The 6TM family of K channels comprises the voltage-gated K_V subfamilies, the EAG subfamily (which includes hERG channels), the Ca²⁺-activated Slo subfamily (actually with 7TM, termed BK) and the Ca²⁺-activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. K_v1.1 with K_v1.2; K_v7.2 with K_v7.3). The pharmacology largely reflects the subunit composition of the functional channel.

K_v7 channels

K_v7.1-K_v7.5 (KCNQ1-5) K⁺ channels are voltage-gated K⁺ channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K⁺ currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases [1,21,50].

1. Abbott GW. (2020) KCNQs: Ligand- and Voltage-Gated Potassium Channels. Front Physiol, 11: 583. [PMID:32655402]

2. Bal M, Zhang J, Zaika O, Hernandez CC, Shapiro MS. (2008) Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. J Biol Chem, 283 (45): 30668-76. [PMID:18786918]

3. Bartok A, Toth A, Somodi S, Szanto TG, Hajdu P, Panyi G, Varga Z. (2014) Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels. Toxicon, 87: 6-16. [PMID:24878374]

4. Bohannon BM, de la Cruz A, Wu X, Jowais JJ, Perez ME, Dykxhoorn DM, Liin SI, Larsson HP. (2020) Polyunsaturated fatty acid analogues differentially affect cardiac Na_V, Ca_V, and K_V channels through unique mechanisms. Elife, 9. DOI: 10.7554/eLife.51453 [PMID:32207683]

5. Coleman SK, Newcombe J, Pryke J, Dolly JO. (1999) Subunit composition of Kv1 channels in human CNS. J Neurochem, 73 (2): 849-58. [PMID:10428084]

6. Diochot S, Schweitz H, Béress L, Lazdunski M. (1998) Sea anemone peptides with a specific blocking activity against the fast inactivating potassium channel Kv3.4. J Biol Chem, 273 (12): 6744-9. [PMID:9506974]

7. Dupuis DS, Schrøder RL, Jespersen T, Christensen JK, Christophersen P, Jensen BS, Olesen SP. (2002) Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352. Eur J Pharmacol, 437 (3): 129-37. [PMID:11890900]

8. Fedida D, Wible B, Wang Z, Fermini B, Faust F, Nattel S, Brown AM. (1993) Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current. Circ Res, 73 (1): 210-6. [PMID:8508531]

9. Felix JP, Bugianesi RM, Schmalhofer WA, Borris R, Goetz MA, Hensens OD, Bao JM, Kayser F, Parsons WH, Rupprecht K et al.. (1999) Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3. Biochemistry, 38 (16): 4922-30. [PMID:10213593]

10. Ferber M, Al-Sabi A, Stocker M, Olivera BM, Terlau H. (2004) Identification of a mammalian target of kappaM-conotoxin RIIIK. Toxicon, 43 (8): 915-21. [PMID:15208025]

11. Garcia-Calvo M, Leonard RJ, Novick J, Stevens SP, Schmalhofer W, Kaczorowski GJ, Garcia ML. (1993) Purification, characterization, and biosynthesis of margatoxin, a component of Centruroides margaritatus venom that selectively inhibits voltage-dependent potassium channels. J Biol Chem, 268 (25): 18866-74. [PMID:8360176]

12. Ghanshani S, Wulff H, Miller MJ, Rohm H, Neben A, Gutman GA, Cahalan MD, Chandy KG. (2000) Up-regulation of the IKCa1 potassium channel during T-cell activation. Molecular mechanism and functional consequences. J Biol Chem, 275 (47): 37137-49. [PMID:10961988]

13. Grissmer S, Nguyen AN, Aiyar J, Hanson DC, Mather RJ, Gutman GA, Karmilowicz MJ, Auperin DD, Chandy KG. (1994) Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol Pharmacol, 45 (6): 1227-34. [PMID:7517498]

14. Grupe A, Schröter KH, Ruppersberg JP, Stocker M, Drewes T, Beckh S, Pongs O. (1990) Cloning and expression of a human voltage-gated potassium channel. A novel member of the RCK potassium channel family. EMBO J, 9 (6): 1749-56. [PMID:2347305]

15. Hadley JK, Noda M, Selyanko AA, Wood IC, Abogadie FC, Brown DA. (2000) Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels. Br J Pharmacol, 129 (3): 413-5. [PMID:10711337]

16. He Y, Kang Y, Leung YM, Xia F, Gao X, Xie H, Gaisano HY, Tsushima RG. (2006) Modulation of Kv2.1 channel gating and TEA sensitivity by distinct domains of SNAP-25. Biochem J, 396 (2): 363-9. [PMID:16478442]

17. Herrington J, Solly K, Ratliff KS, Li N, Zhou YP, Howard A, Kiss L, Garcia ML, McManus OB, Deng Q et al.. (2011) Identification of novel and selective Kv2 channel inhibitors. Mol Pharmacol, 80 (6): 959-64. [PMID:21948463]

18. Herrington J, Zhou YP, Bugianesi RM, Dulski PM, Feng Y, Warren VA, Smith MM, Kohler MG, Garsky VM, Sanchez M et al.. (2006) Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion. Diabetes, 55 (4): 1034-42. [PMID:16567526]

19. Hurst RS, Busch AE, Kavanaugh MP, Osborne PB, North RA, Adelman JP. (1991) Identification of amino acid residues involved in dendrotoxin block of rat voltage-dependent potassium channels. Mol Pharmacol, 40 (4): 572-6. [PMID:1921987]

20. Isbrandt D, Leicher T, Waldschütz R, Zhu X, Luhmann U, Michel U, Sauter K, Pongs O. (2000) Gene structures and expression profiles of three human KCND (Kv4) potassium channels mediating A-type currents I(TO) and I(SA). Genomics, 64 (2): 144-54. [PMID:10729221]

21. Jones F, Gamper N, Gao H. (2021) Kv7 Channels and Excitability Disorders. Handb Exp Pharmacol, 267: 185-230. [PMID:33860384]

22. Kalman K, Nguyen A, Tseng-Crank J, Dukes ID, Chandy G, Hustad CM, Copeland NG, Jenkins NA, Mohrenweiser H, Brandriff B et al.. (1998) Genomic organization, chromosomal localization, tissue distribution, and biophysical characterization of a novel mammalian Shaker-related voltage-gated potassium channel, Kv1.7. J Biol Chem, 273 (10): 5851-7. [PMID:9488722]

23. Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, Reynolds W, Viviani F, Tabart M, Rampe D. (2005) Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel. Mol Pharmacol, 67 (3): 827-36. [PMID:15548764]

24. Keserü GM. (2003) Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett, 13 (16): 2773-5. [PMID:12873512]

25. Lang R, Lee G, Liu W, Tian S, Rafi H, Orias M, Segal AS, Desir GV. (2000) KCNA10: a novel ion channel functionally related to both voltage-gated potassium and CNG cation channels. Am J Physiol Renal Physiol, 278 (6): F1013-21. [PMID:10836990]

26. Larsson JE, Frampton DJA, Liin SI. (2020) Polyunsaturated Fatty Acids as Modulators of K_V7 Channels. Front Physiol, 11: 641. [PMID:32595524]

27. Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K. (2000) Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem, 275 (29): 22395-400. [PMID:10787416]

28. Li T, Wu K, Yue Z, Wang Y, Zhang F, Shen H. (2021) Structural Basis for the Modulation of Human KCNQ4 by Small-Molecule Drugs. Mol Cell, 81 (1): 25-37.e4. [PMID:33238160]

29. Li X, Zhang Q, Guo P, Fu J, Mei L, Lv D, Wang J, Lai D, Ye S, Yang H et al.. (2021) Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res, 31 (1): 52-61. [PMID:32884139]

30. Lien CC, Martina M, Schultz JH, Ehmke H, Jonas P. (2002) Gating, modulation and subunit composition of voltage-gated K(+) channels in dendritic inhibitory interneurones of rat hippocampus. J Physiol (Lond.), 538 (Pt 2): 405-19. [PMID:11790809]

31. Ma D, Zhong L, Yan Z, Yao J, Zhang Y, Ye F, Huang Y, Lai D, Yang W, Hou P et al.. (2022) Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers. Proc Natl Acad Sci U S A, 119 (45): e2207067119. [PMID:36763058]

32. Manville RW, Abbott GW. (2018) Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels. Mol Pharmacol, 94 (4): 1155-1163. [PMID:30021858]

33. Mattmann ME, Yu H, Lin Z, Xu K, Huang X, Long S, Wu M, McManus OB, Engers DW, Le UM et al.. (2012) Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator. Bioorg Med Chem Lett, 22 (18): 5936-41. [PMID:22910039]

34. Ohya S, Sergeant GP, Greenwood IA, Horowitz B. (2003) Molecular variants of KCNQ channels expressed in murine portal vein myocytes: a role in delayed rectifier current. Circ Res, 92 (9): 1016-23. [PMID:12690036]

35. Perry M, de Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, Mitcheson J. (2004) Structural determinants of HERG channel block by clofilium and ibutilide. Mol Pharmacol, 66 (2): 240-9. [PMID:15266014]

36. Rampe D, Roy ML, Dennis A, Brown AM. (1997) A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. FEBS Lett, 417 (1): 28-32. [PMID:9395068]

37. Rettig J, Wunder F, Stocker M, Lichtinghagen R, Mastiaux F, Beckh S, Kues W, Pedarzani P, Schröter KH, Ruppersberg JP. (1992) Characterization of a Shaw-related potassium channel family in rat brain. EMBO J, 11 (7): 2473-86. [PMID:1378392]

38. Rochat H, Kharrat R, Sabatier JM, Mansuelle P, Crest M, Martin-Eauclaire MF, Sampieri F, Oughideni R, Mabrouk K, Jacquet G et al.. (1998) Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 36 (11): 1609-11. [PMID:9792177]

39. Schmalz F, Kinsella J, Koh SD, Vogalis F, Schneider A, Flynn ER, Kenyon JL, Horowitz B. (1998) Molecular identification of a component of delayed rectifier current in gastrointestinal smooth muscles. Am J Physiol, 274 (5 Pt 1): G901-11. [PMID:9612272]

40. Schroeder BC, Hechenberger M, Weinreich F, Kubisch C, Jentsch TJ. (2000) KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J Biol Chem, 275 (31): 24089-95. [PMID:10816588]

41. Schröter KH, Ruppersberg JP, Wunder F, Rettig J, Stocker M, Pongs O. (1991) Cloning and functional expression of a TEA-sensitive A-type potassium channel from rat brain. FEBS Lett, 278 (2): 211-6. [PMID:1840526]

42. Singleton DH, Boyd H, Steidl-Nichols JV, Deacon M, Groot MJ, Price D, Nettleton DO, Wallace NK, Troutman MD, Williams C et al.. (2007) Fluorescently labeled analogues of dofetilide as high-affinity fluorescence polarization ligands for the human ether-a-go-go-related gene (hERG) channel. J Med Chem, 50 (13): 2931-41. [PMID:17536794]

43. Stühmer W, Ruppersberg JP, Schröter KH, Sakmann B, Stocker M, Giese KP, Perschke A, Baumann A, Pongs O. (1989) Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J, 8 (11): 3235-44. [PMID:2555158]

44. Sun J, MacKinnon R. (2017) Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome. Cell, 169 (6): 1042-1050.e9. [PMID:28575668]

45. Sun J, MacKinnon R. (2020) Structural Basis of Human KCNQ1 Modulation and Gating. Cell, 180 (2): 340-347.e9. [PMID:31883792]

46. Søgaard R, Ljungstrøm T, Pedersen KA, Olesen SP, Jensen BS. (2001) KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol, Cell Physiol, 280 (4): C859-66. [PMID:11245603]

47. Tatulian L, Delmas P, Abogadie FC, Brown DA. (2001) Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci, 21 (15): 5535-45. [PMID:11466425]

48. Towart R, Linders JT, Hermans AN, Rohrbacher J, van der Linde HJ, Ercken M, Cik M, Roevens P, Teisman A, Gallacher DJ. (2009) Blockade of the I(Ks) potassium channel: an overlooked cardiovascular liability in drug safety screening?. J Pharmacol Toxicol Methods, 60 (1): 1-10. [PMID:19439185]

49. Vega-Saenz de Miera E, Moreno H, Fruhling D, Kentros C, Rudy B. (1992) Cloning of ShIII (Shaw-like) cDNAs encoding a novel high-voltage-activating, TEA-sensitive, type-A K+ channel. Proc Biol Sci, 248 (1321): 9-18. [PMID:1381835]

50. Vigil FA, Carver CM, Shapiro MS. (2020) Pharmacological Manipulation of K _v 7 Channels as a New Therapeutic Tool for Multiple Brain Disorders. Front Physiol, 11: 688. [PMID:32636759]

51. Wang HS, Brown BS, McKinnon D, Cohen IS. (2000) Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. Mol Pharmacol, 57 (6): 1218-23. [PMID:10825393]

52. Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D. (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science, 282 (5395): 1890-3. [PMID:9836639]

53. Wang L, Qiao GH, Hu HN, Gao ZB, Nan FJ. (2019) Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity. ACS Med Chem Lett, 10 (1): 27-33. [PMID:30655942]

54. Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK. (2000) Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol, 58 (3): 591-600. [PMID:10953053]

55. Willegems K, Eldstrom J, Kyriakis E, Ataei F, Sahakyan H, Dou Y, Russo S, Van Petegem F, Fedida D. (2022) Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277. Nat Commun, 13 (1): 3760. [PMID:35768468]

56. Zheng Y, Liu H, Chen Y, Dong S, Wang F, Wang S, Li GL, Shu Y, Xu F. (2022) Structural insights into the lipid and ligand regulation of a human neuronal KCNQ channel. Neuron, 110 (2): 237-247.e4. [PMID:34767770]

57. Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT. (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J, 74 (1): 230-41. [PMID:9449325]

58. Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT. (1999) Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol, 10 (6): 836-43. [PMID:10376921]

Subcommittee members: Lily Y. Jan (Chairperson) Howard Hughes Medical Institute Department of Physiology and Biochemistry University of California San Francisco San Francisco CA 94143, USA Bernard Attali Dept of Physiology and Pharmacology 5th Floor, Room 546 Sackler Medical School, Tel Aviv University Tel Aviv 69978 Israel Jeanne Nerbonne Division of Biology and Biomedical Sciences Washington University St. Louis MO 63110, USA Michael C. Sanguinetti Eccles Institute of Human Genetics University of Utah Salt Lake City UT 84101, USA James S. Trimmer (Past contributor) (Past contributor) University of California Davis Davis CA 95616, USA

Other contributors: K. George Chandy Department of Physiology and Biophysics University of California Irvine Irvine CA 92697 USA M. Hunter Giese Department of Physiology and Cellular Biophysics Columbia University New York NY 10032, USA Stephan Grissmer Institute of Applied Physiology Ulm University Albert-Einstein-Allee 11 89081 Ulm Germany George A. Gutman Department of Microbiology and Molecular Genetics University of California Irvine Irvine CA 92697 USA Michel Lazdunski Institut de Pharmacologie Moleculaire et Cellulaire CNRS-Unité Propre de Recherche 411 Valbonne France David Mckinnon Department of Neurobiology and Behavior The State University of New York at Stony Brook Health Sciences Center Stony Brook NY, 11794 USA Luis A. Pardo Max Planck Institute for Experimental Medicine Abt. Molekulare Biologie Neuronaler Signale Gottingen Germany Gail A. Robertson Department of Physiology University of Wisconsin-Madison Madison WI, 53706 USA Bernardo Rudy Department of Physiology, Neuroscience, and Biochemistry New York University School of Medicine New York NY, 10016 USA Walter Stühmer Max Planck Institute for Experimental Medicine Abt. Molekulare Biologie Neuronaler Signale Gottingen Germany Xiaoliang Wang Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing China