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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. LV. Nomenclature and Molecular Relationships of Two-P Potassium Channels

Steve A. N. Goldstein, Douglas A. Bayliss, Donghee Kim, Florian Lesage, Leigh Daniel Plant and Sindhu Rajan
Pharmacological Reviews December 2005, 57 (4) 527-540; DOI: https://doi.org/10.1124/pr.57.4.12

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Phylogenetic tree for K2P channels. Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human K2P family were generated as described in the legend for Fig. 1 of “LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels.” K2P18.1 was added to the topology shown in the previous edition of this compendium by use of maximum parsimony and neighbor-joining algorithms. International Union of Pharmacology and HUGO Gene Nomenclature Committee names of the genes are shown together with their chromosomal localization.

Tables

  • TABLE 1

    K2P1.1 channels

    Channel name K2P1.1
    Description Two-pore domain potassium channel subunit1
    Other names KCNK1, TWIK-1, hOHO
    Molecular information Human: 336aa, NM_002245, chr. 1q42-43, KCNK1,2,3 GeneID: 3775, PMID: 86058691
    Rat: 336aa, AF022819
    Mouse: 336aa, NM_008430, chr. 8, kcnk14
    Associated subunits Small ubiquitin-related modifier protein (SUMO-1) is covalently attached at lysine 2746; exchange factor (EFA6) for small G protein ADP-ribosylation factor 6 (ARF6) (see “Comments”)7
    Functional assays Electrophysiological
    Current Open rectifier
    Conductance 32pS
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Not established
    Gating inhibitors None
    Blockers External pH (6.7)6
    Radioligands None
    Channel distribution Brain, heart, lung, kidney, liver, placenta4,5
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Covalent attachment of SUMO to lysine 274 silences K2P1; mutation of lysine 274 or desumoylation of K2P1 by a SUMO-specific protease (SENP) reveals an open rectifier; like K2P3 and K2P9, K2P1 is blocked by extracellular acidification due to titration of a histidine residue in the first pore loop; EFA6 interacts with the C-terminal part of K2P1—this interaction may be important for channel internalization and recycling7

    • aa, amino acid; chr., chromosome; SUMO, small ubiquitin-related modifier protein.

    • ↵1. Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, and Barhanin J (1996) TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J 15:1004-1011

    • ↵2. Orias M, Velazquez H, Tung F, Lee G, and Desir GV (1997) Cloning and localization of a double-pore K channel, KCNK1: exclusive expression in distal nephron segments. Am J Physiol 273: F663-F666

    • ↵3. Lesage F, Mattei MG, Fink M, Barhanin J, and Lazdunski M (1996) Assignment of the human weak inward rectifier K+ channel TWIK-1 gene to chromosome 1q42-q43. Genomics 34:153-155

    • ↵4. Lesage F, Lauritzen I, Duprat F, Reyes R, Fink M, Heurteaux C, and Lazdunski M (1997) The structure, function and distribution of the mouse TWIK-1 K+ channel. FEBS Lett 402:28-32

    • ↵5. Goldstein SAN, Wang KW, Ilan N, and Pausch M (1998) Sequence and function of the two P domain potassium channels: implications of an emerging superfamily. J Mol Med 76:13-20

    • ↵6. Rajan S, Plant LD, Rabin ML, Butler MH, and Goldstein SAN (2005) Sumoylation silences the plasma membrane leak K+ channel K2P1. Cell 121:37-47

    • ↵7. Decressac S, Franco M, Bendahhou S, Warth R, Knauer S, Barhanin J, Lazdunski M, and Lesage F (2004) ARF6-dependent interaction of the TWIK1 K + channel with EFA6, GDP/GTP exchange factor for ARF6. EMBO Rep 5:1171-1175

  • TABLE 2

    K2P2.1 channels

    Channel name K2P2.1
    Description Two-pore domain potassium channel subunit1; open rectifier or voltage-dependent
    Other names KCNK2, TREK-1, TPKC1
    Molecular information Human: 426aa, NM_014217, chr. 1q41, KCNK2,2 GeneID: 3776, PMID: 90037613
    Rat: 426aa, AF325671, chr. 5
    Mouse: 411aa, XM_123605, chr. 1, kcnk23
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Open or voltage-dependent4,5 (see “Comments”)
    Conductance 90pS (see “Comments”)
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Arachidonic acid (10 mM) and unsaturated fatty acids,10 lysophospholipids,7 volatile anesthetics,6,11 mechanical stress,7,11 internal acidification12
    Gating inhibitors None
    Blockers Ba2+ (1 mM), quinidine (100 mM), PKA, PKC
    Radioligands None
    Channel distribution Brain,2 heart
    Physiological functions Not established
    Mutations and pathophysiology Characterization of K2P2 knockout mice suggests a loss of sensitivity to general anesthetics and increased vulnerability to ischemia and reperfusion injury8,9
    Pharmacological significance Not established
    Comments Phosphorylation of serine 348 regulates reversible interconversion between leak and voltage-dependent phenotypes5; “activation” and “deactivation” with voltage steps seem to be instantaneous; the mouse variant may have a smaller conductance

    • aa, amino acids; chr., chromosome; PKA, protein kinase A; PKC, protein kinase C.

    • ↵1. Goldstein SAN, Wang KW, Ilan N, and Pausch M (1998) Sequence and function of the two P domain potassium channels: implications of an emerging superfamily. J Mol Med 76:13-20

    • ↵2. Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C, Medhurst AD, Murdock P, and Chapman CG (2000) Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel. Pflueg Arch Eur J Physiol 439:714-722

    • ↵3. Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, and Lazdunski M (1996) Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J 15:6854-6862

    • ↵4. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, and Honoré E (2000) TREK-1 is a heat-activated background K(+) channel. EMBO J 19:2483-2491

    • ↵5. Bockenhauer D, Zilberberg N, and Goldstein SAN (2001) KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci 4:486-491

    • ↵6. Terrenoire C, Lauritzen I, Lesage F, Romey G, and Lazdunski M (2001) A TREK-1-like potassium channel in atrial cells inhibited by beta-adrenergic stimulation and activated by volatile anesthetics. Circ Res 89:336-342

    • ↵7. Maingret F, Patel AJ, Lesage F, Lazdunski M, and Honoré E (2000). Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem 275:10128-10133

    • ↵8. Buckler KJ and Honoré E (2004) The lipid-activated K2P channel TREK-1 is resistant to hypoxia: implication for ischemic neuroprotection. J Physiol 562:213-222

    • ↵9. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, et al. (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23:2684-2695

    • ↵10. Patel AJ, Honoré E, Lesage F, Fink M, Romey G, and Lazdunski M (1999) Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 2:422-426

    • ↵11. Maingret F, Patel AJ, Lesage F, Lazdunski M, and Honoré E (1999) Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J Biol Chem 274:26691-26696

  • TABLE 3

    K2P3.1 channels

    Channel name K2P3.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK3, TASK-1, TBAK-1, OAT-1
    Molecular information Human: 394aa, NM_002246, chr. 2p24.1-23.3,1 KCNK3,2 GeneID: 3777, PMID: 931200520
    Rat: 411aa, NP_203694, kcnk33
    Mouse: 409aa, AF065162, chr. 5B,1 kcnk3
    Associated subunits 14-3-316,17 and p11 (annexin II subunit),18 see “Comments”
    Functional assays Electrophysiological
    Current Open rectifier4
    Conductance 10pS5
    Ion selectivity Rb+ > K+ > Cs+ > NH4+ >> Na+ > Li+
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Volatile anesthetics6,7: halothane (1 mM),5 isofluorane (2 mM)
    Gating inhibitors None
    Blockers Ba2+ (500 mM), external pH (7.3),8,9,10 arachidonic acid (100 mM) (see “Comments”), and anandamide (3 μM)19
    Radioligands None
    Channel distribution Brain,11 heart,12 lung, kidney,13 small intestine, colon, pancreas, prostate, uterus, placenta
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seems to be instantaneous, but there is also a small, time-dependent change in Po; current is half-blocked at pH 7.3 at physiological external conditions—increasing external potassium decreases proton blockade; pharmacology studies of the rat variant reveal blockade also by zinc, TEA, and quinidine14,15; K2P3-like currents are reported in cerebellar granular neurons and motor-neurons11,15; interaction with 14-3-3 protein is essential for forward trafficking; K2P3 can form heterodimers with K2P9.1 in heterologous expression systems consistent with electrophysiological studies that suggest heterodimerzation; K2P3 is also suggested to be a target for transmitter modulation of neuronal excitability11,15

    • aa, amino acids; chr., chromosome; TEA, tetrylethylammonium.

    • ↵1. Manjunath NA, Bray-Ward P, Goldstein SAN, and Gallagher PG (1999) Assignment of the 2P domain, acid-sensitive potassium channel gene OAT1 (KCNK3) to human chromosome 2p23.3p24.1 and murine chromosome band 5B by in situ hybridization. Cytogenet Cell Gen 86:242-243

    • ↵2. Kim D, Fujita A, Horio Y, and Kurachi Y (1998) Cloning and functional expression of a novel cardiac two-pore background K+ channel (cTBAK-1). Circ Res 82:513-518

    • ↵3. Leonoudakis D, Gray AT, Winegar BD, Kindler CH, Harada M, Taylor DM, Chavez RA, Forsayeth JR, and Yost CS (1998) An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum. J Neurosci 18:868-877

    • ↵4. Lopes CMB, Gallagher PG, Wong C, Buck M, and Goldstein SAN (1998) OATs: open, acid-sensitive, two P domain K+ channels from mouse heart. J Biophys 74:A44

    • ↵5. Washburn CP, Sirois JE, Talley EM, Guyenet PG, and Bayliss DA (2002) Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci 22:1256-1265

    • ↵6. Buckler KJ, Williams BA, and Honoré E (2000) An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemo-receptor cells. J Physiol (Lond) 525:135-142

    • ↵7. Sirois JE, Lei Q, Talley EM, Lynch C 3rd, and Bayliss DA (2000) The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 20:6347-6354

    • ↵8. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, and Lazdunski M (1997) TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16:5464-5471

    • ↵9. Lopes CMB, Gallagher PG, Buck ME, Butler MH, and Goldstein SAN (2000) Proton block and voltage-gating are potassium-dependent in the cardiac leak channel kcnk3. J Biol Chem 275:16969-16978

    • ↵10. Lopes CMB, Zilberberg N, and Goldstein SAN (2001) Block of Kcnk3 by protons: evidence that 2-P-domain potassium channel subunits function as homodimers. J Biol Chem 276:24449-24452

    • ↵11. Millar JA, Barratt L, Southan AP, Page KM, Fyffe RE, Robertson B, and Mathie A (2000) A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proc Natl Acad Sci USA 97:3614-3618

    • ↵12. Kim Y, Bang H, and Kim D (1999) TBAK-1 and TASK-1, two-pore K(+) channel subunits: kinetic properties and expression in rat heart. Am J Physiol 277:H1669-H1678

    • ↵13. Czirjak G, Fischer T, Spat A, Lesage F, and Enyedi P (2000) TASK (TWIK-related acid-sensitive K+ channel) is expressed in glomerulosa cells of rat adrenal cortex and inhibited by angiotensin II. Mol Endocrinol 14:863-874

    • ↵14. Kindler CH, Yost CS, and Gray AT (1999) Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem. Anesthesiology 90:1092-1102

    • ↵15. Talley EM, Lei QB, Sirois JE, and Bayliss DA (2000) TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25:399-410

    • ↵16. Rajan S, Preisig-Muller R, Wischmeyer E, Nehring R, Hanley PJ, Renigunta V, Musset B, Schlichthorl G, Derst C, Karschin A, et al. (2002) Interaction with 14-3-3proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. J Physiol 545:13-26

    • ↵17. O'Kelly I, Butler MH, Zilberberg N, and Goldstein SA (2002) Forward transport. 14-3-3 binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111:577-588

    • ↵18. Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M, and Borsotto M (2002) p11, an annexin II subunit, an auxiliary protein associated with the background K+ channel, TASK-1. EMBO J 21:4439-4448

    • ↵19. Maingret F, Patel AJ, Lazdunski M, and Honoré E (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J 15:47-54

    • ↵20. Duprat F, Lesage F, Fink M, Reyes R, Heurteaux C, and Lazdunski M (1997) TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J 16:5464-5471

  • TABLE 4

    K2P4.1 channels

    Channel name K2P4.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK4, TRAAK
    Molecular information Human: 393aa, NM_016611, chr. 11q13, KCNK4,1 GeneID: 50801, PMID: 107674091
    Rat: 397aa, NM_053804, kcnk4
    Mouse: 398aa, NM_008431, chr. 19, kcnk4
    Associated subunits Not established
    Functional assays Electrophysiological2
    Current Open rectifier
    Conductance 46pS
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Arachidonic acid (10 mM),3 mechanical stress,4 heat6 (see “Comments”), unsaturated fatty acids,3 lysopholipids,7 riluzole8
    Gating inhibitors None
    Blockers Gd+
    Radioligands None
    Channel distribution Brain,5 kidney, small intestine, placenta, prostate
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; knockout mice have no obvious phenotype9; the open probability of K2P4 increases with temperature with an activation threshold of 31°C in COS-7 cells

    • aa, amino acids; chr., chromosome.

    • ↵1. Lesage F, Maingret F, and Lazdunski M (2000) Cloning and expression of human TRAAK, a poly-unsaturated fatty acids-activated and mechano-sensitive K(+) channel. FEBS Lett 471:137-140

    • ↵2. Kim Y, Bang H, Gnatenco C, and Kim D (2001) Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali. Pflueg Arch Eur J Physiol 442:64-72

    • ↵3. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, and Lazdunski M (1998) A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J 17:3297-3308

    • ↵4. Maingret F, Fosset M, Lesage F, Lazdunski M, and Honoré E (1999) TRAAK is a mammalian neuronal mechanogated K+ channel. J Biol Chem 274:1381-1387

    • ↵5. Reyes R, Lauritzen I, Lesage F, Ettaiche M, Fosset M, and Lazdunski M (2000) Immunolocalization of the arachidonic acid and mechanosensitive baseline traak potassium channel in the nervous system. Neuroscience 95:893-901

    • ↵6. Kang DW, Choe CY, and Kim D (2005) Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol 564.1:103-116

    • ↵7. Maingret F, Patel AJ, Lesage F, Lazdunski M, and Honoré E (2000) Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK-1 and TRAAK. J Biol Chem 275:10128-10133

    • ↵8. Duprat F, Lesage F, Patel AJ, Fink M, Romey G, and Lazdunski M (2000) The neuroprotective agent riluzole activates the two P domain K + channels TREK-1 and TRAAK. Mol Pharmacol 57:906-912

    • ↵9. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, et al. (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23:2684-2695

  • TABLE 5

    K2P5.1 channels

    Channel name K2P5.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK5, TASK-2
    Molecular information Human: 499aa, NM_003740, chr. 6p21, KCNK5,1 GeneID: 8645, PMID: 98129781
    Rat: not cloned
    Mouse: 502aa, NM_021542, kcnk5
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Open rectifier
    Conductance See “Comments”
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Volatile anaesthetics2: halothane (∼570 mM)
    Gating inhibitors None
    Blockers Quinidine (22 mM), external pH (6.5),6 local anesthetics: lidocaine (1 mM), bupivacaine (1 mM), clofilium (25 μM)7
    Radioligands None
    Channel distribution Brain,3 kidney, liver, small intestine, pancreas, placenta
    Physiological functions A role in cell volume regulation7,8 (see “Comments”) and sensing external basolateral pH changes associated with Embedded Image transport in primary-cultured proximal tubular cells4
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem instantaneous; the conductance of K2P5 depends on the ionic conditions; the slope conductance was reported as 15pS with 5 mM external potassium and as high as 60pS when external potassium is high (155 mM)1 this may reflect an Na+-dependent inward rectification that becomes progressively less pronounced with time5; like K2P16 and 17, current through K2P5 channels is diminished at physiological pH; channel open probability increases with external pH; formation of an intersubunit disulfide bridge in K2P5 does not affect channel activity9; exposure to hypotonicity (change from 300—200 mOsm in external solution) enhanced mK2P5 currents when this channel was heterologously expressed in HEK293 cells, and osmotic cell shrinkage led to inhibition (change from 300—400 mOsm in external solution)

    • aa, amino acids; chr., chromosome.

    • ↵1. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, and Lazdunski M (1998) Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J Biol Chem 273:30863-30869

    • ↵2. Gray AT, Zhao BB, Kindler CH, Winegar BD, Mazurek MJ, Xu J, Chavez RA, Forsayeth JR, and Yost CS (2000) Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5. Anesthesiology 92:1722-1730

    • ↵3. Gabriel A, Abdallah M, Yost CS, Winegar BD, and Kindler CH (2002) Localization of the tandem pore domain K+ channel KCNK5 (TASK-2) in the rat central nervous system. Brain Res Mol Brain Res 98:153-163

    • ↵4. Warth R, Barriere H, Meneton P, Bloch M, Thomas J, Tauc M, Heitzmann D, Romeo E, Verrey F, Mengual R, et al. (2004) Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc Natl Acad Sci USA 101:8215-8220

    • ↵5. Morton MJ, Chipperfield S, Abohamed A, Sivaprasadarao A, and Hunter M (2004) Na+-induced in ward rectification in the two-pore domain K+ channel, TASK-2. Am J Physiol Renal Physiol 288:F162-F169

    • ↵6. Kang DW and Kim D (2004) Single channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochem Biophys Res Comm 315:836-844

    • ↵7. Niemeyer MI, Cid LP, Barros LF, and Sepulveda FV (2001) Modulation of the two-pore domain acid-sensitive K+ channel TASK-2 (KCNK5) by changes in cell volume. J Biol Chem 276:43166-43174

    • ↵8. Barriere H, Belfodil R, Rubera I, Tauc M, Lesage F, Poujeol C, Guy N, Barhanin J, and Poujeol P (2003) Role of TASK2 potassium channels regarding volume regulation in primary cultures of mouse proximal tubules. J Gen Physiol 122:177-190

    • ↵9. Niemeyer MI, Cid LP, Valenzuela X, Paeile V, and Sepulveda FV (2003) Extracellular conserved cysteine forms anointer subunit disulphide bridge in the KCNK5 (TASK-2) K+ channel without having an essential effect upon activity. Mol Membr Biol 20:185-191

  • TABLE 6

    K2P6.1 channels

    Channel name K2P6.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK6, TWIK-2, TOSS
    Molecular information Human: 313aa,1 NM_004823, chr0.19q13-1,2 KCNK6, GeneID: 9424, PMID: 103590731
    Rat: 313aa, NM_053806, kcnk6
    Mouse: not cloned
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Open rectifier3,4
    Conductance <5pS
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Arachidonic acid
    Gating inhibitors None
    Blockers Ba2+ (100 μM), quinidine (100 mM), volatile anesthetics
    Radioligands None
    Channel distribution Pancreas, placenta, heart (see “Comments”)
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; displays time-dependent inactivation at depolarized potentials4; the rat variant has been reported to be widely expressed (including brain, lung, kidney, liver, spleen, heart, esophagus, stomach, colon, and skeletal muscle)

    • aa, amino acids; chr., chromosome; TOSS, TWIK-originated similarity sequence.

    • ↵1. Pountney DJ, Gulkarov I, Vega-Saenz de Miera E, Holmes D, Saganich M, Rudy B, Artman M, and Coetzee WA (1999) Identification and cloning of TWIK-originated similarity sequence (TOSS): a novel human 2-pore K+ channel principal subunit. FEBS Lett 450:191-196

    • ↵2. Gray AT, Kindler CH, Sampson ER, and Yost CS (1999) Assignment of KCNK6 encoding the human weak inward rectifier potassium channel TWIK-2 to chromosome band 19q13.1 by radiation hybrid mapping. Cytogenet Cell Genet 84:190-191

    • ↵3. Chavez RA, Gray AT, Zhao BB, Kindler CH, Mazurek MJ, Mehta Y, Forsayeth JR, and Yost CS (1999) TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family. J Biol Chem 274:7887-7892

    • ↵4. Patel AJ, Maingret F, Magnone V, Fosset M, Lazdunski M, and Honoré E (2000) TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem 275:28722-28730

  • TABLE 7

    K2P7.1 channels

    Channel name K2P7.1
    Description Two-pore domain potassium channel subunit
    Other names KCNK7, kcnk8 (see “Comments”)
    Molecular information Human: 307aa (see “Comments”), NM_033347, chr0.11q13, KCNK7, GeneID:10089, PMID: 102069911
    Rat: not cloned
    Mouse: 335aa, NM_010609, chr. 19,2B, kcnk8 (see “Comments”)1,2
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Not established (see “Comments”)
    Conductance Not established
    Ion selectivity Not established
    Activation Not established
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers None
    Radioligands None
    Channel distribution Brain (human), retina (mouse)
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments The product of this gene has not yet been shown to form a functional channel; five splice variants have been identified in human; the mouse isolate was cited as kcnk6 and then kcnk8 but is now called K2P7 due to its homology and syntenic location to human KCNK72

    • aa, amino acids; chr., chromosome.

    • ↵1. Salinas M, Reyes R, Lesage F, Fosset M, Heurteaux C, Romey G, and Lazdunski M (1999) Cloning of a new mouse two-P domain channel subunit and a human homologue with a unique pore structure. J Biol Chem 274:11751-11760

    • ↵2. Bockenhauer D, Nimmakayalu MA, Ward DC, Goldstein SAN, and Gallagher PG (2000) Genomic organization and chromosomal localization of the murine 2 P domain potassium channel gene Kcnk8: conservation of gene structure in 2P domain potassium channels. Gene 261:365-372

  • TABLE 8

    K2P9.1 channels

    Channel name K2P9.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK9, TASK-3
    Molecular information Human: 374aa, NM_016601, chr0.8q24-3, KCNK9,1,2,3 GeneID: 51305, PMID:10734076
    Rat: 395aa, NM_053405, kcnk9
    Mouse: not cloned
    Associated subunits 14-3-3 (see “Comments”)7,8
    Functional assays Electrophysiological1,2,3,5,6,7,8,9,10,11
    Current Not established (see “Comments”)
    Conductance 27pS (see “Comments”)
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators None
    Gating inhibitors None
    Blockers External pH (6.5),3 ruthenium red (700 nM)8
    Radioligands None
    Channel distribution Brain (see “Comments”)1
    Physiological functions See “Comments”4,5,6
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; the guinea pig variant is reported to have the same conductance and distribution as human and a conductance of 60pS; Northern blot analysis suggests that rat K2P9.1 expression outside the CNS is extremely low, as is noted for the human and guinea pig gene; K2P9 gene is amplified in several human carcinomas, and overexpression of K2P9 protein in cell lines promotes tumor formation4,5; like K2P3, surface expression of K2P9 depends on its association with 14-3-3 to release it from the endoplasmic reticulum7,8; potential heterodimerization of K2P9 is discussed under K2P39

    • aa, amino acids; chr., chromosome; CNS, central nervous system.

    • ↵1. Chapman CG, Meadows HJ, Godden RJ, Campbell DA, Duckworth M, Kelsell RE, Murdock PR, Randall AD, Rennie GI, and Gloger IS (2000) Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel. Mol Brain Res 82:74-83

    • ↵2. Kim Y, Bang H, and Kim D (2000) TASK-3, a new member of the tandem pore K(+) channel family. J Biol Chem 275:9340-9347

    • ↵3. Rajan S, Wischmeyer E, Xin Liu G, Preisig-Muller R, Daut J, Karschin A, and Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel—an extracellular histidine as pH sensor. J Biol Chem 275:16650-16657

    • ↵4. Mu D, Chen L, Zhang X, See LH, Koch CM, Yen C, Tong JJ, Spiegel L, Nguyen KC, Servoss A, et al. (2003) Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 3:297-302

    • ↵5. Pei L, Wiser O, Slavin A, Mu D, Powers S, Jan LY, and Hoey T (2003) Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. Proc Natl Acad Sci USA 100:7803-7807

    • ↵6. Lauritzen I, Zanzouri M, Honoré E, Duprat F, Ehrengruber MU, Lazdunski M, and Patel AJ (2003) K+-dependent cerebellar granule neuron apoptosis: role of TASK leak K+ channels. J Biol Chem 278:32068-32076

    • ↵7. Rajan S, Preisig-Muller R, Wischmeyer E, Nehring R, Hanley PJ, Renigunta V, Musset B, Schlichthorl G, Derst C, Karschin A, et al. (2002) Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. J Physiol 545:13-26

    • ↵8. O'Kelly I, Butler MH, Zilberberg N, and Goldstein SA (2002) Forward transport. 14-3-3binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111:577-588

    • ↵9. Kang DW, Han JH, Talley EM, Bayliss DA, and Kim D (2004) Functional expression of TASK-1/TASK-3 heteromer in cerebellar granule neurons. J Physiol 554:64-77

    • ↵10. Czirjak G and Enyedi P (2003) Ruthenium red inhibits TASK-3 potassium channel by interconnecting glutamate 70 of the two subunits. Mol Pharmacol 63:646-652

    • ↵11. Vega-Saenz de Miera E, Lau DH, Zhadina M, Pountney D, Coetzee WA, and Rudy B (2001) KT3.2 and KT3.3, two novel human two-pore K(+) channels closely related to TASK-1. J Neurophysiol 86:130-142

  • TABLE 9

    K2P10.1 channels

    Channel name K2P10.1
    Description Two-pore domain potassium channel subunit; open rectifier1
    Other names KCNK10, TREK-2
    Molecular information Human: 538aa (see `Comments'), NM_138317, chr0.14q31, KCNK10, GeneID: 54207, PMID: 107479111
    Rat: 538aa, NM_023096, kcnk10
    Mouse: not cloned
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Open rectifier2
    Conductance 100pS (see “Comments”)
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Arachidonic acid, docosahexaenoic acid, linoleic acid, lysophosphatidylcholine,3 intracellular acidification, volatile anesthetics: halothane (∼1 mM), isoflurane (∼1 mM); riluzole (∼1 mM), heat,6 mechanical stress3
    Gating inhibitors None
    Blockers Quinidine (100 mM), PKA, PKC
    Radioligands None
    Channel distribution Kidney, pancreas, prostate, thymus, liver, heart (see “Comments”)2
    Physiological functions See “Comments”4,5
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; splice variants have been identified in human and rat; the rat variant is reported to have a conductance of 68pS and to be expressed in brain; K2P10-like currents are observed in cerebellar granular neurons, magnocellular neurosecretory cells of rat supraoptic nucleus,4,5 rat cortical astrocytes,7 and insulin-secreting MIN6 cells8

    • aa, amino acids; chr., chromosome; PKA, protein kinase A; protein kinase C.

    • ↵1. Bang H, Kim Y, and Kim D (2000) TREK-2, a new member of the mechano-sensitive tandem-pore K+ channel family. J Biol Chem 275:17412-17419

    • ↵2. Gu W, Schlichthorl G, Hirsch JR, Engels H, Karschin C, Karschin A, Derst C, Steinlein OK, and Daut J (2002) Expression pattern and functional characteristics of two novel splice variants of the two-pore-domain potassium channel TREK-2. J Physiol 539:657-668

    • ↵3. Lesage F, Terrenoire C, Romey G, and Lazdunski M (2000) Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J Biol Chem 275:28398-28405

    • ↵4. Han J, Truell J, Gnatenco C, and Kim D (2002) Characterization of four types of background potassium channels in rat cerebellar granule neurons. J Physiol 542:431-444

    • ↵5. Han J, Gnatenco C, Sladek CD, and Kim D (2003) Background and tandem-pore potassium channels in magnocellular neurosecretory cells of the rat supraoptic nucleus. J Physiol 546:625-639

    • ↵6. Kang DW, Choe CY, and Kim D (2005) Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol 564:103-116

    • ↵7. Gnatenco C, Han JH, Snyder AK, and Kim D (2002) Functional expression of TREK-2 K+ channel in cultured astrocytes. Brain Res 931:56-67

    • ↵8. Kang DW, Choe C, and Kim D (2004) Functional expression ofTREK-2 in insulin-secreting MIN6 cells. Biochem Biophys Res Commun 323:323-331

  • TABLE 10

    K2P12.1 channels

    Channel name K2P12.1
    Description Two-pore domain potassium channel subunit1
    Other names KCNK12, THIK-2
    Molecular information Human: 430aa, NM_022055, chr0.2p22-p21, KCNK12, GeneID: 56660, PMID: 110603161
    Rat: 430aa, NM_022292, kcnk12
    Mouse: not cloned
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Not established (see “Comments”)1,2
    Conductance No function demonstrated
    Ion selectivity Not established
    Activation Not established
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers None
    Radioligands None
    Channel distribution Brain, heart, lung, kidney, liver, small intestine, colon, pancreas, prostate, placenta, spleen, thymus, ovary
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments The product of this gene has not yet been shown to be a functional channel

    • aa, amino acids; chr., chromosome.

    • ↵1. Rajan S, Wischmeyer E, Karschin C, Preisig-Muller R, Grzeschik KH, Daut J, Karschin A, and Derst C (2001) THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. J Biol Chem 276:7302-7311

    • ↵2. Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey G, Lazdunski M, and Lesage F (2001) Genomic and functional characteristics of novel human pancreatic 2P domain K+ channels. Biochem Biophys Res Commun 282:249-256

  • TABLE 11

    K2P13.1 channels

    Channel name K2P13.1
    Description Two-pore domain potassium channel subunit; open rectifier1
    Other names KCNK13, THIK-1
    Molecular information Human: 408aa, NM_022054, chr0.14q24.1-24.3, KCNK13, GeneID: 56659, PMID: 110603161
    Rat: 405aa, NM_022293, kcnk13
    Mouse: not cloned
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Open rectifier
    Conductance Not established
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Arachidonic acid (0.98 mM)
    Gating inhibitors None
    Blockers Ba2+, halothane (2.83 mM)
    Radioligands None
    Channel distribution Brain, heart, lung, kidney, liver, spleen
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; K2P13-like channels are found in the central nervous system of Aplysia californica2

    • aa, amino acids; chr., chromosome.

    • ↵1. Rajan S, Wischmeyer E, Karschin C, Preisig-Muller R, Grzeschik KH, Daut J, Karschin A, and Derst C (2001) THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. J Biol Chem 276:7302-7311

    • ↵2. Jezzini SH and Moroz LL (2004) Identification and distribution of a two-pore domain potassium channel in the CNS of Aplysia californica. Brain Res Mol Brain Res 27:7-38

  • TABLE 12

    K2P15.1 channels

    Channel name K2P15.1
    Description Two-pore domain potassium channel subunit
    Other names KCNK15, TASK-5,1,2 KT3.33
    Molecular information Human: 330aa, NM_022358, chr0.20q12, KCNK15, GeneID: 60598, PMID: 114098811
    Rat: 318aa, AF467250
    Mouse: 324aa, XM_141526
    Associated subunits Not established
    Functional assays Electrophysiological
    Current Not established (see “Comments”)
    Conductance Not established
    Ion selectivity Not established
    Activation Not established
    Inactivation Not established
    Activators None
    Gating inhibitors None
    Blockers None
    Radioligands None
    Channel distribution Brain, heart, lung, kidney, liver, pancreas, adrenal gland, thyroid, salivary gland, placenta
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments The product of this gene has not yet been shown to be a functional channel

    • aa, amino acids; chr., chromosome.

    • ↵1. Kim D and Gnatenco C (2001) TASK-5, a new member of the tandem-pore K(+) channel family. Biochem Biophys Res Commun 284:923-930

    • ↵2. Ashmole I, Goodwin PA, and Stanfield PR (2001) TASK-5, a novel member of the tandem pore K+ channel family. Pflueg Arch Eur J Physiol 442:828-833

    • ↵3. Vega-Saenz de Miera E, Lau DH, Zhadina M, Pountney D, Coetzee WA, and Rudy B (2001) KT3.2 and KT3.3, two novel human two-pore K(+) channels closely related toTASK-1. J Neurophysiol 86:130-142

  • TABLE 13

    K2P16.1 channels

    Channel name K2P16.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK16, TALK-1
    Molecular information Human: 309aa, NM_032115, chr0.6p21.1-2, KCNK16, GeneID: 83795, PMID: 112639991
    Rat: not cloned
    Mouse: 337aa, XM_138942
    Associated subunits Not established
    Functional assays Electrophysiological1
    Current Open rectifier
    Conductance 21pS at -60 mV and 10 pS at +60 mV2
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Isoflurane (∼800 mM), nitric oxide and reactive oxygen species3
    Gating inhibitors None
    Blockers Ba2+ (1 mM), quinidine (100 mM), chloroform (∼800 mM), external pH (see “Comments”)
    Radioligands None
    Channel distribution Heart, lung, liver, pancreas,1 and placenta
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; the open probability of both K2P16 and 17 increases with external pH–at present, it is unclear whether this represents proton block at physiological levels or activation of the channel by supraphysiological alkaline pHo; there are four splice variants of K2P16, two of which are functional4

    • aa, amino acids; chr., chromosome.

    • ↵1. Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey G, Lazdunski M, and Lesage F (2001) Genomic and functional characteristics of novel human pancreatic 2P domain K(+) channels. Biochem Biophys Res Commun 282:249-256

    • ↵2. Kang D and Kim D (2004) Single-channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochem Biophys Res Commun 315:836-844

    • ↵3. Duprat F, Girard C, Jarretou G, and Lazdunski M (2004) Pancreatic two P domain K+ channels TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species. J Physiol 562:235-244

    • ↵4. Han JH, Kang D, and Kim D (2003) Functional properties of four splice variants of a human pancreatic tandem-pore K+ channel, TALK-1. Am J Physiol 285:C529-C538

  • TABLE 14

    K2P17.1 channels

    Channel name K2P17.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK17, TASK-4, TALK-2
    Molecular information Human: 332aa, NM_031460, chr0.6p21.1-2, KCNK17,1 GeneID: 89822, PMID: 112639991
    Rat: not cloned
    Mouse: not cloned
    Associated subunits Not established
    Functional assays Electrophysiological1
    Current Open rectifier
    Conductance Not established
    Ion selectivity Not established
    Activation See “Comments”
    Inactivation See “Comments”
    Activators Nitric oxide and reactive oxygen species3
    Gating inhibitors None
    Blockers Ba2+, external pH,2,3 chloroform (∼800 mM)
    Radioligands None
    Channel distribution Heart, lung, liver, pancreas,1 placenta
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation and deactivation with voltage steps seem to be instantaneous; the open probability of K2P17 increases as pHo is raised above physiological levels (see K2P16)

    • aa, amino acids; chr., chromosome.

    • ↵1. Girard C, Duprat F, Terrenoire C, Tinel N, Fosset M, Romey G, Lazdunski M, and Lesage F (2001) Genomic and functional characteristics of novel human pancreatic 2P domain K(+) channels. Biochem Biophys Res Commun 282:249-256

    • ↵2. Decher N, Maier M, Dittrich W, Gassenhuber J, Bruggemann A, Busch AE, and Steinmeyer K (2001) Characterization of TASK-4, a novel member of the pH-sensitive, two-pore domain potassium channel family. FEBS Lett 492:84-89

    • ↵3. Duprat F, Girard C, Jarretou G, and Lazdunski M (2004) Pancreatic two P domain K+ channels TALK-1 and TALK-2 are activated by nitric oxide and reactive oxygen species. J Physiol 562:235-244

  • TABLE 15

    K2P18.1 channels

    Channel name K2P18.1
    Description Two-pore domain potassium channel subunit; open rectifier
    Other names KCNK18, TRESK-1/TRESK-2 (see “Comments”)
    Molecular information Human: 384aa, NM_181840, chr. 10q26.11, GeneID: 338567, PMID: 127542591
    Rat: 405aa, NM_001003820
    Mouse: 394aa, NM_207261
    Associated subunits Not established
    Functional assays Electrophysiological1
    Current Open rectifier
    Conductance 13pS at +60 mV and 16pS at –60 mV for mouse K2P183
    Ion selectivity Not established
    Activation Rapid
    Inactivation Slow
    Activators Cytoplasmic Ca2+ via calcineurin, volatile anesthetics2,4
    Gating inhibitors None
    Blockers Ba2+ (3 mM), quinine (100 mM) quinidine (100 mM), free fatty acids, external acidic pH
    Radioligands None
    Channel distribution Cerebrum, cerebellum, brain stem, spinal cord, and testis
    Physiological functions Not established
    Mutations and pathophysiology Not established
    Pharmacological significance Not established
    Comments Activation is instantaneous; single channel currents are noninactivating and time-dependent; TRESK2 was cloned from mouse testis and shares 65% homology with human K2P18; as study continues, it will become clear whether this is the true correlate of the human channel or a distinct gene (K2P19); personal communication indicates that distinct cDNAs for both TRESK-1 and TRESK-2 are present in human tissues (D. Kim, personal communication)

    • aa, amino acids; chr., chromosome.

    • ↵1. Sano Y, Inamura K, Miyake A, Mochizuki S, Kitada C, Yokoi H, Nozawa K, Okada H, Matsushime H, and Furuichi K (2003) A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord. J Biol Chem 278:27406-27412

    • ↵2. Czirjak G, Toth ZE, and Enyedi P (2004) The two-pore-domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J Biol Chem 279:18550-18558

    • ↵3. Kang D, Mariash E, and Kim D (2004) Functional expression of TRESK-2, a new member of the tandem-pore K + channel family. J Biol Chem 279:28063-28070

    • ↵4. Liu C, Au JD, Zou HL, Cotton JF, and Yost CS (2004) Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth Analg 99:1715-1722

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OtherIUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. LV. Nomenclature and Molecular Relationships of Two-P Potassium Channels

Steve A. N. Goldstein, Douglas A. Bayliss, Donghee Kim, Florian Lesage, Leigh Daniel Plant and Sindhu Rajan
Pharmacological Reviews December 1, 2005, 57 (4) 527-540; DOI: https://doi.org/10.1124/pr.57.4.12
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