KV7.1 channels

Channel name KV7.1
Description Voltage-gated potassium channel, delayed rectifier
Other names KVLQT1,1 slow delayed rectifier
Molecular information Human: 676aa, NM_000218 (transcript variant 1), chr. 11p15.5, KCNQ1, GeneID: 3784, PMID: 85282441
Mouse: 668aa, NM_008434, chr. 7
Rat: 669aa, NM_032073, chr. 1q41
Associated subunits KCNE1 (minK/IsK), KCNE3 [minK-related peptide 2 (MiRP2)]
Functional assays Voltage-clamp
Current IKs (with KCNE1),2,3 IKcAMP (with KCNE3)16
Conductance 1.8pS (KCNQ1 alone), 5pS (with KCNE1)
Ion selectivity K+
Activation KCNQ1 alone: Va = 12 mV, τa = 30, and 800 ms at +40 mV
KCNQ1 + KCNE1: Va = +8 mV, τa = 0.7, 1.5, and 8 s at +40 mV
Inactivation KCNQ1 alone: Vh = +18 mV, τh = 130 ms at 20 mV
Activators R-L3 (= L364373, 1 μM for KCNQ1 alone; R-L3 does not activate the KCNQ1/KCNE1 complex; the S enantiomer blocks KCNQ1)4; mefenamic acid, niflumic acid, and 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (10–100 μM)5,6
Gating inhibitors None
Blockers Chromanol 293B (1 μM),7 L735821 (80 nM),8 mefloquine (0.88 μM),9 azimilide (3 μM),9,10 HMR-1556 (120 nM), XE991 (0.78 μM KCNQ1 alone; 11.1 μM KCNQ1/KCNE1),11 linopirdine (8.9 μM KCNQ1 alone)
Radioligands None
Channel distribution Heart, kidney, rectum, ear, germ, pancreas, lung, cochlea, placenta
Physiological functions Repolarization of cardiac action potentials (KCNQ1 and minK/ISK/KCNE1 coassemble to form the cardiac IKs channel); potassium recycling at basolateral membrane of intestinal crypt cells (with KCNE3) and inner ear
Mutations and pathophysiology Loss of function mutations in the KCNQ1 gene can cause either RWS (autosomal dominant) or JLNS (autosomal recessive); RWS is characterized by congenital long QT syndrome and electrocardiographically distinguished by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes), which may result in recurrent syncopes, seizure, or sudden death; JLNS patients have deafness, congenital and functional heart disease, a prolonged QT interval on an electrocardiogram, and sudden death cardioauditory syndrome; KCNQ1 is disrupted by chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome,13 as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumor; gain-of-function mutations in KCNQ1 cause atrial fibrillation and short QT syndrome
Pharmacological significance Blockers developed as class III antiarrhythmic agents to target ventricular arrhythmias14,15; activators could be useful for the treatment of some long QT syndromes6
  • aa, amino acids; chr., chromosome; RWS, Romano-Ward syndrome; JLNS, Jervell and Lange-Nielsen syndrome; L735821, 3-(2,4-dichlorophenyl)-N-(6-methyl-5-oxo-2-phenyl-3,6-diazabicyclo[5.4.0]undeca-2,7,9,11-tetraen-4-yl)-prop-2-enamide; XE991, 10,10-bis(pyridin-4-ylmethyl)anthracen-9-one; HMR-1556, N-(6-cyano-3-hydroxy-2,2-dimethyl-chroman-4-yl)N-methyl-ethansesulfonamide.

  • 1. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, Van Raay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, et al. (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17-23

  • 2. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, and Keating MT (1996) Coassembly of KV LQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature (Lond) 384:80-83

  • 3. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, and Romey G (1996) KV LQT1and lsK (minK) proteins associate to form the IKs cardiac potassium current. Nature (Lond) 384:78-80

  • 4. Salata JJ, Jurkiewicz NK, Wang J, Evans BE, Orme HT, and Sanguinetti MC (1998) A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol 54:220-230

  • 5. Busch AE, Herzer T, Wagner CA, Schmidt F, Raber G, Waldegger S, and Lang F (1994) Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes. Mol Pharmacol 46:750-753

  • 6. Abitbol I, Peretz A, Lerche C, Busch AE, and Attali B (1999) Stilbenes and fenamates rescue the loss of IKS channel function induced by an LQT5 mutation and other IsK mutants. EMBO J 18:4137-4148

  • 7. Yang IC, Scherz MW, Bahinski A, Bennett PB, and Murray KT (2000) Stereoselective interactions of the enantiomers of chromanol 293B with human voltage-gated potassium channels. J Pharmacol Exp Ther 294:955-962

  • 8. Tinel N, Lauritzen I, Chouabe C, Lazdunski M, and Borsotto M (1998) The KCNQ2 potassium channel: splice variants, functional and develo pMental expression: brain localization and comparison with KCNQ3. FEBS Lett 438:171-176

  • 9. Kang J, Chen XL, Wang L, and Rampe D (2001) Interactions of the antimalarial drug mefloquine with the human cardiac potassium channels KvLQT1/minK and HERG. J Pharmacol Exp Ther 299:290-296

  • 10. Busch AE, Busch GL, Ford E, Suessbrich H, Lang HJ, Greger R, Kunzelmann K, Attali B, and Stuhmer W (1997) The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. Br J Pharmacol 122:187-189

  • 11. Wang HS, Brown BS, McKinnon D, and Cohen, IS (2000) Molecular basis for differential sensitivity of KCNQ and IKs channels to the cognitive enhancer XE991. Mol Pharmacol 57:1218-1223

  • 12. Keating MT and Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569-580

  • 13. Lee MP, Hu RJ, Johnson LA, and Feinberg AP (1997) Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndromechromosomal rearrangements. Nat Genetics 15:181-185

  • 14. Coghlan MJ, Carroll WA, and Gopalakrishnan M (2001) Recent develo pMents in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J Med Chem 44:1627-1653

  • 15. Shieh CC, Coghlan M, Sullivan JP, and Gopalakrishnan M (2000) Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52:557-594

  • 16. Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, and Jentsch TJ (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature (Lond) 403:196-199