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Kv7.4

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Target not currently curated in GtoImmuPdb

Target id: 563

Nomenclature: Kv7.4

Family: Voltage-gated potassium channels

Gene and Protein Information Click here for help
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 Click here for help
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 Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Kv7.3 1
Kv7.5 1
Auxiliary Subunits
Name References
KCNE3 19
Other Associated Proteins
Name References
Calmodulin 10
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 Click here for help
Species:  Human
Single channel conductance (pS):  2.1
References:  16
Ion Selectivity and Conductance Comments
  • ion selectivity K+ ~ Rb+ > Cs+ > Na+ [13]
Voltage Dependence Click here for help
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -10.0 – -17.0 (median: -14.0) 350.0 – 600.0 13,18,20,23 Xenopus laevis oocyte Human
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -13.0 – -28.0 (median: -18.0) 163.0 9,21,26 CHO cells Human
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -32.0 45.0 – 531.0 24 HEK 293 cells Human
Inactivation  - -

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
ML213 Small molecule or natural product Hs Activation 6.3 pEC50 - - 32
pEC50 6.3 (EC50 5.1x10-7 M) [32]
retigabine derivative 10g Small molecule or natural product Click here for species-specific activity table Hs - 6.0 pEC50 - - 29
pEC50 6.0 [29]
retigabine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs - 5.2 pEC50 - - 26
pEC50 5.2 (EC50 6.31x10-6 M) [26]
flindokalner Small molecule or natural product Click here for species-specific activity table Hs - 5.0 pEC50 - - 24
pEC50 5.0 [24]
zinc pyrithione Small molecule or natural product Click here for species-specific activity table Hs - 5.0 pEC50 - - 30
pEC50 5.0 [30]
NC00075159 Small molecule or natural product Hs Activation 5.0 pEC50 - - 14
pEC50 5.0 [14]
PIP2 Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs - 3.7 pEC50 - - 15
pEC50 3.7 [15]
(S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide Small molecule or natural product Click here for species-specific activity table Hs - 5.0 pIC50 - - 3
pIC50 5.0 (IC50 1.04x10-5 M) [3]
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
XE991 Small molecule or natural product Click here for species-specific activity table Hs - 5.3 pIC50 - - 24
pIC50 5.3 (IC50 5.5x10-6 M) [24]
linopirdine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - 4.9 pIC50 - - 24
pIC50 4.9 (IC50 1.4x10-5 M) [24]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
bepridil Small molecule or natural product Approved drug Hs - 5.0 pIC50 - - 24
pIC50 5.0 [24]
tetraethylammonium Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - 1.3 pIC50 - - 1
pIC50 1.3 (IC50 5.2x10-2 M) [1]
Tissue Distribution Click here for help
Expressed in the outer, but not the inner, sensory hair cells of the cochlea, brain
Species:  Mouse
Technique:  RT-PCR
References:  13
Expressed in the outer, but not the inner, sensory hair cells of the cochlea
Species:  Mouse
Technique:  In situ hybridisation
References:  13
KCNQ4 is restricted to the type I hair cells and the afferent calyx-like nerve endings ensheathing these sensory cells, expressed in the braistem and central auditory pathway
Species:  Mouse
Technique:  Immunofluorescence
References:  12
Kcnq4 is not restricted to the auditory system but is likely to be ubiquitously expressed
Species:  Mouse
Technique:  RT-PCR
References:  2
KCNQ4 is expressed in vascular smooth muscle cells
Species:  Rat
Technique:  Real time qPCR, immunihistochemistry
References:  22
Physiological Functions Click here for help
May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea
Species:  Human
Tissue: 
References:  12-13
KCNQ4 channels are regulators of the vascular smooth cell tone in veins and arteries
Species:  Rat
Tissue: 
References:  22
KCNQ4 channels play a permissive role in skeletal muscle myogenesis and depends on PIP2
Species:  Mouse
Tissue: 
References:  11
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4tm1.2Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004434 abnormal cochlear outer hair cell physiology PMID: 16437162 
Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4tm1.2Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004737 absent distortion product otoacoustic emissions PMID: 16437162 
Kcnq4tm1.1Tjj Kcnq4tm1.1Tjj/Kcnq4tm1.1Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004404 cochlear outer hair cell degeneration PMID: 16437162 
Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4tm1.2Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004404 cochlear outer hair cell degeneration PMID: 16437162 
Kcnq4+|Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4+
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004404 cochlear outer hair cell degeneration PMID: 16437162 
Kcnq4tm1.1Tjj Kcnq4tm1.1Tjj/Kcnq4tm1.1Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004765 decreased brainstem auditory evoked potential PMID: 16437162 
Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4tm1.2Tjj
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004765 decreased brainstem auditory evoked potential PMID: 16437162 
Kcnq4+|Kcnq4tm1.2Tjj Kcnq4tm1.2Tjj/Kcnq4+
involves: 129/Sv * C57BL/6
MGI:1926803  MP:0004765 decreased brainstem auditory evoked potential PMID: 16437162 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Deafness, autosomal dominant 2A; DFNA2A
Synonyms: Autosomal dominant nonsyndromic deafness [Disease Ontology: DOID:0050564]
Autosomal dominant non-syndromic sensorineural deafness type DFNA [Orphanet: ORPHA90635]
Disease Ontology: DOID:0050564
OMIM: 600101
Orphanet: ORPHA90635
Role: 
References:  6,13,25,27-28
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift: Deletion Human G70fs c.211_224del 6
Missense Human L274H 28
Missense Human W276S 827G>C Pore region 6,27
Missense Human L281S 824T>C 25
Missense Human G285S 853G>A Exon 6. Pore region 13
Missense Human G285C 853G>T 6,13
Missense Human G296S 886G>A 17
Missense Human G321S 961G>A Exon 6. S6 transmembrane domain of the protein. 6
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].

References

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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]

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