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Gene Review

KCNQ2  -  potassium channel, voltage gated KQT-like...

Homo sapiens

Synonyms: BFNC, BFNS1, EBN, EBN1, EIEE7, ...
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Disease relevance of KCNQ2

  • To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3) [1].
  • KCNQ2 and KCNQ3 subunits belong to the six transmembrane domain K+ channel family and loss of function mutations are associated with benign familial neonatal convulsions [2].
  • We propose that a difference in firing patterns between motoneurons and central neurons, combined with the drastically slowed voltage activation of the R207W mutant, explains why this particular KCNQ2 mutant causes myokymia in addition to BFNC [3].
  • A depolarizing shift in the activation curve of macroscopic KCNQ2/3 currents and single KCNQ2/3 channels was caused by acidosis, while alkalosis caused a hyperpolarizing shift [4].
  • (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: an orally bioavailable KCNQ2 opener with significant activity in a cortical spreading depression model of migraine [5].

Psychiatry related information on KCNQ2


High impact information on KCNQ2


Biological context of KCNQ2

  • Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq [8].
  • In 1998, a decade of clinical and laboratory-based genetics work resulted in the cloning of the KCNQ2 potassium channel gene at the BFNC locus on chromosome 20 [9].
  • Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels [10].
  • Membrane potential recordings in oocytes expressing the KCNQ2/3 heteromeric channel showed that application of retigabine leads to a concentration-dependent hyperpolarization of the oocyte, from a resting potential of -63 mV under control conditions to -85 mV in the presence of 100 microM retigabine (IC(50) = 5.2 microM) [11].
  • We found suggestive linkage of the BFNC phenotype to the 20q13-EBN1 locus (lod score, 2.03) and an intronic mutation IVS14-6 C>A in KCNQ2 segregating with the trait in all affected members, but absent in 100 unrelated control subjects [12].

Anatomical context of KCNQ2


Associations of KCNQ2 with chemical compounds

  • NEM increased the P(o) of KCNQ2, KCNQ4, and KCNQ5 by threefold to fourfold but had no effect on their unitary conductances, suggesting that the increase in macroscopic currents can be accounted for by increases in P(o) [17].
  • The cysteine-modifying reagent N-ethylmaleimide (NEM) is known to augment currents from native M-channels in sympathetic neurons and cloned KCNQ2 channels [17].
  • Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine [11].
  • L-735,821, a benzodiazepine molecule which inhibits the KCNQ1 channel activity (EC50 = 0.08 microM), also blocks KCNQ2 currents (EC50 = 1.5 microM) [16].
  • Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium [18].

Physical interactions of KCNQ2

  • Conversely, a KCNQ3-sid(Q1) chimaera no longer affects KCNQ2 but interacts with KCNQ1 [19].

Regulatory relationships of KCNQ2

  • During brain development, KCNQ3 is expressed later than KCNQ2 [16].
  • We now show that the RNA encoding the novel KCNQ5 channel is also expressed in brain and in sympathetic ganglia where it overlaps largely with KCNQ2 and KCNQ3 [20].
  • We have studied the contribution of KCNQ/M-channels to the control of neuronal excitability by using transgenic mice that conditionally express dominant-negative KCNQ2 subunits in brain [21].
  • 5. Further, the compound enhanced the maximal current amplitude at all potentials for Kv7.4 and Kv7.5 whereas the combined activation/block of Kv7.2 and Kv7.2/3 was strongly voltage-dependent [22].

Other interactions of KCNQ2

  • Here, we show that KCNE2 is present in brain, in areas which also express KCNQ2 and KCNQ3 channels [2].
  • Quantitative PCR of whole-ganglion mRNA revealed stable levels of KCNQ2 and KCNQ5 mRNA between P7 and P45, but excess and incrementing levels of KCNQ3 mRNA [18].
  • The importance of ionic channels as cause of epilepsies was further demonstrated with the identification of the association between the benign neonatal epilepsy and mutations in genes coding for potassium channel subunits (KCNQ2, KCNQ3) [23].
  • In a screen of 23 SMEI patients with missense mutations of SCN1A, no second-site mutations in KCNQ2 were identified [24].
  • Considerable genetic, molecular, physiological and pharmacological evidence now exists to support a role for K(+) channels such as KCNQ2/Q3, Kv1.1, KATP and GIRK2 in the control of neuronal excitability and epileptogenesis [25].

Analytical, diagnostic and therapeutic context of KCNQ2


  1. 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]
  2. M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit. Tinel, N., Diochot, S., Lauritzen, I., Barhanin, J., Lazdunski, M., Borsotto, M. FEBS Lett. (2000) [Pubmed]
  3. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Dedek, K., Kunath, B., Kananura, C., Reuner, U., Jentsch, T.J., Steinlein, O.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  4. Mechanisms underlying modulation of neuronal KCNQ2/KCNQ3 potassium channels by extracellular protons. Prole, D.L., Lima, P.A., Marrion, N.V. J. Gen. Physiol. (2003) [Pubmed]
  5. (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]- 3-phenylacrylamide: an orally bioavailable KCNQ2 opener with significant activity in a cortical spreading depression model of migraine. Wu, Y.J., Boissard, C.G., Greco, C., Gribkoff, V.K., Harden, D.G., He, H., L'Heureux, A., Kang, S.H., Kinney, G.G., Knox, R.J., Natale, J., Newton, A.E., Lehtinen-Oboma, S., Sinz, M.W., Sivarao, D.V., Starrett, J.E., Sun, L.Q., Tertyshnikova, S., Thompson, M.W., Weaver, D., Wong, H.S., Zhang, L., Dworetzky, S.I. J. Med. Chem. (2003) [Pubmed]
  6. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Borgatti, R., Zucca, C., Cavallini, A., Ferrario, M., Panzeri, C., Castaldo, P., Soldovieri, M.V., Baschirotto, C., Bresolin, N., Dalla Bernardina, B., Taglialatela, M., Bassi, M.T. Neurology (2004) [Pubmed]
  7. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Singh, N.A., Charlier, C., Stauffer, D., DuPont, B.R., Leach, R.J., Melis, R., Ronen, G.M., Bjerre, I., Quattlebaum, T., Murphy, J.V., McHarg, M.L., Gagnon, D., Rosales, T.O., Peiffer, A., Anderson, V.E., Leppert, M. Nat. Genet. (1998) [Pubmed]
  8. Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq. Suh, B.C., Horowitz, L.F., Hirdes, W., Mackie, K., Hille, B. J. Gen. Physiol. (2004) [Pubmed]
  9. Potassium channels: how genetic studies of epileptic syndromes open paths to new therapeutic targets and drugs. Cooper, E.C. Epilepsia (2001) [Pubmed]
  10. Identification by mass spectrometry and functional characterization of two phosphorylation sites of KCNQ2/KCNQ3 channels. Surti, T.S., Huang, L., Jan, Y.N., Jan, L.Y., Cooper, E.C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  11. Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Main, M.J., Cryan, J.E., Dupere, J.R., Cox, B., Clare, J.J., Burbidge, S.A. Mol. Pharmacol. (2000) [Pubmed]
  12. A novel splicing mutation in KCNQ2 in a multigenerational family with BFNC followed for 25 years. de Haan, G.J., Pinto, D., Carton, D., Bader, A., Witte, J., Peters, E., van Erp, G., Vandereyken, W., Boezeman, E., Wapenaar, M.C., Boon, P., Halley, D., Koeleman, B.P., Lindhout, D. Epilepsia (2006) [Pubmed]
  13. 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]
  14. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. Tatulian, L., Delmas, P., Abogadie, F.C., Brown, D.A. J. Neurosci. (2001) [Pubmed]
  15. Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. Roche, J.P., Westenbroek, R., Sorom, A.J., Hille, B., Mackie, K., Shapiro, M.S. Br. J. Pharmacol. (2002) [Pubmed]
  16. The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. Tinel, N., Lauritzen, I., Chouabe, C., Lazdunski, M., Borsotto, M. FEBS Lett. (1998) [Pubmed]
  17. Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. Li, Y., Gamper, N., Shapiro, M.S. J. Neurosci. (2004) [Pubmed]
  18. Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. Hadley, J.K., Passmore, G.M., Tatulian, L., Al-Qatari, M., Ye, F., Wickenden, A.D., Brown, D.A. J. Neurosci. (2003) [Pubmed]
  19. A carboxy-terminal domain determines the subunit specificity of KCNQ K+ channel assembly. Schwake, M., Jentsch, T.J., Friedrich, T. EMBO Rep. (2003) [Pubmed]
  20. KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. Schroeder, B.C., Hechenberger, M., Weinreich, F., Kubisch, C., Jentsch, T.J. J. Biol. Chem. (2000) [Pubmed]
  21. Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Peters, H.C., Hu, H., Pongs, O., Storm, J.F., Isbrandt, D. Nat. Neurosci. (2005) [Pubmed]
  22. The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Bentzen, B.H., Schmitt, N., Calloe, K., Dalby Brown, W., Grunnet, M., Olesen, S.P. Neuropharmacology (2006) [Pubmed]
  23. Ion channel variation causes epilepsies. Moulard, B., Picard, F., le Hellard, S., Agulhon, C., Weiland, S., Favre, I., Bertrand, S., Malafosse, A., Bertrand, D. Brain Res. Brain Res. Rev. (2001) [Pubmed]
  24. Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Kearney, J.A., Yang, Y., Beyer, B., Bergren, S.K., Claes, L., Dejonghe, P., Frankel, W.N. Hum. Mol. Genet. (2006) [Pubmed]
  25. Potassium channels as anti-epileptic drug targets. Wickenden, A.D. Neuropharmacology (2002) [Pubmed]
  26. Changes in KCNQ2 immunoreactivity in the amygdala in two rat models of temporal lobe epilepsy. Penschuck, S., Bastlund, J.F., Jensen, H.S., Stensbol, T.B., Egebjerg, J., Watson, W.P. Brain Res. Mol. Brain Res. (2005) [Pubmed]
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