TABLE 36

KV11.1 channels

Channel name KV11.1
Description Voltage-gated potassium channel with inwardly rectifying properties
Other names Human ether-à-go-go-related gene, HERG, erg1, Hergb1,2,3,4,5,6,7,8
Molecular information Human: 1159aa, NM_000238 (transcript variant 1), chr. 7q35-36,1 KCNH2, GeneID: 3757, PMID: 81597661
Mouse: 1162aa, NM_013569, chr. 5
Rat: 1163aa, NM_053949, chr. 4q11
Associated subunits minK,9,25 possibly MiRP1 (KCNE2)10
Functional assays Voltage-clamp
Current Cardiac IKr current3,26
Conductance 2pS (in physiological [K]o), 10pS (100 mM [K]o)11
Ion selectivity K+
Activation Activation at currents more positive than –50 mV3,26
Inactivation Exhibits C-type inactivation4; inward rectification arises from a rapid and voltage-dependent inactivation process that reduces conductance at positive voltages3,26,27
Activators None
Gating inhibitors None
Blockers Astemizole (1 nM),13 BeKM-1 (3 nM),14 ergtoxin (12 nM),15 sertindole (3 nM), dofetilide (15–35 nM),16 cisapride (6–40 nM), pimozide (18 nM), terfenadine (56 nM), halofantrine (200 nM), BRL32872 (240 nM), E-4031 (7.7 nM), CT haloperidol (1 μM), imipramine (3 μM), cocaine (5 μM), ketoconazole
Radioligands None
Channel distribution Heart, leiomyosarcoma, hippocampus, neuroblastoma, blood cells, brain, kidney, liver, lung, ovary, pancreas, testis, prostate, small intestine, tonsil, uterus, microglia
Physiological functions HERG proteins form cardiac IKr channels3,26; in the heart, HERG channels produce a resurgent current during repolarization20 due to the recovery from C-type inactivation4 and a slow deactivation due to an interaction with an N-terminal domain (AA2–16) and the internal mouth of the pore1,22; HERG contains a tetramerization domain called NAB and a structurally defined PAS domain in distinct regions of the N terminus17; HERG forms a complex with MiRP1,10 but it is as yet unclear whether MiRP1 forms a stable part of the channel itself or is otherwise involved in regulation of HERG expression or stability23
Mutations and pathophysiology Mutations of this gene cause the autosomal dominant long QT syndrome 2 due to gating defects28 and trafficking abnormalities29,30,31,32,33 and a prolonged QT interval on the electrocardiogram; syncope, sudden cardiac death, ventricular fibrillation, and torsades de pointes are also implicated in acquired long QT syndrome; mutations in MiRP1 are the cause of long QT syndrome 6 and are also found in many tumors18,19
Pharmacological significance Proarrhythmic potential (QT prolongation) of histamine H1 receptor antagonists, antipsychotics, and tricyclic antidepressants that leads to torsades de points in some individuals (acquired long QT syndrome)
Comments A shorter isoform encoded by an alternative transcript (1b) of Kv11.15,7 or a truncated isoform6 can coassemble with and modulate the behavior of full-length HERG and Merg1, the mouse ortholog; the TCC domain at the C-terminal end of Kv10 and Kv11 confers specificity for multimer formation, allowing Kv10.1/Kv10.2 heteromerization and Kv11 homomerization, but not Kv10.x/Kv11.x heteromerization24; this C-terminal TCC domain has been identified in many other channels, and mutations of the TCC are found to be linked to genetic channelopathies; C terminus interacts with Golgi matrix protein GM13034

  • aa, amino acids; chr., chromosome; MiRP1, MinK-related peptide 1; TCC, tetramerizing coiled-coiled; E-4031, N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride.

  • ↵1. Warmke JW and Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA 91:3438-3442

  • ↵2. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, and Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795-803

  • ↵3. Sanguinetti MC, Jiang C, Curran ME, and Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299-307

  • ↵4. Smith PL, Baukrowitz T, and Yellen G (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature (Lond) 379:833-836

  • ↵5. Lees-Miller JP, Kondo C, Wang L, and Duff HJ (1997) Electrophysiological characterization of an alternatively processed ERG K+ channel in mouse and human hearts. Circ Res 81:719-726

  • ↵6. Kupershmidt S, Snyders DJ, Raes A, and Roden DM (1998) A K+ channel splice variant common in human heart lacks a C-terminal domain required for expression of rapidly activating delayed rectifier current. J Biol Chem 273:27231-27235

  • ↵7. London B, Trudeau MC, Newton KP, Beyer AK, Copeland NG, Gilbert DJ, Jenkins NA, Satler CA, and Robertson GA (1997) Two isoforms of the mouse ether-à-go-go-related gene co-assemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current. Circ Res 81:870-878

  • ↵8. Itoh T, Tanaka T, Nagai R, Kamiya T, Sawayama T, Nakayama T, Tomoike H, Sakurada H, Yazaki Y, and Nakamura Y (1998) Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome. Hum Genet 102:435-439

  • ↵9. McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, and Fishman GI (1997) A minK-HERG complex regulates the cardiac potassium current IKr. Nature (Lond) 388:289-292

  • ↵10. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, and Goldstein SA (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175-187

  • ↵11. Kiehn J, Lacerda AE, Wible B, and Brown AM (1996) Molecular physiology and pharmacology of HERG: single-channel currents and block by dofetilide. Circulation 94:2572-2579

  • ↵12. Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, and January CT (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 74:230-241

  • ↵13. Suessbrich H, Waldegger S, Lang F, and Busch AE (1996) Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Lett 385:77-80

  • ↵14. Korolkova YV, Kozlov SA, Lipkin AV, Pluzhnikov KA, Hadley JK, Filippov AK, Brown DA, Angelo K, Strobaek D, Jespersen T, et al. (2001) An ERG channel inhibitor from the scorpion Buthus eupeus. J Biol Chem 276:9868-9876

  • ↵15. Pardo-Lopez L, Zhang M, Liu J, Jiang M, Possani LD, and Tseng GN (2002) Mapping the binding site of a human ether-à-go-go-related gene-specific peptide toxin (ErgTx) to the channel's outer vestibule. J Biol Chem 277:16403-16411

  • ↵16. Spector PS, Curran ME, Keating MT, and Sanguinetti MC (1996) Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel: open-channel block by methane sulfonanilides. Circ Res 78:499-503

  • ↵17. Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, and Mackinnon R (1998) Crystal structure and functional analysis of the HERG potassium channel N terminus: aeukaryotic PAS domain. Cell 95:649-655

  • ↵18. Bianchi L, Wible B, Arcangeli A, Taglialatela M, Morra F, Castaldo P, Crociani O, Rosati B, Faravelli L, Olivotto M, and Wanke E (1998) herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells? Cancer Res 58:815-822

  • ↵19. Smith GA, Tsui HW, Newell E, Jiang X, Zhu XP, Tsui FW, and Schlichter LC (2002) Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells. J Biol Chem 277:18528-18534

  • ↵20. Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, and January CT (1998) Properties of HERG channels stably expressed in HEK 293 cells. Biophys J 74:230-241

  • ↵21. Wang J, Trudeau MC, Zappia AM, and Robertson GA (1998) Regulation of deactivation by an amino terminal domain in human ether-à-go-go-related gene potassium channels. J Gen Physiol 112:637-647

  • ↵22. Wang J, Myers CD, and Robertson GA (2000) Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K+ channels. J Gen Physiol 115:749-758

  • ↵23. Weerapura M, Nattel S, Chartier D, Caballero R, and Hebert TE (2002) 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 540:15-27

  • ↵24. Jenke M, Sanchez A, Monje F, Stuhmer W, Weseloh RM, and Pardo LA (2003) C-terminal domains implicated in the functional surface expression of potassium channels. EMBO J 22:395-403

  • ↵25. Finley MR, Li Y, Hua F, Lillich J, Mitchell KE, Ganta S, Gilmour RF Jr, and Freeman LC (2002) Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart. Am J Physiol Heart Circ Physiol 283:H126-H138

  • ↵26. Trudeau M, Warmke JW, Ganetzky B, and Robertson GA (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science (Wash DC) 269:92-95

  • ↵27. Spector PS, Curran EM, Zou A, Keating MT, and Sanguinetti MC (1996) Fast inactivation causes rectification of the IKr channel. J Gen Physiol 107:611-619

  • ↵28. Sanguinetti MC, Curran ME, Spector PS, and Keating MT (1996) Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia[published erratum appears in Proc Natl Acad Sci USA (1996) 93:8796]. Proc Natl Acad Sci USA 93:2208-2212

  • ↵29. Furutani M, Trudeau MC, Hagiwara N, Seki A, Gong Q, Zhou Z, Imamura S, Nagashima H, Kasanuki H, Takao A, et al. (1999) Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation 99:2290-2294

  • ↵30. Zhou Z, Gong Q, and January CT (1999) Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 274:31123-31126

  • ↵31. Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, and Brown AM (2000) Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome. J Mol Cell Cardiol 32:2327-2337

  • ↵32. Ficker E, Thomas D, Viswanathan PC, Dennis AT, Priori SG, Napolitano C, Memmi M, Wible BA, Kaufman ES, Iyengar S, et al. (2000) Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. Am J Physiol Heart Circ Physiol 279:H1748-H1756

  • ↵33. Rajamani S, Anderson CL, Anson BD, and January CT (2002) Pharmacological rescue of human K+ channel long-QT2 mutations: human ether-à-go-go-related gene rescue without block. Circulation 105:2830-2835

  • ↵34. Roti Roti EC, Myers CD, Ayers RA, Boatman DE, Delfosse SA, Chan EK, Ackerman MJ, January CT, and Robertson GA (2002) Interaction with GM130 during HERG ion channel trafficking: disruption by type 2 congenital long QT syndrome mutations. J Biol Chem 277:47779-47785