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Kv10.1

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Target id: 570

Nomenclature: Kv10.1

Family: Voltage-gated potassium channels

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 989 1q32.2 KCNH1 potassium voltage-gated channel subfamily H member 1 32
Mouse 6 1 989 1 H6 Kcnh1 potassium voltage-gated channel, subfamily H (eag-related), member 1
Rat 6 1 962 13q27 Kcnh1 potassium voltage-gated channel subfamily H member 1
Previous and Unofficial Names Click here for help
eag1a | eag1b | eag1 | EAG channel 1 | ether-a-go-go potassium channel 1 | ether a go-go | potassium voltage-gated channel, subfamily H (eag-related), member 1 | potassium channel, voltage gated eag related subfamily H, member 1 | potassium voltage-gated channel
Database Links Click here for help
CATH/Gene3D 2.60.120.10
ChEMBL Target CHEMBL3841 (Hs), CHEMBL4295858 (Rn)
Ensembl Gene ENSG00000143473 (Hs), ENSMUSG00000058248 (Mm), ENSRNOG00000003841 (Rn)
Entrez Gene 3756 (Hs), 16510 (Mm), 65198 (Rn)
Human Protein Atlas ENSG00000143473 (Hs)
KEGG Gene hsa:3756 (Hs), mmu:16510 (Mm), rno:65198 (Rn)
OMIM 603305 (Hs)
Pharos O95259 (Hs)
RefSeq Nucleotide NM_172362 (Hs), NM_002238 (Hs), NM_010600 (Mm), NM_031742 (Rn)
RefSeq Protein NP_758872 (Hs), NP_002229 (Hs), NP_034730 (Mm), NP_113930 (Rn)
UniProtKB O95259 (Hs), Q60603 (Mm), Q63472 (Rn)
Wikipedia KCNH1 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Kv10.2 37
Auxiliary Subunits
Name References
Hyperkinetic (Hk) 28
Slob 36
epsin 33
KCR1 17
Other Associated Proteins
Name References
CaM 38,44
PIST 16
Cortactin 15
Rabaptin-5 27
S100B 35
Ion Selectivity and Conductance Click here for help
Species:  Rat
Rank order:  K+ [1.0 pS] > Cs+ [0.42 pS]
References:  31
Species:  Rat
Macroscopic current rectification:  Delayed Rectifier Current
References:  31
Ion Selectivity and Conductance Comments
  • Cation selectivity ranks in Drosophila is : Rb+ [0.75 pS] > NH4+ [0.25 pS] > Na+ [0.11 pS] > Li+ [0.08 pS] [1] and the rectification is virtually identical in all species tested (rat, mouse, bovine) [7]
  • Drosophila ether-a-go-go (eag) mutant on Xenopus laevis oocyte [1]
Voltage Dependence Click here for help
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  10.0 11.0 – 100.0 Xenopus laevis oocyte Human
Inactivation  - -
Comments  Activation time constant (tau) is dependent upon holding potential and extracellular Mg2+ concentration.

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

Gating inhibitors Click here for help
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
ICA-105574 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.9 pIC50 - - 9
⤷ pIC50 5.9 [9]
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
LY97241 Small molecule or natural product Click here for species-specific activity table Hs - 8.3 pIC50 - - 10
⤷ pIC50 8.3 [10]
terfenadine Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs - 7.8 pIC50 - - 11
⤷ pIC50 7.8 [11]
dofetilide Small molecule or natural product Approved drug Click here for species-specific activity table Hs - 7.5 pIC50 - - 12
⤷ pIC50 7.5 [12]
calmodulin {Sp: Human} Peptide Click here for species-specific activity table Rn - 7.2 pIC50 - - 41
⤷ pIC50 7.2 [41]
astemizole Small molecule or natural product Approved drug Click here for species-specific activity table Hs - 6.7 pIC50 - - 8
⤷ pIC50 6.7 [8]
clofilium Small molecule or natural product Click here for species-specific activity table Hs - 6.6 pIC50 - - 10
⤷ pIC50 6.6 [10]
E4031 Small molecule or natural product Click here for species-specific activity table Hs - 6.4 pIC50 - - 10
⤷ pIC50 6.4 [10]
haloperidol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - 6.2 pIC50 - - 10
⤷ pIC50 6.2 [10]
MK-499 Small molecule or natural product Hs - 6.0 pIC50 - - 11-12
⤷ pIC50 6.0 [11-12]
quinidine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - 5.8 pIC50 - - 37
⤷ pIC50 5.8 [37]
imipramine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - 5.7 pIC50 - - 8
⤷ pIC50 5.7 [8]
View species-specific channel blocker tables
Channel Blocker Comments
mAb56 monoclonal antibody pIC50 7.1 [13]
Tissue Distribution Click here for help
Myoblasts, skeletal muscle
Species:  Human
Technique:  Northern Blot
References:  28
Differentiated mesenchimal stem cells
Species:  Human
Technique:  Immunocytochemistry
References:  23
Spiral ligament
Species:  Rat
Technique:  In situ hybridisation
References:  20
Brain (amygdala, caudate nucleus, cerebral cortex, cerebellum, putamen, hippocampus, frontal lobe, occipital lobe, temporal lobe, subthalamic nucleus) [Not in substantia nigra, thalamus or medulla oblongata]
Species:  Rat
Technique:  Immunohistochemistry, non-radioactive in situ hybridization (NR-ISH)
References:  34
Physiological Functions Click here for help
Role in controlling the cell cycle and / or cell proliferation. EAG-1 is thought to encode the non-inactivating delayed rectifier potassium channel K(NI) that is activated at the onset of human myoblast formation.
Species:  Human
Tissue:  CHO cells
References:  3,32
Role in controlling the cell cycle and / or cell proliferation. EAG-1 is thought to encode the non-inactivating delayed rectifier potassium channel K(NI) that is activated at the onset of human myoblast formation.
Species:  Rat
Tissue:  Xenopus laevis oocytes
References:  2
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Cervical cancer
Disease Ontology: DOID:4362
OMIM: 603956
Role:  EAG mRNA expression and channel activity detected in cervical carcinoma tissue
Comments:  EAG expression and channel activity have been suggested to be important in cell proliferation. EAG considered potential cervical cancer tumour marker / membrane therapeutic target. Inhibition by siRNA showed suppression of tumour cell proliferation and treatment with antibodies (in vitro and in vivo) has shown similar results. However ion permeation blocking mutations failed to abolish xenograft tumour formation.
References:  5-6,13,43
Gene Expression and Pathophysiology Click here for help
Aberrantly expressed in majority of sarcomas and carcinomas
Tissue or cell type:  colorectal, neuroblastoma melanoma, cervical and breast carcinoma, fibrosarcoma, rhabdomyosarcoma
Pathophysiology: 
Species:  Human
Technique:  reverse transcriptase RT-PCR
References:  4,14,24,30
Aberrantly expressed in many tumour cell lines
Tissue or cell type:  Human neuroblastoma, MCF-7 cells, melanoma cells, colonic carcinoma cells
Pathophysiology: 
Species:  Human
Technique:  RT-PCR, patch clamp
References:  13,25-26,29,32,40
General Comments
Extracellular Mg2+ and other divalent cations slow activation in a dose- and voltage-dependent manner, based on their enthalpy of hydration [42]. Low external pH also slows activation. Hyperpolarisation slows down the kinetics of activation, depolarisation accelerates the kinetics of activation [22].

This channel has the following features:

  • GFG (rather than the common GYG) potassium channel signature sequence
  • a PAS domain in the distal part of the cytosolic N-terminus
  • a cNBD domain in the proximal portion of the C-terminus
  • a C-terminal assembly domain (CAD)
  • a CaM binding domain
  • a bNLS domain in the C-terminus
  • a C-terminal domain required for assembly [21].

The tetramerizing coiled-coil (TCC) domain at the C-terminal end of Kv10 and Kv11 confers specificity for multimer formation, allowing Kv10.1 / Kv10.2 heteromerization, and Kv11.1 homomerization, but not Kv10.x / Kv11.1 heteromerization [18]. This C-terminal TCC domain has been identified in many other channels, and mutations of the TCC have been found to be linked to genetic channelopathies.

References

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1. Brüggemann A, Pardo LA, Stühmer W, Pongs O. (1993) Ether-à-go-go encodes a voltage-gated channel permeable to K+ and Ca2+ and modulated by cAMP. Nature, 365 (6445): 445-8. [PMID:7692301]

2. Brüggemann A, Stühmer W, Pardo LA. (1997) Mitosis-promoting factor-mediated suppression of a cloned delayed rectifier potassium channel expressed in Xenopus oocytes. Proc Natl Acad Sci USA, 94 (2): 537-42. [PMID:9012819]

3. Camacho J, Sánchez A, Stühmer W, Pardo LA. (2000) Cytoskeletal interactions determine the electrophysiological properties of human EAG potassium channels. Pflugers Arch, 441 (2-3): 167-74. [PMID:11211100]

4. Ding XW, Yan JJ, An P, Lü P, Luo HS. (2007) Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines. World J Gastroenterol, 13 (8): 1257-61. [PMID:17451210]

5. Downie BR, Sánchez A, Knötgen H, Contreras-Jurado C, Gymnopoulos M, Weber C, Stühmer W, Pardo LA. (2008) Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumors. J Biol Chem, 283 (52): 36234-40. [PMID:18927085]

6. Farias LM, Ocaña DB, Díaz L, Larrea F, Avila-Chávez E, Cadena A, Hinojosa LM, Lara G, Villanueva LA, Vargas C, Hernández-Gallegos E, Camacho-Arroyo I, Dueñas-González A, Pérez-Cárdenas E, Pardo LA, Morales A, Taja-Chayeb L, Escamilla J, Sánchez-Peña C, Camacho J. (2004) Ether a go-go potassium channels as human cervical cancer markers. Cancer Res, 64 (19): 6996-7001. [PMID:15466192]

7. Frings S, Brüll N, Dzeja C, Angele A, Hagen V, Kaupp UB, Baumann A. (1998) Characterization of ether-à-go-go channels present in photoreceptors reveals similarity to IKx, a K+ current in rod inner segments. J Gen Physiol, 111 (4): 583-99. [PMID:9524140]

8. García-Ferreiro RE, Kerschensteiner D, Major F, Monje F, Stühmer W, Pardo LA. (2004) Mechanism of block of hEag1 K+ channels by imipramine and astemizole. J Gen Physiol, 124 (4): 301-17. [PMID:15365094]

9. Garg V, Stary-Weinzinger A, Sanguinetti MC. (2013) ICA-105574 interacts with a common binding site to elicit opposite effects on inactivation gating of EAG and ERG potassium channels. Mol Pharmacol, 83 (4): 805-13. [PMID:23319419]

10. Gessner G, Heinemann SH. (2003) Inhibition of hEAG1 and hERG1 potassium channels by clofilium and its tertiary analogue LY97241. Br J Pharmacol, 138 (1): 161-71. [PMID:12522086]

11. Gessner G, Zacharias M, Bechstedt S, Schönherr R, Heinemann SH. (2004) Molecular determinants for high-affinity block of human EAG potassium channels by antiarrhythmic agents. Mol Pharmacol, 65 (5): 1120-9. [PMID:15102940]

12. Gómez-Varela D, Contreras-Jurado C, Furini S, García-Ferreiro R, Stühmer W, Pardo LA. (2006) Different relevance of inactivation and F468 residue in the mechanisms of hEag1 channel blockage by astemizole, imipramine and dofetilide. FEBS Lett, 580 (21): 5059-66. [PMID:16949586]

13. Gómez-Varela D, Zwick-Wallasch E, Knötgen H, Sánchez A, Hettmann T, Ossipov D, Weseloh R, Contreras-Jurado C, Rothe M, Stühmer W et al.. (2007) Monoclonal antibody blockade of the human Eag1 potassium channel function exerts antitumor activity. Cancer Res, 67 (15): 7343-9. [PMID:17671204]

14. Hemmerlein B, Weseloh RM, Mello de Queiroz F, Knötgen H, Sánchez A, Rubio ME, Martin S, Schliephacke T, Jenke M, Heinz-Joachim-Radzun W, Pardo LA. (2006) Overexpression of Eag1 potassium channels in clinical tumours. Mol Cancer, 5: 41. [PMID:17022810]

15. Herrmann S, Ninkovic M, Kohl T, Lörinczi É, Pardo LA. (2012) Cortactin controls surface expression of the voltage-gated potassium channel K(V)10.1. J Biol Chem, 287 (53): 44151-63. [PMID:23144454]

16. Herrmann S, Ninkovic M, Kohl T, Pardo LA. (2013) PIST (GOPC) modulates the oncogenic voltage-gated potassium channel KV10.1. Front Physiol, 4: 201. [PMID:23966943]

17. Hoshi N, Takahashi H, Shahidullah M, Yokoyama S, Higashida H. (1998) KCR1, a membrane protein that facilitates functional expression of non-inactivating K+ currents associates with rat EAG voltage-dependent K+ channels. J Biol Chem, 273 (36): 23080-5. [PMID:9722534]

18. Jenke M, Sánchez A, Monje F, Stühmer W, Weseloh RM, Pardo LA. (2003) C-terminal domains implicated in the functional surface expression of potassium channels. EMBO J, 22 (3): 395-403. [PMID:12554641]

19. Ju M, Wray D. (2002) Molecular identification and characterisation of the human eag2 potassium channel. FEBS Lett, 524 (1-3): 204-10. [PMID:12135768]

20. Lecain E, Sauvaget E, Crisanti P, Van Den Abbeele T, Huy PT. (1999) Potassium channel ether à go-go mRNA expression in the spiral ligament of the rat. Hear Res, 133 (1-2): 133-8. [PMID:10416871]

21. Ludwig J, Owen D, Pongs O. (1997) Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-à-go-go potassium channel. EMBO J, 16 (21): 6337-45. [PMID:9400421]

22. Ludwig J, Terlau H, Wunder F, Brüggemann A, Pardo LA, Marquardt A, Stühmer W, Pongs O. (1994) Functional expression of a rat homologue of the voltage gated either á go-go potassium channel reveals differences in selectivity and activation kinetics between the Drosophila channel and its mammalian counterpart. EMBO J, 13 (19): 4451-8. [PMID:7925287]

23. Mareschi K, Novara M, Rustichelli D, Ferrero I, Guido D, Carbone E, Medico E, Madon E, Vercelli A, Fagioli F. (2006) Neural differentiation of human mesenchymal stem cells: Evidence for expression of neural markers and eag K+ channel types. Exp Hematol, 34 (11): 1563-72. [PMID:17046576]

24. Mello de Queiroz F, Suarez-Kurtz G, Stühmer W, Pardo LA. (2006) Ether à go-go potassium channel expression in soft tissue sarcoma patients. Mol Cancer, 5: 42. [PMID:17022811]

25. Meyer R, Heinemann SH. (1998) Characterization of an eag-like potassium channel in human neuroblastoma cells. J Physiol (Lond.), 508 ( Pt 1): 49-56. [PMID:9490815]

26. Meyer R, Schönherr R, Gavrilova-Ruch O, Wohlrab W, Heinemann SH. (1999) Identification of ether à go-go and calcium-activated potassium channels in human melanoma cells. J Membr Biol, 171 (2): 107-15. [PMID:10489423]

27. Ninkovic M, Mitkovski M, Kohl T, Stühmer W, Pardo LA. (2012) Physical and functional interaction of KV10.1 with Rabaptin-5 impacts ion channel trafficking. FEBS Lett, 586 (19): 3077-84. [PMID:22841712]

28. Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J. (1998) Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett, 434 (1-2): 177-82. [PMID:9738473]

29. Ouadid-Ahidouch H, Le Bourhis X, Roudbaraki M, Toillon RA, Delcourt P, Prevarskaya N. (2001) Changes in the K+ current-density of MCF-7 cells during progression through the cell cycle: possible involvement of a h-ether.a-gogo K+ channel. Recept Channels, 7 (5): 345-56. [PMID:11697078]

30. Ousingsawat J, Spitzner M, Puntheeranurak S, Terracciano L, Tornillo L, Bubendorf L, Kunzelmann K, Schreiber R. (2007) Expression of voltage-gated potassium channels in human and mouse colonic carcinoma. Clin Cancer Res, 13 (3): 824-31. [PMID:17289873]

31. Pardo LA, Brüggemann A, Camacho J, Stühmer W. (1998) Cell cycle-related changes in the conducting properties of r-eag K+ channels. J Cell Biol, 143 (3): 767-75. [PMID:9813096]

32. Pardo LA, del Camino D, Sánchez A, Alves F, Brüggemann A, Beckh S, Stühmer W. (1999) Oncogenic potential of EAG K(+) channels. EMBO J, 18 (20): 5540-7. [PMID:10523298]

33. Piros ET, Shen L, Huang XY. (1999) Purification of an EH domain-binding protein from rat brain that modulates the gating of the rat ether-à-go-go channel. J Biol Chem, 274 (47): 33677-83. [PMID:10559257]

34. Saganich MJ, Machado E, Rudy B. (2001) Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci, 21 (13): 4609-24. [PMID:11425889]

35. Sahoo N, Tröger J, Heinemann SH, Schönherr R. (2010) Current inhibition of human EAG1 potassium channels by the Ca2+ binding protein S100B. FEBS Lett, 584 (18): 3896-900. [PMID:20708613]

36. Schopperle WM, Holmqvist MH, Zhou Y, Wang J, Wang Z, Griffith LC, Keselman I, Kusinitz F, Dagan D, Levitan IB. (1998) Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel. Neuron, 20 (3): 565-73. [PMID:9539129]

37. Schönherr R, Gessner G, Löber K, Heinemann SH. (2002) Functional distinction of human EAG1 and EAG2 potassium channels. FEBS Lett, 514 (2-3): 204-8. [PMID:11943152]

38. Schönherr R, Löber K, Heinemann SH. (2000) Inhibition of human ether à go-go potassium channels by Ca(2+)/calmodulin. EMBO J, 19 (13): 3263-71. [PMID:10880439]

39. Silverman WR, Tang CY, Mock AF, Huh KB, Papazian DM. (2000) Mg(2+) modulates voltage-dependent activation in ether-à-go-go potassium channels by binding between transmembrane segments S2 and S3. J Gen Physiol, 116 (5): 663-78. [PMID:11055995]

40. Spitzner M, Ousingsawat J, Scheidt K, Kunzelmann K, Schreiber R. (2007) Voltage-gated K+ channels support proliferation of colonic carcinoma cells. FASEB J, 21 (1): 35-44. [PMID:17135369]

41. Stansfeld CE, Röper J, Ludwig J, Weseloh RM, Marsh SJ, Brown DA, Pongs O. (1996) Elevation of intracellular calcium by muscarinic receptor activation induces a block of voltage-activated rat ether-à-go-go channels in a stably transfected cell line. Proc Natl Acad Sci USA, 93 (18): 9910-4. [PMID:8790430]

42. Terlau H, Ludwig J, Steffan R, Pongs O, Stühmer W, Heinemann SH. (1996) Extracellular Mg2+ regulates activation of rat eag potassium channel. Pflugers Arch, 432 (2): 301-12. [PMID:8662307]

43. Weber C, Mello de Queiroz F, Downie BR, Suckow A, Stühmer W, Pardo LA. (2006) Silencing the activity and proliferative properties of the human EagI Potassium Channel by RNA Interference. J Biol Chem, 281 (19): 13030-7. [PMID:16537547]

44. Ziechner U, Schönherr R, Born AK, Gavrilova-Ruch O, Glaser RW, Malesevic M, Küllertz G, Heinemann SH. (2006) Inhibition of human ether à go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J, 273 (5): 1074-86. [PMID:16478480]

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