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Gene Review

KCNQ1  -  potassium channel, voltage gated KQT-like...

Homo sapiens

Synonyms: ATFB1, ATFB3, IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1, JLNS1, KCNA8, ...
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Disease relevance of KCNQ1

  • Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells [1].
  • KCNQ1 (KvLQT1) interacts with the beta-subunit KCNE1 (IsK, minK) to form the slow, depolarization-activated potassium current I(Ks) that is affected in some forms of cardiac arrhythmia [2].
  • This localization and the pharmacology, voltage-dependence and stimulation by cyclic AMP of KCNQ1/KCNE3 currents indicate that these proteins may assemble to form the potassium channel that is important for cyclic AMP-stimulated intestinal chloride secretion and that is involved in secretory diarrhoea and cystic fibrosis [2].
  • RESULTS: We identified KCNQ1, which is mutated in cardiac long QT syndrome, as a K+ channel located in tubulovesicles and apical membrane of parietal cells, where it colocalized with H+/K+-adenosine triphosphatase [3].
  • Thus, stomach- and subunit-specific inhibitors of KCNQ1 might offer new therapeutical perspectives for peptic ulcer disease [3].

Psychiatry related information on KCNQ1

  • Based on the observation that physical exertion and emotional stress are significant triggers for cardiac events in the setting of congenital long QT syndrome (specifically the LQT1 and LQT2 genotypes), avoidance of competitive sports seems to be a prudent lifestyle modification [4].

High impact information on KCNQ1

  • These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression [5].
  • Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy [1].
  • RESULTS: The frequency of cardiac events was higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (P<0.001 for the comparison of all three groups) [6].
  • By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family [7].
  • A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family [7].

Chemical compound and disease context of KCNQ1


Biological context of KCNQ1

  • Amino acid sequence comparison reveals that both genes share strong homology to KvLQT1, the potassium channel encoded by KCNQ1, which is responsible for over 50% of inherited long QT syndrome [12].
  • We therefore examined the role of KCNQ1 S4 charges in channel activation using alanine-scanning mutagenesis and two-electrode voltage clamp [13].
  • Alanine replacement of R231, at the N-terminal side of S4, produced constitutive activation in homomeric KCNQ1 channels, a phenomenon not observed with previous single amino acid substitutions in S4 of other channels [13].
  • In this study, we examined the role of the minK subunit in determining the response of KCNQ1 channels to blockade by the cognitive enhancer XE991 [14].
  • KCNQ1 K+ channels in humans are important for repolarization of cardiac action potentials and for K+ secretion in the inner ear [15].

Anatomical context of KCNQ1


Associations of KCNQ1 with chemical compounds

  • CONCLUSIONS: We identified KCNQ1 as the missing luminal K+ channel in parietal cells and characterized its crucial role in acid secretion [3].
  • An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands [19].
  • The Role of S4 Charges in Voltage-dependent and Voltage-independent KCNQ1 Potassium Channel Complexes [13].
  • KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells [20].
  • Inhibition of KCNQ1 by the chromanol 293B strongly diminished H+ secretion [17].

Physical interactions of KCNQ1

  • Conversely, a KCNQ3-sid(Q1) chimaera no longer affects KCNQ2 but interacts with KCNQ1 [21].
  • However, co-expression of these inhibitory subunits with a disease-associated mutation (S140G-KCNQ1) led to currents that were almost undistinguishable from the KCNQ1/KCNE1 canonical complex [22].
  • Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D) [23].
  • Regulatory subunit KCNE3 (E3) interacts with KCNQ1 (Q1) in epithelia, regulating its activation kinetics and augmenting current density [24].
  • These results suggest that KCNE2 can functionally couple to KCNQ1 even in the presence of KCNE1 [25].

Co-localisations of KCNQ1


Regulatory relationships of KCNQ1

  • We speculate that since KCNE5 is expressed in cardiac tissue it may here along with the KCNE1 beta-subunit regulate KCNQ1 channels [27].
  • hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics [28].
  • Thus, KCNQ1 expressed in Xenopus oocytes is regulated by cAMP and Ca2+ but is not affected by CFTR [29].
  • In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test) [30].
  • The antiarrhythmic KCNQ1 channel blocker bepridil inhibited KCNQ4 with an IC(50) value of 9.4 microM, whereas clofilium was without significant effect at 100 microM [31].

Other interactions of KCNQ1

  • These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder [32].
  • The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels [33].
  • KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel [34].
  • Using a chimaeric strategy, we show that a cytoplasmic carboxy-terminal subunit interaction domain (sid) suffices to transfer assembly properties between KCNQ3 and KCNQ1 [21].
  • Recently, two further gain-of-function mutations in the KCNQ1 gene encoding the alpha-subunit of the KvLQT1 (I(Ks)) channel and in the KCNJ2 gene encoding the strong inwardly rectifying channel protein Kir2.1 confirmed a genetically heterogeneous disease [35].

Analytical, diagnostic and therapeutic context of KCNQ1

  • METHODS: Acid secretion was measured in vivo and in vitro; KCNQ1 protein localization was assessed by immunofluorescence, and acid-sensitivity of KCNQ1 by patch-clamp [3].
  • Here, sequence alignments revealed that the voltage-sensing S4 domain of KCNQ1 bears lower net charge (+3) than that of any other eukaryotic voltage-gated ion channel [13].
  • METHODS: The phenotypic effects of this polymorphism were investigated in vitro by electrophysiological experiments in HEK-293 cells and in vivo by exercise electrocardiography in a group of LQTS patients carrying the same genetically proven KCNQ1 mutation [36].
  • METHODS: We have carried out a comparative study of all KCNE subunits with KCNQ1 using the patch-clamp technique in mammalian cells [22].
  • During a maximal exercise test in 39 LQT1 patients carrying an identical KCNQ1 mutation (G589D) and showing a prolonged QT interval (>440 ms), QT intervals were longer in patients carrying the 897T allele than in those homozygous for the 897K allele [36].


  1. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Kubisch, C., Schroeder, B.C., Friedrich, T., Lütjohann, B., El-Amraoui, A., Marlin, S., Petit, C., Jentsch, T.J. Cell (1999) [Pubmed]
  2. A constitutively open potassium channel formed by KCNQ1 and KCNE3. Schroeder, B.C., Waldegger, S., Fehr, S., Bleich, M., Warth, R., Greger, R., Jentsch, T.J. Nature (2000) [Pubmed]
  3. The cardiac K+ channel KCNQ1 is essential for gastric acid secretion. Grahammer, F., Herling, A.W., Lang, H.J., Schmitt-Gräff, A., Wittekindt, O.H., Nitschke, R., Bleich, M., Barhanin, J., Warth, R. Gastroenterology (2001) [Pubmed]
  4. The heterogeneous spectrum of the long QT syndrome. Patel, N.D., Singh, B.K., Mathew, S.T. Eur. J. Intern. Med. (2006) [Pubmed]
  5. Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice. Cleary, M.A., van Raamsdonk, C.D., Levorse, J., Zheng, B., Bradley, A., Tilghman, S.M. Nat. Genet. (2001) [Pubmed]
  6. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. Zareba, W., Moss, A.J., Schwartz, P.J., Vincent, G.M., Robinson, J.L., Priori, S.G., Benhorin, J., Locati, E.H., Towbin, J.A., Keating, M.T., Lehmann, M.H., Hall, W.J. N. Engl. J. Med. (1998) [Pubmed]
  7. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Charlier, C., Singh, N.A., Ryan, S.G., Lewis, T.B., Reus, B.E., Leach, R.J., Leppert, M. Nat. Genet. (1998) [Pubmed]
  8. KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. Liu, W., Yang, J., Hu, D., Kang, C., Li, C., Zhang, S., Li, P., Chen, Z., Qin, X., Ying, K., Li, Y., Li, Y., Li, Z., Cheng, X., Li, L., Qi, Y., Chen, S., Wang, Q. Hum. Mutat. (2002) [Pubmed]
  9. Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome. Nemec, J., Ackerman, M.J., Tester, D.J., Hejlik, J., Shen, W.K. Pacing and clinical electrophysiology : PACE. (2003) [Pubmed]
  10. Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk. Chouabe, C., Neyroud, N., Richard, P., Denjoy, I., Hainque, B., Romey, G., Drici, M.D., Guicheney, P., Barhanin, J. Cardiovasc. Res. (2000) [Pubmed]
  11. Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome. Park, K.H., Piron, J., Dahimene, S., Mérot, J., Baró, I., Escande, D., Loussouarn, G. Circ. Res. (2005) [Pubmed]
  12. Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. Yang, W.P., Levesque, P.C., Little, W.A., Conder, M.L., Ramakrishnan, P., Neubauer, M.G., Blanar, M.A. J. Biol. Chem. (1998) [Pubmed]
  13. The Role of S4 Charges in Voltage-dependent and Voltage-independent KCNQ1 Potassium Channel Complexes. Panaghie, G., Abbott, G.W. J. Gen. Physiol. (2007) [Pubmed]
  14. Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. Wang, H.S., Brown, B.S., McKinnon, D., Cohen, I.S. Mol. Pharmacol. (2000) [Pubmed]
  15. Tight coupling of rubidium conductance and inactivation in human KCNQ1 potassium channels. Seebohm, G., Sanguinetti, M.C., Pusch, M. J. Physiol. (Lond.) (2003) [Pubmed]
  16. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. Roepke, T.K., Anantharam, A., Kirchhoff, P., Busque, S.M., Young, J.B., Geibel, J.P., Lerner, D.J., Abbott, G.W. J. Biol. Chem. (2006) [Pubmed]
  17. Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. Heitzmann, D., Grahammer, F., von Hahn, T., Schmitt-Gräff, A., Romeo, E., Nitschke, R., Gerlach, U., Lang, H.J., Verrey, F., Barhanin, J., Warth, R. J. Physiol. (Lond.) (2004) [Pubmed]
  18. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Dedek, K., Waldegger, S. Pflugers Arch. (2001) [Pubmed]
  19. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Yang, Y., Xia, M., Jin, Q., Bendahhou, S., Shi, J., Chen, Y., Liang, B., Lin, J., Liu, Y., Liu, B., Zhou, Q., Zhang, D., Wang, R., Ma, N., Su, X., Niu, K., Pei, Y., Xu, W., Chen, Z., Wan, H., Cui, J., Barhanin, J., Chen, Y. Am. J. Hum. Genet. (2004) [Pubmed]
  20. KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Robbins, J. Pharmacol. Ther. (2001) [Pubmed]
  21. A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly. Schwake, M., Jentsch, T.J., Friedrich, T. EMBO Rep. (2003) [Pubmed]
  22. In vitro molecular interactions and distribution of KCNE family with KCNQ1 in the human heart. Bendahhou, S., Marionneau, C., Haurogne, K., Larroque, M.M., Derand, R., Szuts, V., Escande, D., Demolombe, S., Barhanin, J. Cardiovasc. Res. (2005) [Pubmed]
  23. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Marx, S.O., Kurokawa, J., Reiken, S., Motoike, H., D'Armiento, J., Marks, A.R., Kass, R.S. Science (2002) [Pubmed]
  24. Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. Mazhari, R., Nuss, H.B., Armoundas, A.A., Winslow, R.L., Marbán, E. J. Clin. Invest. (2002) [Pubmed]
  25. Modulation of functional properties of KCNQ1 channel by association of KCNE1 and KCNE2. Toyoda, F., Ueyama, H., Ding, W.G., Matsuura, H. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  26. KCNE2 is colocalized with KCNQ1 and KCNE1 in cardiac myocytes and may function as a negative modulator of I(Ks) current amplitude in the heart. Wu, D.M., Jiang, M., Zhang, M., Liu, X.S., Korolkova, Y.V., Tseng, G.N. Heart rhythm : the official journal of the Heart Rhythm Society (2006) [Pubmed]
  27. KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current. Angelo, K., Jespersen, T., Grunnet, M., Nielsen, M.S., Klaerke, D.A., Olesen, S.P. Biophys. J. (2002) [Pubmed]
  28. hKCNE4 inhibits the hKCNQ1 potassium current without affecting the activation kinetics. Grunnet, M., Olesen, S.P., Klaerke, D.A., Jespersen, T. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  29. Regulation and properties of KCNQ1 (K(V)LQT1) and impact of the cystic fibrosis transmembrane conductance regulator. Boucherot, A., Schreiber, R., Kunzelmann, K. J. Membr. Biol. (2001) [Pubmed]
  30. Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome. Itoh, T., Kikuchi, K., Odagawa, Y., Takata, S., Yano, K., Okada, S., Haneda, N., Ogawa, S., Nakano, O., Kawahara, Y., Kasai, H., Nakayama, T., Fukutomi, T., Sakurada, H., Shimizu, A., Yazaki, Y., Nagai, R., Nakamura, Y., Tanaka, T. J. Hum. Genet. (2001) [Pubmed]
  31. KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Søgaard, R., Ljungstrøm, T., Pedersen, K.A., Olesen, S.P., Jensen, B.S. Am. J. Physiol., Cell Physiol. (2001) [Pubmed]
  32. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Wang, Q., Shen, J., Splawski, I., Atkinson, D., Li, Z., Robinson, J.L., Moss, A.J., Towbin, J.A., Keating, M.T. Cell (1995) [Pubmed]
  33. A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. Schmitt, N., Schwarz, M., Peretz, A., Abitbol, I., Attali, B., Pongs, O. EMBO J. (2000) [Pubmed]
  34. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. Tinel, N., Diochot, S., Borsotto, M., Lazdunski, M., Barhanin, J. EMBO J. (2000) [Pubmed]
  35. Short QT syndrome. Schimpf, R., Wolpert, C., Gaita, F., Giustetto, C., Borggrefe, M. Cardiovasc. Res. (2005) [Pubmed]
  36. Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG). Paavonen, K.J., Chapman, H., Laitinen, P.J., Fodstad, H., Piippo, K., Swan, H., Toivonen, L., Viitasalo, M., Kontula, K., Pasternack, M. Cardiovasc. Res. (2003) [Pubmed]
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