KvLQT2 explained

K_v7.2 (KvLQT2) is a voltage- and lipid-gated potassium channel protein coded for by the gene KCNQ2.

Mutations in the KCNQ2 gene are dominant autosomally inherited causes of benign familial neonatal epilepsy.^[1]

Function

The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene.^[2]

Ligands

• ICA-069673: channel opener at KCNQ2/Q3, 20-fold selective over KCNQ3/Q5, no measurable activity against a panel of cardiac ion channels (hERG, Nav1.5, L type channels, and KCNQ1) and no activity on GABA_A gated channels at 10 μM. A range of related benzamides exhibited activity, of which compound number 40 is shown here.^[3]
• ML252: channel inhibitor, IC₅₀ = 70nM.^[4]
• Phosphatidylinositol 4,5-bisphosphate (PIP₂)

Further reading

• Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X . International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels . Pharmacological Reviews . 57 . 4 . 473–508 . December 2005 . 16382104 . 10.1124/pr.57.4.10 . 219195192 .
• Yokoyama M, Nishi Y, Yoshii J, Okubo K, Matsubara K . Identification and cloning of neuroblastoma-specific and nerve tissue-specific genes through compiled expression profiles . DNA Research . 3 . 5 . 311–20 . October 1996 . 9039501 . 10.1093/dnares/3.5.311 . free .
• Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert M . A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns . Nature Genetics . 18 . 1 . 25–9 . January 1998 . 9425895 . 10.1038/ng0198-25 . 30469895 .
• Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK . A potassium channel mutation in neonatal human epilepsy . Science . 279 . 5349 . 403–6 . January 1998 . 9430594 . 10.1126/science.279.5349.403 . 1998Sci...279..403B .
• Yang WP, Levesque PC, Little WA, Conder ML, Ramakrishnan P, Neubauer MG, Blanar MA . Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy . The Journal of Biological Chemistry . 273 . 31 . 19419–23 . July 1998 . 9677360 . 10.1074/jbc.273.31.19419 . free .
• Tinel N, Lauritzen I, Chouabe C, Lazdunski M, Borsotto M . The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3 . FEBS Letters . 438 . 3 . 171–6 . November 1998 . 9827540 . 10.1016/S0014-5793(98)01296-4 . 1998FEBSL.438..171T . 33708352 .
• Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D . KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel . Science . 282 . 5395 . 1890–3 . December 1998 . 9836639 . 10.1126/science.282.5395.1890 . 1998Sci...282.1890W .
• Schroeder BC, Kubisch C, Stein V, Jentsch TJ . Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy . Nature . 396 . 6712 . 687–90 . December 1998 . 9872318 . 10.1038/25367 . 1998Natur.396..687S . 4417442 .
• Biervert C, Steinlein OK . Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions . Human Genetics . 104 . 3 . 234–40 . March 1999 . 10323247 . 10.1007/PL00008713 . 30751027 .
• Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Delmas P, Buckley NJ, London B, Brown DA . Two types of K(+) channel subunit, Erg1 and KCNQ2/3, contribute to the M-like current in a mammalian neuronal cell . The Journal of Neuroscience . 19 . 18 . 7742–56 . September 1999 . 10479678 . 10.1523/jneurosci.19-18-07742.1999. 6782456 .
• Shapiro MS, Roche JP, Kaftan EJ, Cruzblanca H, Mackie K, Hille B . Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current . The Journal of Neuroscience . 20 . 5 . 1710–21 . March 2000 . 10684873 . 10.1523/jneurosci.20-05-01710.2000. 6772928 . free .
• Rundfeldt C, Netzer R . The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits . Neuroscience Letters . 282 . 1–2 . 73–6 . March 2000 . 10713399 . 10.1016/S0304-3940(00)00866-1 . 28431577 .
• Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA . Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors . The Journal of Physiology . 522 . 3 . 349–55 . February 2000 . 10713961 . 2269765 . 10.1111/j.1469-7793.2000.t01-2-00349.x .
• Cooper EC, Aldape KD, Abosch A, Barbaro NM, Berger MS, Peacock WS, Jan YN, Jan LY . Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy . Proceedings of the National Academy of Sciences of the United States of America . 97 . 9 . 4914–9 . April 2000 . 10781098 . 18332 . 10.1073/pnas.090092797 . 2000PNAS...97.4914C . free .
• Schwake M, Pusch M, Kharkovets T, Jentsch TJ . Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy . The Journal of Biological Chemistry . 275 . 18 . 13343–8 . May 2000 . 10788442 . 10.1074/jbc.275.18.13343 . free .
• Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA . Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine . Molecular Pharmacology . 58 . 2 . 253–62 . August 2000 . 10908292 . 10.1124/mol.58.2.253. 11112809 .
• Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK . Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels . Molecular Pharmacology . 58 . 3 . 591–600 . September 2000 . 10953053 . 10.1124/mol.58.3.591.
• Tinel N, Diochot S, Lauritzen I, Barhanin J, Lazdunski M, Borsotto M . M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit . FEBS Letters . 480 . 2–3 . 137–41 . September 2000 . 11034315 . 10.1016/S0014-5793(00)01918-9 . 8386123 . free . 2000FEBSL.480..137T .
• Smith JS, Iannotti CA, Dargis P, Christian EP, Aiyar J . Differential expression of kcnq2 splice variants: implications to m current function during neuronal development . The Journal of Neuroscience . 21 . 4 . 1096–103 . February 2001 . 11160379 . 10.1523/jneurosci.21-04-01096.2001. 6762257 . free .
• Miraglia del Giudice E, Coppola G, Scuccimarra G, Cirillo G, Bellini G, Pascotto A . Benign familial neonatal convulsions (BFNC) resulting from mutation of the KCNQ2 voltage sensor . European Journal of Human Genetics . 8 . 12 . 994–7 . December 2000 . 11175290 . 10.1038/sj.ejhg.5200570 . free .

Notes and References

1. KCNQ2-Related Disorders . National Library of Medicine . 1993 . GeneReviews . 20437616 . 8 September 2024 . Adam . M. P. . Feldman . J. . Mirzaa . G. M. . Pagon . R. A. . Wallace . S. E. . Amemiya . A. . Miceli . F. . Soldovieri . M. V. . Weckhuysen . S. . Cooper . E. . Taglialatela . M. .
2. Web site: Entrez Gene: KCNQ2 potassium voltage-gated channel, KQT-like subfamily, member 2.
3. 10.1021/ml200053x . 2 . N -Pyridyl and Pyrimidine Benzamides as KCNQ2/Q3 Potassium Channel Openers for the Treatment of Epilepsy . 2011 . ACS Medicinal Chemistry Letters . 481–484 . Amato G. 6 . 24900334 . 4018159 .
4. Cheung YY, Yu H, Xu K, Zou B, Wu M, McManus OB, Li M, Lindsley CW, Hopkins CR . Discovery of a series of 2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)acetamides as novel molecular switches that modulate modes of K(v)7.2 (KCNQ2) channel pharmacology: identification of (S)-2-phenyl-N-(2-(pyrrolidin-1-yl)phenyl)butanamide (ML252) as a potent, brain penetrant K(v)7.2 channel inhibitor . Journal of Medicinal Chemistry . 55 . 15 . 6975–9 . August 2012 . 22793372 . 3530927 . 10.1021/jm300700v .