K<SUB>v</SUB>7.3 | Voltage-gated potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

Kv7.3

Target id: 562

Nomenclature: Kv7.3

Family: Voltage-gated potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for Kv7.3 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 872 8q24 KCNQ3 potassium voltage-gated channel subfamily Q member 3 2,23
Mouse 6 1 873 15 D1-D2 Kcnq3 potassium voltage-gated channel, subfamily Q, member 3 16
Rat 6 1 873 7q33 Kcnq3 potassium voltage-gated channel subfamily Q member 3 29
Previous and Unofficial Names
EBN2 | potassium channel subunit alpha KvLQT3 | potassium voltage-gated channel, KQT-like subfamily, member 3 | potassium channel, voltage gated KQT-like subfamily Q, member 3 | potassium channel, voltage-gated KQT-like subfamily Q, member 3 | potassium voltage-gated channel
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Kv7.2 10,23,29
Kv7.5 12,22
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Calmodulin 11
Associated Protein Comments
Gating and modulation: PIP2 exhibits high affinity to KCNQ3 (≈ 2.6 µM) and stabilizes the channel in the open state by increasing the open probability [8,25]. In contrast to KCNQ2, KCNQ4 and KCNQ5, Ca2+-calmodulin does not reduce the currents produced by KCNQ3 [26]. Src tyrosine kinase reduces KCNQ3 current amplitude and slows the activation kinetics [5].
Functional Characteristics
M current as heteromeric KV7.2/KV7.3 or KV7.3/KV7.5
Ion Selectivity and Conductance
Species:  Human
Single channel conductance (pS):  8.5
References:  13
Ion Selectivity and Conductance Comments
Ion selectivity rank: K+ > Rb+ > Cs+ > NH4+ [20].
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -37.0 – -29.0 64.0 1,6,24 CHO cells Human
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -50.0 - 1 Xenopus laevis oocyte Human
Inactivation  - -

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
retigabine Hs - 6.2 pEC50 - - 28
pEC50 6.2 (EC50 6.31x10-7 M) [28]
Activator Comments
Heteromeric specific affinities are listed below :
  • KCNQ2/KCNQ3: retigabine, pEC50 ~ 5.8-6.5 [6,14]
  • KCNQ3/KCNQ5: retigabine, pEC50 ~ 5.8 [30]
  • KCNQ2/KCNQ3: zinc pyrithione, pEC50 ~ 5.6 [32]
  • KCNQ2/KCNQ3: diclofenac, pEC50 ~ 5.6 [19]
  • KCNQ2/KCNQ3: meclofenamate , pEC50 ~ 4.6 [19]
  • KCNQ2/KCNQ3: flupirtine, pEC50 ~ 5.0 [15]
In contrast to KCNQ2, ICA-27243, ztz240 and QO-58 do not activate KCNQ3 [7,17,34].
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
linopirdine Rn - 5.4 pIC50 - - 29
pIC50 5.4 (IC50 4x10-6 M) [29]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
tetraethylammonium Hs - 1.5 pIC50 - - 9
pIC50 1.5 [9]
Channel Blocker Comments
Heteromeric specific affinities are listed below :
  • KCNQ2/KCNQ3: XE991, pEC50 ~ 6.2 [29]
  • KCNQ2/KCNQ3: linopirdine, pEC50 ~ 5.4 [6,29]
  • KCNQ2/KCNQ3:amitriptyline, pEC50 ~ 5.0 [21]
  • KCNQ3/KCNQ5: linopirdine, pEC50 ~ 5.0 [30]
  • KCNQ3/KCNQ5: Ba2+ , pEC50 ~ 4.6 [30]
Tissue Distribution
Predominantly expressed in brain
Species:  Human
Technique:  Northern Blot
References:  23,33
Cortex, hippocampus
Species:  Human
Technique:  Immunohistochemistry
References:  4
Broad distribution in brain
Species:  Rat
Technique:  In situ hybridisation
References:  23
Sympathetic ganglia, lower expression levels in the cerebellum than in cortex and hippocampus
Species:  Rat
Technique:  Northern Blot
References:  29
KCNQ2/KCNQ3 heteromers are expressed at the axon initial segment in various regions of the brain. A short motif, common to KCNQ2 and KCNQ3, mediates ankyrin-G interaction and retention of the subunits at the axon initial segment.
Species:  Rat
Technique:  Immunohistochemistry
References:  18
Physiological Functions
Human and rat studies shown that KCNQ3 is probably important in the regulation of neuronal excitability. Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current. ). In hippocampal pyramidal neurons, axo-somatic KCNQ channels are crucial for setting the spike frequency and the action potential threshold. They contribute to the medium afterhyperpolarization and reduce the spike afterdepolarization by limiting its amplitude and duration, thereby precluding its escalation to a burst.
Species:  Human
Tissue:  Neurons
References:  4,23,25,29,31-33
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnq3tm1Dgen Kcnq3tm1Dgen/Kcnq3tm1Dgen
Not Specified
MGI:1336181  MP:0003412 abnormal afterhyperpolarization PMID: 19060215 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0000807 abnormal hippocampus morphology PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1336181  MP:0004811 abnormal neuron physiology PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * FVB/N
MGI:1336181  MP:0004811 abnormal neuron physiology PMID: 18483067 
Kcnq3tm1Dgen Kcnq3tm1Dgen/Kcnq3tm1Dgen
Not Specified
MGI:1336181  MP:0008872 abnormal physiological response to xenobiotic PMID: 19060215 
Kcnq3+|Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1336181  MP:0001650 abnormal seizure response to electrical stimulation PMID: 18483067 
Kcnq3+|Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3+
involves: 129S1/Sv * 129X1/SvJ * FVB/N
MGI:1336181  MP:0001650 abnormal seizure response to electrical stimulation PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0003354 astrocytosis PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
B6.129-Kcnq3
MGI:1336181  MP:0001265 decreased body size PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0001265 decreased body size PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0001651 necrosis PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0002058 neonatal lethality PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1336181  MP:0002082 postnatal lethality PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
B6.129-Kcnq3
MGI:1336181  MP:0002082 postnatal lethality PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * FVB/N
MGI:1336181  MP:0002082 postnatal lethality PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
B6.129-Kcnq3
MGI:1336181  MP:0002083 premature death PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0002083 premature death PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1336181  MP:0002064 seizures PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
B6.129-Kcnq3
MGI:1336181  MP:0002064 seizures PMID: 18483067 
Kcnq3tm1.1Naas Kcnq3tm1.1Naas/Kcnq3tm1.1Naas
FVB.129-Kcnq3
MGI:1336181  MP:0002064 seizures PMID: 18483067 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Benign familial infantile epilepsy
Synonyms: Benign familial infantile convulsions
Benign familial infantile seizures
Disease Ontology: DOID:0060169
Orphanet: ORPHA306
Disease:  Juvenile myoclonic epilepsy
Disease Ontology: DOID:4890
Orphanet: ORPHA307
Disease:  Seizures, benign familial neonatal, 2; BFNS2
Synonyms: Benign familial neonatal seizures [Orphanet: ORPHA1949]
Benign neonatal seizures [Disease Ontology: DOID:14264]
Disease Ontology: DOID:14264
OMIM: 121201
Orphanet: ORPHA1949
Role: 
Drugs: 
Side effects:  For retigabine: chills, pain, symptomatic hypotension, dizziness, nausea, myalgia, sweating, vomiting, asthenia and somnolence. For flupirtine: drowsiness, dizziness, dry mouth, pruritis and nausea.
Therapeutic use:  Retigabine and flupirtine have shown antiepileptic activity in humans and in a broad range of seizure models in rodents. Retigabine and flupirtine may possess actions unrelated to KCNQ opening. It is unclear, therefore, if the efficacy of retigabine and flupirtine in animals models of epilepsy and pain and in human studies is entirely due to KCNQ activation.
Comments: 
References:  2-3,8,23,27,31
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human G236V Pore region 2
Missense Human D305G 26
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.

References

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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. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M. (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat. Genet., 18 (1): 53-5. [PMID:9425900]

3. Coghlan MJ, Carroll WA, Gopalakrishnan M. (2001) Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J. Med. Chem., 44 (11): 1627-53. [PMID:11356099]

4. Cooper EC, Aldape KD, Abosch A, Barbaro NM, Berger MS, Peacock WS, Jan YN, Jan LY. (2000) Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. Proc. Natl. Acad. Sci. U.S.A., 97 (9): 4914-9. [PMID:10781098]

5. 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]

6. 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]

7. 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]

8. Gilling M, Rasmussen HB, Calloe K, Sequeira AF, Baretto M, Oliveira G, Almeida J, Lauritsen MB, Ullmann R, Boonen SE et al.. (2013) Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders. Front Genet, 4: 54. [PMID:23596459]

9. Hadley JK, Noda M, Selyanko AA, Wood IC, Abogadie FC, Brown DA. (2000) Differential tetraethylammonium sensitivity of KCNQ1-4 potassium channels. Br. J. Pharmacol., 129 (3): 413-5. [PMID:10711337]

10. 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]

11. Haitin Y, Attali B. (2008) The C-terminus of Kv7 channels: a multifunctional module. J. Physiol. (Lond.), 586 (7): 1803-10. [PMID:18218681]

12. Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K. (2000) Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J. Biol. Chem., 275 (29): 22395-400. [PMID:10787416]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. Peretz A, Degani N, Nachman R, Uziyel Y, Gibor G, Shabat D, Attali B. (2005) Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties. Mol. Pharmacol., 67 (4): 1053-66. [PMID:15598972]

20. Prole DL, Marrion NV. (2004) Ionic permeation and conduction properties of neuronal KCNQ2/KCNQ3 potassium channels. Biophys. J., 86 (3): 1454-69. [PMID:14990473]

21. Punke MA, Friederich P. (2007) Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels. Anesth. Analg., 104 (5): 1256-64, tables of contents. [PMID:17456683]

22. Schroeder BC, Hechenberger M, Weinreich F, Kubisch C, Jentsch TJ. (2000) KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J. Biol. Chem., 275 (31): 24089-95. [PMID:10816588]

23. 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]

24. 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]

25. Shapiro MS, Roche JP, Kaftan EJ, Cruzblanca H, Mackie K, Hille B. (2000) Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current. J. Neurosci., 20 (5): 1710-21. [PMID:10684873]

26. Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, Anderson VE, Sanguinetti MC, Leppert MF. (2003) KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: expansion of the functional and mutation spectrum. Brain, 126 (Pt 12): 2726-37. [PMID:14534157]

27. Soldovieri MV, Boutry-Kryza N, Milh M, Doummar D, Heron B, Bourel E, Ambrosino P, Miceli F, De Maria M, Dorison N et al.. (2014) Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A. Hum. Mutat., 35 (3): 356-67. [PMID:24375629]

28. 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]

29. 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]

30. Wickenden AD, Zou A, Wagoner PK, Jegla T. (2001) Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br. J. Pharmacol., 132 (2): 381-4. [PMID:11159685]

31. Wua YJ, Dworetzky SI. (2005) Recent developments on KCNQ potassium channel openers. Curr. Med. Chem., 12 (4): 453-60. [PMID:15720253]

32. 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]

33. 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]

34. 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]

Contributors

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How to cite this page

Bernard Attali, K. George Chandy, Stephan Grissmer, George A. Gutman, Michel Lazdunski, David Mckinnon, Luis A. Pardo, Gail A. Robertson, Bernardo Rudy, Michael C. Sanguinetti, Walter Stühmer, Xiaoliang Wang.
Voltage-gated potassium channels: Kv7.3. Last modified on 20/07/2015. Accessed on 20/10/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=562.