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Gene and Protein Information ![]() |
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Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 6 | 1 | 872 | 20q13.33 | KCNQ2 | potassium voltage-gated channel subfamily Q member 2 | 32 |
Mouse | 6 | 1 | 759 | 2 103.57 cM | Kcnq2 | potassium voltage-gated channel, subfamily Q, member 2 | 23 |
Rat | 6 | 1 | 852 | 3q43 | Kcnq2 | potassium voltage-gated channel subfamily Q member 2 | 16 |
Database Links ![]() |
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Alphafold | O43526 (Hs), Q9Z351 (Mm), O88943 (Rn) |
ChEMBL Target | CHEMBL2476 (Hs), CHEMBL2985 (Mm), CHEMBL5530 (Rn) |
DrugBank Target | O43526 (Hs) |
Ensembl Gene | ENSG00000075043 (Hs), ENSMUSG00000016346 (Mm), ENSRNOG00000011624 (Rn) |
Entrez Gene | 3785 (Hs), 16536 (Mm), 170848 (Rn) |
Human Protein Atlas | ENSG00000075043 (Hs) |
KEGG Gene | hsa:3785 (Hs), mmu:16536 (Mm), rno:170848 (Rn) |
OMIM | 602235 (Hs) |
Orphanet | ORPHA122808 (Hs) |
Pharos | O43526 (Hs) |
RefSeq Nucleotide | NM_172107 (Hs), NM_010611 (Mm), NM_133322 (Rn) |
RefSeq Protein | NP_742105 (Hs), NP_034741 (Mm), NP_579856 (Rn) |
UniProtKB | O43526 (Hs), Q9Z351 (Mm), O88943 (Rn) |
Wikipedia | KCNQ2 (Hs) |
Associated Proteins ![]() |
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Associated Protein Comments | ||||||||||||||||||||||||
Gating and modulation: PIP2 exhibits low affinity to KCNQ2 (≈205 µM) and stabilizes the channel in the open state by increasing the open probability [8,19]. KCNQ2 subunit tethers PIP2, CaM, AKAP79/150, and PKC. Activation of PLC by muscarinic stimulation depletes PIP2 and activates PKC, which phosphorylates KCNQ2 subunit. The phosphorylation of KCNQ2 at S541 located in the distal segment of the CaM-binding site induces dissociation of CaM from the KCNQ2 channel, which lowers affinity towards PIP2. This produces profound suppression of the M-channel activity [17]. Ca2+-Calmodulin reduces the currents produced by KCNQ2, KCNQ4 and KCNQ5, but not those of KCNQ1 and KCNQ3 [8]. |
Functional Characteristics ![]() |
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M current as a heteromer between KV7.2 and KV7.3 |
Ion Selectivity and Conductance ![]() |
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Ion Selectivity and Conductance Comments | ||||||
Voltage Dependence ![]() |
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Download all structure-activity data for this target as a CSV file
Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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View species-specific activator tables |
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Channel Blockers | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Tissue Distribution ![]() |
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Physiological Functions ![]() |
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Phenotypes, Alleles and Disease Models ![]() |
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology ![]() |
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Biologically Significant Variants ![]() |
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General Comments |
The M current is a slowly activating and deactivating potassium conductance that plays a critical role in determining the sub-threshold excitability of neurones as well as the responsiveness to synaptic inputs. The M current was first described in peripheral sympathetic neurones, and differential expression of this conductance produces subtypes of sympathetic neurones with distinct firing patterns. The M current is also expressed in many neurons in the central nervous system. The M-current is mediated by members of the Kv7 family, which form a heterotetrameric channel consisting of KCNQ3 subunits associated with either KCNQ2 or KCNQ5 subunits. Expression of KCNQ2, KCNQ3 and KCNQ5 proteins mostly overlaps with distribution of M current. The activation mechanism of KCNQ2 has been elicidated using high-resolution structures of the channel generated by cryo-electron microscopy [18]. Retigabine binds at the pore domain and activates the channel by an allosteric modulation, whereas ztz240 binds at the voltage-sensing domain and directly stabilizes the channel in the activated state [18]. |
1. Abbott GW, Butler MH, Bendahhou S, Dalakas MC, Ptacek LJ, Goldstein SA. (2001) MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell, 104 (2): 217-31. [PMID:11207363]
2. Bentzen BH, Schmitt N, Calloe K, Dalby Brown W, Grunnet M, Olesen SP. (2006) The acrylamide (S)-1 differentially affects Kv7 (KCNQ) potassium channels. Neuropharmacology, 51 (6): 1068-77. [PMID:16904708]
3. Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK. (1998) A potassium channel mutation in neonatal human epilepsy. Science, 279 (5349): 403-6. [PMID:9430594]
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7. Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK. (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci USA, 98 (21): 12272-7. [PMID:11572947]
8. Gamper N, Li Y, Shapiro MS. (2005) Structural requirements for differential sensitivity of KCNQ K+ channels to modulation by Ca2+/calmodulin. Mol Biol Cell, 16 (8): 3538-51. [PMID:15901836]
9. Gamper N, Stockand JD, Shapiro MS. (2003) Subunit-specific modulation of KCNQ potassium channels by Src tyrosine kinase. J Neurosci, 23 (1): 84-95. [PMID:12514204]
10. Gao Z, Zhang T, Wu M, Xiong Q, Sun H, Zhang Y, Zu L, Wang W, Li M. (2010) Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions. J Biol Chem, 285 (36): 28322-32. [PMID:20584905]
11. Gu N, Vervaeke K, Hu H, Storm JF. (2005) Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J Physiol (Lond.), 566 (Pt 3): 689-715. [PMID:15890705]
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13. Hadley JK, Passmore GM, Tatulian L, Al-Qatari M, Ye F, Wickenden AD, Brown DA. (2003) Stoichiometry of expressed KCNQ2/KCNQ3 potassium channels and subunit composition of native ganglionic M channels deduced from block by tetraethylammonium. J Neurosci, 23 (12): 5012-9. [PMID:12832524]
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16. Jow F, Wang K. (2000) Cloning and functional expression of rKCNQ2 K(+) channel from rat brain. Brain Res Mol Brain Res, 80 (2): 269-78. [PMID:11038262]
17. Kosenko A, Kang S, Smith IM, Greene DL, Langeberg LK, Scott JD, Hoshi N. (2012) Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation. EMBO J, 31 (14): 3147-56. [PMID:22643219]
18. Li X, Zhang Q, Guo P, Fu J, Mei L, Lv D, Wang J, Lai D, Ye S, Yang H et al.. (2021) Molecular basis for ligand activation of the human KCNQ2 channel. Cell Res, 31 (1): 52-61. [PMID:32884139]
19. Li Y, Gamper N, Hilgemann DW, Shapiro MS. (2005) Regulation of Kv7 (KCNQ) K+ channel open probability by phosphatidylinositol 4,5-bisphosphate. J Neurosci, 25 (43): 9825-35. [PMID:16251430]
20. Li Y, Gamper N, Shapiro MS. (2004) Single-channel analysis of KCNQ K+ channels reveals the mechanism of augmentation by a cysteine-modifying reagent. J Neurosci, 24 (22): 5079-90. [PMID:15175377]
21. Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA. (2000) Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol, 58 (2): 253-62. [PMID:10908292]
22. Martire M, Castaldo P, D'Amico M, Preziosi P, Annunziato L, Taglialatela M. (2004) M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci, 24 (3): 592-7. [PMID:14736843]
23. McCormack T, Rudy B, Seldin MF. (1999) Chromosomal mapping of the potassium channel genes Kcnq2 and Kcnq3 in mouse. Genomics, 56 (3): 360-1. [PMID:10087209]
24. Padilla K, Wickenden AD, Gerlach AC, McCormack K. (2009) The KCNQ2/3 selective channel opener ICA-27243 binds to a novel voltage-sensor domain site. Neurosci Lett, 465 (2): 138-42. [PMID:19733209]
25. Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD, Bennett V, Scherer SS, Cooper EC. (2006) A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci, 26 (10): 2599-613. [PMID:16525039]
26. Peters HC, Hu H, Pongs O, Storm JF, Isbrandt D. (2005) Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nat Neurosci, 8 (1): 51-60. [PMID:15608631]
27. Prole DL, Marrion NV. (2004) Ionic permeation and conduction properties of neuronal KCNQ2/KCNQ3 potassium channels. Biophys J, 86 (3): 1454-69. [PMID:14990473]
28. Schenzer A, Friedrich T, Pusch M, Saftig P, Jentsch TJ, Grötzinger J, Schwake M. (2005) Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci, 25 (20): 5051-60. [PMID:15901787]
29. Schroeder BC, Kubisch C, Stein V, Jentsch TJ. (1998) Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature, 396 (6712): 687-90. [PMID:9872318]
30. Schrøder RL, Jespersen T, Christophersen P, Strøbaek D, Jensen BS, Olesen SP. (2001) KCNQ4 channel activation by BMS-204352 and retigabine. Neuropharmacology, 40 (7): 888-98. [PMID:11378159]
31. Shah MM, Migliore M, Valencia I, Cooper EC, Brown DA. (2008) Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons. Proc Natl Acad Sci USA, 105 (22): 7869-74. [PMID:18515424]
32. Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV et al.. (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet, 18 (1): 25-9. [PMID:9425895]
33. Smith JS, Iannotti CA, Dargis P, Christian EP, Aiyar J. (2001) Differential expression of kcnq2 splice variants: implications to m current function during neuronal development. J Neurosci, 21 (4): 1096-103. [PMID:11160379]
34. Soldovieri MV, Cilio MR, Miceli F, Bellini G, Miraglia del Giudice E, Castaldo P, Hernandez CC, Shapiro MS, Pascotto A, Annunziato L, Taglialatela M. (2007) Atypical gating of M-type potassium channels conferred by mutations in uncharged residues in the S4 region of KCNQ2 causing benign familial neonatal convulsions. J Neurosci, 27 (18): 4919-28. [PMID:17475800]
35. Tatulian L, Delmas P, Abogadie FC, Brown DA. (2001) Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci, 21 (15): 5535-45. [PMID:11466425]
36. Tinel N, Lauritzen I, Chouabe C, Lazdunski M, Borsotto M. (1998) The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. FEBS Lett, 438 (3): 171-6. [PMID:9827540]
37. Vernier JM, De La Rosa MA, Chen H, Wu JZ, Larson GL, Cheney IW. (2008) Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators. Patent number: WO2008024398A2. Assignee: Valeant Pharmaceuticals International. Priority date: 22/08/2007. Publication date: 28/02/2008.
38. Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D. (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science, 282 (5395): 1890-3. [PMID:9836639]
39. Wickenden AD, Roeloffs R, McNaughton-Smith G, Rigdon GC. (2004) KCNQ potassium channels: drug targets for the treatment of epilepsy and pain. Expert Opin Ther Pat, 14 (4): 1-13.
40. Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK. (2000) Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol, 58 (3): 591-600. [PMID:10953053]
41. Wu YJ, Boissard CG, Greco C, Gribkoff VK, Harden DG, He H, L'Heureux A, Kang SH, Kinney GG, Knox RJ, Natale J, Newton AE, Lehtinen-Oboma S, Sinz MW, Sivarao DV, Starrett JE, Sun LQ, Tertyshnikova S, Thompson MW, Weaver D, Wong HS, Zhang L, Dworetzky SI. (2003) (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. J Med Chem, 46 (15): 3197-200. [PMID:12852750]
42. Xiong Q, Sun H, Li M. (2007) Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants. Nat Chem Biol, 3 (5): 287-96. [PMID:17435769]
43. Yang WP, Levesque PC, Little WA, Conder ML, Ramakrishnan P, Neubauer MG, Blanar MA. (1998) Functional expression of two KvLQT1-related potassium channels responsible for an inherited idiopathic epilepsy. J Biol Chem, 273 (31): 19419-23. [PMID:9677360]
44. Yue C, Yaari Y. (2004) KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal neurons. J Neurosci, 24 (19): 4614-24. [PMID:15140933]
45. Zhang F, Mi Y, Qi JL, Li JW, Si M, Guan BC, Du XN, An HL, Zhang HL. (2013) Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58. Br J Pharmacol, 168 (4): 1030-42. [PMID:23013484]