKinnon, R. & Miller, C. Mutant potassium channels with altered binding of charybdotoxin, a pore-blocking peptide inhibitor. Science 245, 1382–1385 (1989).

    Article  CAS  PubMed  Google Scholar 

  236. MacKinnon, R., Heginbotham, L. & Abramson, T. Mapping the receptor site for charybdotoxin, a pore-blocking potassium channel inhibitor. Neuron 5, 767–771 (1990).

    Article  CAS  PubMed  Google Scholar 

  237. Chandy, K. G. et al. Potassium channels in T lymphocytes: toxins to therapeutic immunosuppressants. Toxicon 39, 1269–1276 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  239. Swartz, K. J. Tarantula toxins interacting with voltage sensors in potassium channels. Toxicon 49, 213–230 (2007).

    Article  CAS  PubMed  Google Scholar 

  240. Phillips, L. R. et al. Voltage-sensor activation with a tarantula toxin as cargo. Nature 436, 857–860 (2005).

    Article  CAS  PubMed  Google Scholar 

  241. Lee, S. Y. & MacKinnon, R. A membrane-access mechanism of ion channel inhibition by voltage sensor toxins from spider venom. Nature 430, 232–235 (2004).

    Article  CAS  PubMed  Google Scholar 

  242. Hamill, O. P., Marty, A., Neher, E., Sakmann, B. & Sigworth, F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391, 85–100 (1981).

    Article  CAS  PubMed  Google Scholar 

  243. Helms, L. M. et al. Margatoxin binds to a homomultimer of KV1.3 channels in Jurkat cells. Comparison with KV1.3 expressed in CHO cells. Biochemistry 36, 3737–3744 (1997).

    Article  CAS  PubMed  Google Scholar 

  244. Felix, J. P. et al. Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3. Biochemistry 38, 4922–4930 (1999).

    Article  CAS  PubMed  Google Scholar 

  245. Finlayson, K., Turnbull, L., January, C. T., Sharkey, J. & Kelly, J. S. [3H]Dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. Eur. J. Pharmacol. 430, 147–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  246. Hanson, D. C. et al. UK-78282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation. Br. J. Pharmacol. 126, 1707–1716 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Wang, K. et al. Validation of an atomic absorption rubidium ion efflux assay for KCNQ/M-channels using the Ion Channel Reader 8000. Assay Drug Dev. Technol. 2, 525–534 (2004).

    Article  CAS  PubMed  Google Scholar 

  248. Weaver, C. D., Harden, D., Dworetzky, S. I., Robertson, B. & Knox, R. J. A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells. J. Biomol. Screen. 9, 671–677 (2004).

    Article  CAS  PubMed  Google Scholar 

  249. Wolff, C., Fuks, B. & Chatelain, P. Comparative study of membrane potential-sensitive fluorescent probes and their use in ion channel screening assays. J. Biomol. Screen. 8, 533–543 (2003).

    Article  CAS  PubMed  Google Scholar 

  250. Ghetti, A., Guia, A. & Xu, J. Automated voltage-clamp technique. Methods Mol. Biol. 403, 59–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  251. Mathes, C., Friis, S., Finley, M. & Liu, Y. QPatch: the missing link between HTS and ion channel drug discovery. Combin. Chem. High Throughput Screen. 12, 78–95 (2009).

    Article  CAS  Google Scholar 

  252. Korsgaard, M. P., Strobaek, D. & Christophersen, P. Automated planar electrode electrophysiology in drug discovery: examples of the use of QPatch in basic characterization and high content screening on Nav, KCa2.3, and KV11.1 channels. Combin. Chem. High Throughput Screen. 12, 51–63 (2009).

    Article  CAS  Google Scholar 

  253. Farre, C. et al. Port-a-patch and patchliner: high fidelity electrophysiology for secondary screening and safety pharmacology. Combin. Chem. High Throughput Screen. 12, 24–37 (2009).

    Article  CAS  Google Scholar 

  254. Jow, F. et al. Validation of a medium-throughput electrophysiological assay for KCNQ2/3 channel enhancers using IonWorks HT. J. Biomol. Screen. 12, 1059–1067 (2007).

    Article  CAS  PubMed  Google Scholar 

  255. Dale, T. J., Townsend, C., Hollands, E. C. & Trezise, D. J. Population patch clamp electrophysiology: a breakthrough technology for ion channel screening. Mol. Biosyst. 3, 714–722 (2007).

    Article  CAS  PubMed  Google Scholar 

  256. Lu, Q. & An, W. F. Impact of novel screening technologies on ion channel drug discovery. Combin. Chem. High Throughput Screen. 11, 185–194 (2008).

    Article  CAS  Google Scholar 

  257. Southan, A. & Clark, G. Recent advances in electrophysiology-based screening technology and the impact upon ion channel discovery research. Methods Mol. Biol. 565, 187–208 (2009).

    Article  CAS  PubMed  Google Scholar 

  258. Fadool, D. A. et al. Kv1.3 channel gene-targeted deletion produces “Super-Smeller Mice” with altered glomeruli, interacting scaffolding proteins, and biophysics. Neuron 41, 389–404 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Koni, P. A. et al. Compensatory anion currents in Kv1.3 channel-deficient thymocytes. J. Biol. Chem. 278, 39443–39451 (2003).

    Article  CAS  PubMed  Google Scholar 

  260. Kopljar, I. et al. A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol. Proc. Natl Acad. Sci. USA 106, 9896–9901 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank B. Zhorov for help with figure 3. This work was supported by the National Institute of Health (RO1 GM076063 to H.W.) and the Max-Planck Society (L.A.P).

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Authors and Affiliations

  1. Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, GBSF Room 3502, Davis, 95616, California, USA

    Heike Wulff

  2. Icagen Inc., 4222 Emperor Boulevard, Suite 350, Durham, 27709, North Carolina, USA

    Neil A. Castle

  3. Max-Planck-Institute of Experimental Medicine, Molecular Biology of Neuronal Signals, Hermann-Rein-Str. 3, D37075, Göttingen, Germany

    Luis A. Pardo

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Competing interests

H.W. is an inventor on the patent claiming PAP-1 and related KV1.3 blockers for immunosuppression. She is also a scientific founder of Airmid, a start-up company that is aiming to develop KV1.3 blockers as immunosuppressants.

N.A.C. is an employee of Icagen, a company that is currently developing KV7.2 and KV7.3 activators for epilepsy.

L.A.P. is a shareholder of iOnGen AG, a company developing ion channel-based diagnostics and therapies in oncology.

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Glossary

Inwardly rectifying

Describes K+ or Ca2+ channels that are closed at depolarized membrane potentials and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current more readily flows through them into than out of the cell.

Venom peptide

A peptide toxin from the venoms of scorpions, sea anemones, cone snails, snakes, spiders or tarantulas. Many venom peptides target voltage- or ligand-gated ion channels.

Effector memory T cells

(TEM). Terminally differentiated memory T cells that home to inflamed tissue and secrete large amounts of inflammatory cytokines. TEM cells are involved in the pathogenesis of T cell-mediated autoimmune diseases and in the clearance of chronic viral infections.

Delayed rectifier

A slowly activating and very slowly inactivating ion channel through which K+ preferentially passes out of, rather than into, the cell.

Transient outward K+ current

A rapidly activating and inactivating K+ current.

Antiarrhythmic

An agent that decreases the incidence of arrhythmias. Class I agents interfere with the cardiac Na+ current. Class II agents are anti-sympathetic nervous system agents (mostly beta blockers). Class III agents affect K+ channels. Class IV agents affect voltage-gated Ca2+ channels and the atrioventricular node. Class V agents work by other or unknown mechanisms.

QT interval

On an electrocardiogram, the QT interval represents the time between the electrical activation and the repolarization of the ventricles. It is measured from the onset of the Q wave to the end of the T wave.

M-current

A slowly activating and deactivating K+ current that exhibits substantial conductance in the voltage range of action potential generation and plays an important part in determining neuronal excitability. It is called M-current because of its inhibition by muscarinic agonists.

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Wulff, H., Castle, N. & Pardo, L. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov 8, 982–1001 (2009). https://doi.org/10.1038/nrd2983

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