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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 | 695 | 1p34.2 | KCNQ4 | potassium voltage-gated channel subfamily Q member 4 | 13 |
| Mouse | 6 | 1 | 696 | 4 D2.2 | Kcnq4 | potassium voltage-gated channel, subfamily Q, member 4 | 5 |
| Rat | - | 1 | 168 | 5q36 | Kcnq4 | potassium voltage-gated channel subfamily Q member 4 | |
| Previous and Unofficial Names |
| DFNA2 | potassium channel subunit alpha KvLQT4 | potassium voltage-gated channel, KQT-like subfamily, member 4 | potassium channel, voltage gated KQT-like subfamily Q, member 4 | potassium channel, voltage-gated KQT-like subfamily Q, member 4 | potassium voltage-gated channel |
| Database Links |
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| Alphafold | P56696 (Hs), Q9JK97 (Mm), Q9JK96 (Rn) |
| ChEMBL Target | CHEMBL3576 (Hs), CHEMBL3621034 (Rn) |
| Ensembl Gene | ENSG00000117013 (Hs), ENSMUSG00000028631 (Mm), ENSRNOG00000060435 (Rn) |
| Entrez Gene | 9132 (Hs), 60613 (Mm), 298496 (Rn) |
| Human Protein Atlas | ENSG00000117013 (Hs) |
| KEGG Gene | hsa:9132 (Hs), mmu:60613 (Mm), rno:298496 (Rn) |
| OMIM | 603537 (Hs) |
| Orphanet | ORPHA122821 (Hs) |
| Pharos | P56696 (Hs) |
| RefSeq Nucleotide | NM_172163 (Hs), NM_004700 (Hs), NM_001081142 (Mm), XM_233477 (Rn) |
| RefSeq Protein | NP_004691 (Hs), NP_751895 (Hs), NP_001074611 (Mm), XP_233477 (Rn) |
| UniProtKB | P56696 (Hs), Q9JK97 (Mm), Q9JK96 (Rn) |
| Wikipedia | KCNQ4 (Hs) |
| Associated Proteins |
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| Associated Protein Comments | ||||||||||||||||||||||
| Gating and modulation: Ca2+-calmodulin reduces the currents produced by KCNQ2, KCNQ4 and KCNQ5, but not those of KCNQ1 and KCNQ3 [7]. Ca2+-calmodulin wraps around the KCNQ4 B helix, which forms an α-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca2+/CaM interaction motif [31]. PIP2 exhibits low affinity to KCNQ2 (≈215 µM) and stabilizes the channel in the open state by increasing the open probability [8,15]. In mesenteric artery smooth muscle cells, protein kinase C phosphorylates both KCNQ4 and KCNQ5 heteromers, thereby reducing the KCNQ4/KCNQ5 currents in response to vasoconstriction [4]. | ||||||||||||||||||||||
| Ion Selectivity and Conductance |
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| Ion Selectivity and Conductance Comments | ||||||
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| Voltage Dependence |
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Download all structure-activity data for this target as a CSV file 
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| Channel Blockers | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Tissue Distribution
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| Physiological Functions
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Biologically Significant Variant Comments |
| Four variants were identified and designated as Kcnq4_v1–v4 differing through alternative use of exons 9–11 Kcnq4_v1 (lacks exons 9 and 11), Kcnq4_v2 (lacks exons 9 and 10), Kcnq4_v3 (lacks exons 10 and 11), Kcnq4_v4 (lacks exons 9, 10 and 11) [2]. Variant Kcnq4_v1 appeared in all tissues examined. Variants Kcnq4_v2 and Kcnq4_v4 were predominantly present in electrically excitable tissues. Variant Kcnq4_v3 appeared to be limited to the sensory epithelium of the cochlea [2]. |
1. Bal M, Zhang J, Zaika O, Hernandez CC, Shapiro MS. (2008) Homomeric and heteromeric assembly of KCNQ (Kv7) K+ channels assayed by total internal reflection fluorescence/fluorescence resonance energy transfer and patch clamp analysis. J Biol Chem, 283 (45): 30668-76. [PMID:18786918]
2. Beisel KW, Rocha-Sanchez SM, Morris KA, Nie L, Feng F, Kachar B, Yamoah EN, Fritzsch B. (2005) Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss. J Neurosci, 25 (40): 9285-93. [PMID:16207888]
3. 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]
4. Brueggemann LI, Mackie AR, Cribbs LL, Freda J, Tripathi A, Majetschak M, Byron KL. (2014) Differential protein kinase C-dependent modulation of Kv7.4 and Kv7.5 subunits of vascular Kv7 channels. J Biol Chem, 289 (4): 2099-111. [PMID:24297175]
5. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi T, Lenhard B, Wells C et al.. (2005) The transcriptional landscape of the mammalian genome. Science, 309 (5740): 1559-63. [PMID:16141072]
6. Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F et al.. (1999) Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet, 8 (7): 1321-8. [PMID:10369879]
7. 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]
8. Gamper N, Shapiro MS. (2007) Regulation of ion transport proteins by membrane phosphoinositides. Nat Rev Neurosci, 8 (12): 921-34. [PMID:17971783]
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. Haitin Y, Attali B. (2008) The C-terminus of Kv7 channels: a multifunctional module. J Physiol (Lond.), 586 (7): 1803-10. [PMID:18218681]
11. Iannotti FA, Silvestri C, Mazzarella E, Martella A, Calvigioni D, Piscitelli F, Ambrosino P, Petrosino S, Czifra G, Bíró T et al.. (2014) The endocannabinoid 2-AG controls skeletal muscle cell differentiation via CB1 receptor-dependent inhibition of Kv7 channels. Proc Natl Acad Sci USA, 111 (24): E2472-81. [PMID:24927567]
12. Kharkovets T, Hardelin JP, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ. (2000) KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci USA, 97 (8): 4333-8. [PMID:10760300]
13. Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. (1999) KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell, 96 (3): 437-46. [PMID:10025409]
14. Li Q, Rottländer M, Xu M, Christoffersen CT, Frederiksen K, Wang MW, Jensen HS. (2011) Identification of novel KCNQ4 openers by a high-throughput fluorescence-based thallium flux assay. Anal Biochem, 418 (1): 66-72. [PMID:21782781]
15. 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]
16. 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]
17. Mencía A, González-Nieto D, Modamio-Høybjør S, Etxeberría A, Aránguez G, Salvador N, Del Castillo I, Villarroel A, Moreno F, Barrio L et al.. (2008) A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum Genet, 123 (1): 41-53. [PMID:18030493]
18. Panaghie G, Abbott GW. (2007) The role of S4 charges in voltage-dependent and voltage-independent KCNQ1 potassium channel complexes. J Gen Physiol, 129 (2): 121-33. [PMID:17227916]
19. Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ. (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature, 403 (6766): 196-9. [PMID:10646604]
20. Seebohm G, Strutz-Seebohm N, Baltaev R, Korniychuk G, Knirsch M, Engel J, Lang F. (2005) Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes. Cell Physiol Biochem, 16 (4-6): 255-62. [PMID:16301825]
21. Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Jentsch TJ, Brown DA. (2000) Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors. J Physiol (Lond.), 522 Pt 3: 349-55. [PMID:10713961]
22. Stott JB, Jepps TA, Greenwood IA. (2014) K(V)7 potassium channels: a new therapeutic target in smooth muscle disorders. Drug Discov Today, 19 (4): 413-24. [PMID:24333708]
23. Su CC, Li SY, Yang JJ, Su MC, Lin MJ. (2006) Studies of the effect of ionomycin on the KCNQ4 channel expressed in Xenopus oocytes. Biochem Biophys Res Commun, 348 (1): 295-300. [PMID:16876114]
24. Søgaard R, Ljungstrøm T, Pedersen KA, Olesen SP, Jensen BS. (2001) KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology. Am J Physiol, Cell Physiol, 280 (4): C859-66. [PMID:11245603]
25. Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD. (1999) Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat, 14 (6): 493-501. [PMID:10571947]
26. 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]
27. Van Camp G, Coucke PJ, Akita J, Fransen E, Abe S, De Leenheer EM, Huygen PL, Cremers CW, Usami S. (2002) A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum Mutat, 20 (1): 15-9. [PMID:12112653]
28. Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CW, Van Camp G. (2000) Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet, 93 (3): 184-7. [PMID:10925378]
29. Wang L, Qiao GH, Hu HN, Gao ZB, Nan FJ. (2019) Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity. ACS Med Chem Lett, 10 (1): 27-33. [PMID:30655942]
30. 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]
31. Xu Q, Chang A, Tolia A, Minor Jr DL. (2013) Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. J Mol Biol, 425 (2): 378-94. [PMID:23178170]
32. Yu H, Wu M, Townsend SD, Zou B, Long S, Daniels JS, McManus OB, Li M, Lindsley CW, Hopkins CR. (2011) Discovery, Synthesis, and Structure Activity Relationship of a Series of N-Aryl- bicyclo[2.2.1]heptane-2-carboxamides: Characterization of ML213 as a Novel KCNQ2 and KCNQ4 Potassium Channel Opener. ACS Chem Neurosci, 2 (10): 572-577. [PMID:22125664]
