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The mechano-gated K2P channel TREK-1

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Abstract

The versatility of neuronal electrical activity is largely conditioned by the expression of different structural and functional classes of K+ channels. More than 80 genes encoding the main K+ channel alpha subunits have been identified in the human genome. Alternative splicing, heteromultimeric assembly, post-translational modification and interaction with auxiliary regulatory subunits further increase the molecular and functional diversity of K+ channels. Mammalian two-pore domain K+ channels (K2P) make up one class of K+ channels along with the inward rectifiers and the voltage- and/or calcium-dependent K+ channels. Each K2P channel subunit is made up of four transmembrane segments and two pore-forming (P) domains, which are arranged in tandem and function as either homo- or heterodimeric channels. This novel structural arrangement is associated with unusual gating properties including “background” or “leak” K+ channel activity, in which the channels show constitutive activity at rest. In this review article, we will focus on the lipid-sensitive mechano-gated K2P channel TREK-1 and will emphasize on the polymodal function of this “unconventional” K+ channel.

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References

  • Alloui A, Zimmermann K, Mamet J, Duprat F, Noel J, Chemin J, Guy N, Blondeau N, Voilley N, Rubat-Coudert C, Borsotto M, Romey G, Heurteaux C, Reeh P, Eschalier A, Lazdunski M (2006) TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 25:2368–2376

    Article  PubMed  CAS  Google Scholar 

  • Bayliss DA, Talley EM, Sirois JE, Lei Q (2001) TASK-1 is a highly modulated pH-sensitive ‘leak’ K(+) channel expressed in brainstem respiratory neurons. Respir Physiol 129:159–174

    Article  PubMed  CAS  Google Scholar 

  • Blondeau N, Lauritzen I, Widmann C, Lazdunski M, Heurteaux C (2002a) A potent protective role of lysophospholipids against global cerebral ischemia and glutamate excitotoxicity in neuronal cultures. J Cereb Blood Flow Metab 22:821–834

    Article  PubMed  CAS  Google Scholar 

  • Blondeau N, Widmann C, Lazdunski M, Heurteaux C (2002b) Polyunsaturated fatty acids induce ischemic and epileptic tolerance. Neuroscience 109:231–241

    Article  PubMed  CAS  Google Scholar 

  • Blondeau N, Petrault O, Manta S, Giordanengo V, Gounon P, Bordet R, Lazdunski M, Heurteaux C (2007) Polyunsaturated fatty acids are cerebral vasodilators via the TREK-1 potassium channel. Circ Res 101(2):119-121

    Article  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chemin J, Girard C, Duprat F, Lesage F, Romey G, Lazdunski M (2003) Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J 22:5403–5411

    Article  PubMed  CAS  Google Scholar 

  • Chemin J, Patel A, Duprat F, Zanzouri M, Lazdunski M, Honoré E (2005a) Lysophosphatidic acid-operated K+ channels. J Biol Chem 280:4415–4421

    Article  PubMed  CAS  Google Scholar 

  • Chemin J, Patel AJ, Duprat F, Lauritzen I, Lazdunski M, Honoré E (2005b) A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO J 24:44–53

    Article  PubMed  CAS  Google Scholar 

  • Chemin J, Patel A, Delmas P, Sachs F, Lazdunski M, Honoré E (2007) Regulation of the mechano-gated K2P channel TREK-1 by membrane phospholipids. Curr Top Membr (in press)

  • Czempinski K, Zimmermann S, Ehrhardt T, Muller-Rober B (1997) New structure and function in plant K+ channels: KCO1, an outward rectifier with a steep Ca2+ dependency. EMBO J 16:2565–2575

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Feliciangeli S, Bendahhou S, Sandoz G, Gounon P, Reichold M, Warth R, Lazdunski M, Barhanin J, Lesage F (2007) Does sumoylation control K2P1/TWIK1 background K+ channels? Cell 130:563–569

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Franks NP, Honoré E (2004) The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol Sci 25:601–608

    Article  PubMed  CAS  Google Scholar 

  • Franks NP, Lieb WR (1999) Background K+ channels: an important target for volatile anesthetics? Nat Neurosci 2:395–396

    Article  PubMed  CAS  Google Scholar 

  • Garry A, Fromy B, Blondeau N, Henrion D, Brau F, Gounon P, Guy N, Heurteaux C, Lazdunski M, Saumet JL (2007) Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO Rep 8:354–359

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Goldstein SA, Price LA, Rosenthal DN, Pausch MH (1996) ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93:13256–13261

    Article  PubMed  CAS  Google Scholar 

  • Goldstein SAN, Bockenhauer D, O’Kelly I, Zilberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2:175–184

    Article  PubMed  CAS  Google Scholar 

  • Gordon JA, Hen R (2006) Treking toward new antidepressants. Nat Neurosci 9:1081–3

    Article  PubMed  CAS  Google Scholar 

  • Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP (2004) Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol 65:443–452

    Article  PubMed  CAS  Google Scholar 

  • Harinath S, Sikdar SK (2004) Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels. Neuropharmacology 46:750–60

    Article  PubMed  CAS  Google Scholar 

  • Hervieu GJ, Cluderay JE, Gray CW, Green PJ, Ranson JL, Randall AD, Meadows HJ (2001) Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 103:899–919

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thummler S, Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M, Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M (2006) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9:1134–1141

    Article  PubMed  CAS  Google Scholar 

  • Hille B (1992) Ion channels of excitable membranes. Sinauer Associates Inc Sunderland, Massachusetts

    Google Scholar 

  • Honoré E (2007) The neuronal background K2P channels: focus on TREK-1. Nat Rev Neurosci 8:251–261

    Article  PubMed  CAS  Google Scholar 

  • Honoré E, Maingret F, Lazdunski M, Patel AJ (2002) An intracellular proton sensor commands lipid- and mechano-gating of the K+ channel TREK-1. EMBO J 21:2968–2976

    Article  PubMed  Google Scholar 

  • Honoré E, Patel AJ, Chemin J, Suchyna T, Sachs F (2006) Desensitization of mechano-gated K2P channels. Proc Natl Acad Sci USA 103:6859–6864

    Article  PubMed  CAS  Google Scholar 

  • Ilan N, Goldstein SA (2001) Kcnko: single, cloned potassium leak channels are multi-ion pores. Biophys J 80:241–253

    Article  PubMed  CAS  Google Scholar 

  • Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005) Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144:821–829

    Article  PubMed  CAS  Google Scholar 

  • Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, Goldstein SAN (1995) A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem. Nature 376:690–695

    Article  PubMed  CAS  Google Scholar 

  • Kim D (2003) Fatty acid-sensitive two-pore domain K+ channels. Trends Pharmacol Sci 24:648–654

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Koh SD, Monaghan KM, Sergeant GP, Ro S, Walker RL, Sanders KM, Horowitz B (2001) TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase. J Biol Chem 47:44338–44346

    Article  Google Scholar 

  • Lang-Lazdunski L, Blondeau N, Jarretou G, Lazdunski M, Heurteaux C (2003) Linolenic acid prevents neuronal cell death and paraplegia after transient spinal cord ischemia in rats. J Vasc Surg 38:564–575

    Article  PubMed  Google Scholar 

  • Lauritzen I, Blondeau N, Heurteaux C, Widmann C, Romey G, Lazdunski M (2000) Poly-unsaturated fatty acids are potent neuroprotectors. EMBO J 19:1784–1793

    Article  PubMed  CAS  Google Scholar 

  • Lauritzen I, Chemin J, Honoré E, Jodar M, Guy N, Lazdunski M, Jane Patel A (2005) Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep 6:642–648

    Article  PubMed  CAS  Google Scholar 

  • Lesage F (2003) Pharmacology of neuronal background potassium channels. Neuropharmacology 44:1–7

    Article  PubMed  CAS  Google Scholar 

  • Lesage F, Lazdunski M (2000) Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Ren Physiol 279:F793–801

    CAS  Google Scholar 

  • Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (1996a) A pH-sensitive yeast outward rectifier K+ channel with two pore domains and novel gating properties. J Biol Chem 271:4183–4187

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Lesage F, Reyes R, Fink M, Duprat F, Guillemare E, Lazdunski M (1996c) Dimerization of TWIK-1 K+ channel subunits via a disulfide bridge. EMBO J 15:6400–6407

    PubMed  CAS  Google Scholar 

  • Lesage F, Terrenoire C, Romey G, 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

    Article  PubMed  CAS  Google Scholar 

  • Lopes CM, Gallagher PG, Buck ME, Butler MH, Goldstein SA (2000) Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3. J Biol Chem 275:16969–16978

    Article  PubMed  CAS  Google Scholar 

  • Lopes CM, Rohacs T, Czirjak G, Balla T, Enyedi P, Logothetis DE (2005) PiP2-hydrolysis underlies agonist-induced inhibition and regulates voltage-gating of 2-P domain K+ channels. J Physiol 564:117–129

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Maingret F, Honoré E, Lazdunski M, Patel AJ (2002) Molecular basis of the voltage-dependent gating of TREK-1, a mechano- sensitive K+ channel. Biochem Biophys Res Commun 292:339–346

    Article  PubMed  CAS  Google Scholar 

  • Martinac B, Adler J, Kung C (1990) Mechanosensitive ion channels of E. Coli activated by amphipaths. Nature 348:261–263

    Article  PubMed  CAS  Google Scholar 

  • Maylie J, Adelman JP (2001) Beam me up, Scottie! TREK channels swing both ways. Nat Neurosci 4:457–458

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger II, Pangalos MN (2001) Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Mol Brain Res 86:101–114

    Article  PubMed  CAS  Google Scholar 

  • Murbartian J, Lei Q, Sando JJ, Bayliss DA (2005) Sequential phosphorylation mediates receptor- and kinase-induced inhibition of TREK-1 background potassium channels. J Biol Chem 280:30175–30184

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • O’Connell AD, Morton MJ, Hunter M (2002) Two-pore domain K+ channels-molecular sensors. Biochimica et Biophysica Acta 1566:152–161

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Patel AJ, Honoré E (2001a) Anesthetic-sensitive 2P domain K+ channels. Anesthesiology 95:1013–1025

    Article  PubMed  CAS  Google Scholar 

  • Patel AJ, Honoré E (2001b) Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci 24:339–346

    Article  PubMed  CAS  Google Scholar 

  • Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M (1998) A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J 17:4283–4290

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Patel AJ, Lazdunski M, Honoré E (2001) Lipid and mechano-gated 2P domain K+ channels. Curr Opin Cell Biol 13:422–428

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Reid JD, Lukas W, Shafaatian R, Bertl A, Scheurmannkettner C, Guy HR, North RA (1996) The S. cerevisiae outwardly-rectifying potassium channel (DUK1) identifies a new family of channels with duplicated pore domains. Receptors Channels 4:51–62

    PubMed  CAS  Google Scholar 

  • Renigunta V, Yuan H, Zuzarte M, Rinne S, Koch A, Wischmeyer E, Schlichthorl G, Gao Y, Karschin A, Jacob R, Schwappach B, Daut J, Preisig-Muller R (2006) The retention factor p11 confers an endoplasmic reticulum-localization signal to the potassium channel TASK-1. Traffic 7:168–181

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sandoz G, Thummler S, Duprat F, Feliciangeli S, Vinh J, Escoubas P, Guy N, Lazdunski M, Lesage F (2006) AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K+ channels into open leak channels. Embo J 25:5864–5872

    Article  PubMed  CAS  Google Scholar 

  • Sheetz MP, Singer SJ (1974) Biological membranes as bilayer couples. A molecular mechanism of drug-erythocyte interactions. Proc Natl Acad Sci USA 71:4457–4461

    Article  PubMed  CAS  Google Scholar 

  • Talley EM, Bayliss DA (2002) Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action. J Biol Chem 277:17733–17742

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001) Cns distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21:7491–7505

    PubMed  CAS  Google Scholar 

  • Talley EM, Sirois JE, Lei Q, Bayliss DA (2003) Two-pore-domain (KCNK) potassium channels: dynamic roles in neuronal function. Neuroscientist 9:46–56

    Article  PubMed  CAS  Google Scholar 

  • Wei A, Jegla T, Salkoff L (1996) Eight potassium channel families revealed by the C. elegans genome project. Neuropharmacology 35:805–829

    Article  PubMed  CAS  Google Scholar 

  • Zhou XL, Vaillant B, Loukin SH, Kung C, Saimi Y (1995) YKC1 encodes the depolarization-activated K+ channel in the plasma membrane of yeast. FEBS Lett 373:170–176

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful to the ANR 2005 Cardiovasculaire-obésité-diabète, to the Association for Information and Research on Genetic Kidney Disease France, to the Fondation del Duca, to the Fondation de France, to the Fondation de la Recherche Médicale, to EEC Marie-Curie fellowships, to the Fondation de Recherche sur l’Hypertension Artérielle, to AFM, to HFSP to INSERM and to CNRS for support.

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Correspondence to Eric Honoré.

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EBSA Satellite meeting: Ion channels, Leeds, July 2007.

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Dedman, A., Sharif-Naeini, R., Folgering, J.H.A. et al. The mechano-gated K2P channel TREK-1. Eur Biophys J 38, 293–303 (2009). https://doi.org/10.1007/s00249-008-0318-8

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