KV10.1 channels

Channel name KV10.1
Description Voltage-gated potassium channel, delayed rectifier
Other names eag1a, eag1b, KCNH1a, KCNH1b, ether-à-go-go1,2,3,4
Molecular information Human: 989aa, NM_172362, chr. 1q32-41, KCNH1 (see “Comments”), GeneID: 3756, PMID: 81597662
Mouse: 989aa, NM_010600, chr. 1
Rat: 962aa, NM_031742, chr. 13q27
Associated subunits Hyperkinetic (Hk),5 CaM,6 Slob,7 epsin,8 KCR1 (K channel regulator)9
Functional assays Voltage-clamp
Current Delayed rectifier
Conductance Not established
Ion selectivity K+ and Ca,2+ 10 variable Cs+
Activation Extracellular Mg2+ and other divalent cations slow activation in a dose- and voltage-dependent manner, based on their enthalpy of hydration11; low external pH also slows activation
Inactivation Not established
Activators Hyperpolarization slows down the kinetics of activation; depolarization accelerates the kinetics of activation3
Gating inhibitors None
Blockers Quinidine (1.4 μM),12 calcium/calmodulin (480 nM)6,13
Radioligands None
Channel distribution 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), myoblasts, skeletal muscle (ESTs, but not detected by Northern), melanoma cells, ectopic expression in cancer cell lines and many tumor cells from different tissues, spiral ligament in rat14,15,16
Physiological functions Role in controlling the cell cycle and/or cell proliferation17,18; eag-1 is thought to encode the noninactivating delayed rectifier potassium channel KNI that is activated at the onset of human myoblast differentiation4
Mutations and pathophysiology KV10.1 has been associated with human cervical carcinoma21
Pharmacological significance KV10.1 blockers might have use in cancer therapy
Comments This channel has a 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, and a C-terminal domain required for assembly19; the 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 heteromerization22; 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; conductance properties have been shown to change with the cell cycle20
  • aa, amino acids; chr., chromosome; CaM, calmodulin; TCC, tetramerizing coiled-coiled; EST, expressed sequence tag.

  • 1. Warmke J, Drysdale R, and Ganetzky B (1991) A distinct potassium channel polypeptide encoded by the Drosophila eag locus. Science (Wash DC) 252:1560-1562

  • 2. Warmke JW and Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA 91:3438-3442

  • 3. Ludwig J, Terlau H, Wunder F, Bruggemann A, Pardo LA, Marquardt A, Stuhmer W, and Pongs O (1994) Functional expression of a rat homologue of the voltage gated ether à go-go potassium channel reveals differences in selectivity and activation kinetics between the Drosophila channel and its mammalian counterpart. EMBO J 13:4451-4458

  • 4. Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, and Fischer-Lougheed J (1998) Cloning of a human ether-à-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett 434:177-182

  • 5. Wilson GF, Wang Z, Chouinard SW, Griffith LC, and Ganetzky B (1998) Interaction of the K channel β subunit, Hyperkinetic, with eag family members. J Biol Chem 273:6389-6394

  • 6. Schonherr R, Lober K, and Heinemann SH (2000) Inhibition of human ether à go-go potassium channels by Ca2+/calmodulin. EMBO J 19:3263-3271

  • 7. Schopperle WM, Holmqvist MH, Zhou Y, Wang J, Wang Z, Griffith LC, Keselman I, Kusinitz F, Dagan D, and Levitan IB (1998) Slob, a novel protein that interacts with the Slowpoke calcium-dependent potassium channel. Neuron 20:565-573

  • 8. Piros ET, Shen L, and 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 274:33677-33683

  • 9. Hoshi N, Takahashi H, Shahidullah M, Yokoyama S, and 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 273:23080-23085

  • 10. Bruggemann A, Pardo LA, Stuhmer W, and Pongs O (1993) Ether-à-go-go encodes a voltage-gated channel permeable to K+ and Ca2+ and modulated by cAMP. Nature (Lond) 365:445-448

  • 11. Terlau H, Ludwig J, Steffan R, Pongs O, Stuhmer W, and Heinemann SH (1996) Extracellular Mg2+ regulates activation of rat eag potassium channel. Pflueg Arch Eur J Physiol 432:301-312

  • 12. Schonherr R, Gessner G, Lober K, and Heinemann SH (2002) Functional distinction of human EAG1 and EAG2 potassium channels. FEBS Lett 514:204-208

  • 13. Stansfeld CE, Roper J, Ludwig J, Weseloh RM, Marsh SJ, Brown DA, and 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 93:9910-9914

  • 14. Lecain E, Sauvaget E, Crisanti P, Van Den Abbeele T, and Huy PT (1999) Potassium channel ether à go-go mRNA expression in the spiral ligament of the rat. Hear Res 133:133-138

  • 15. Meyer R, Schonherr R, Gavrilova-Ruch O, Wohlrab W, and Heinemann SH (1999) Identification of ether à go-go and calcium-activated potassium channels in human melanoma cells. J Membr Biol 171:107-115

  • 16. Saganich MJ, Machado E, and Rudy B (2001) Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci 21:4609-4624

  • 17. Pardo LA, del Camino D, Sanchez A, Alves F, Bruggemann A, Beckh S, and Stuhmer W (1999) Oncogenic potential of EAG K+ channels. EMBO J 18:5540-5547

  • 18. Camacho J, Sanchez A, Stuhmer W, and Pardo LA (2000) Cytoskeletal interactions determine the electrophysiological properties of human EAG potassium channels. Pflueg Arch Eur J Physiol 441:167-174

  • 19. Ludwig J, Owen D, and Pongs O (1997) Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-à-go-go potassium channel EMBO J 16:6337-6345

  • 20. Pardo LA, Brüggemann A, Camacho J, and Stühmer W (1998) Cell-cycle related changes in the conducting properties of r-eag K+ channels. J Cell Biol 143:767-775

  • 21. Farias LM, Ocana DB, Diaz L, Larrea F, Avila-Chavez E, Cadena A, Hinojosa LM, Lara G, Villanueva LA, Vargas C, Hernandez-Gallegos E, et al. (2004) Ether à go-go potassium channels as human cervical cancer markers. Cancer Res 64:6996-7001

  • 22. Jenke M, Sanchez A, Monje F, Stuhmer W, Weseloh RM, and Pardo LA (2003) C-terminal domains implicated in the functional surface expression of potassium channels. EMBO J 22:395-403