Skip to main content

Advertisement

SpringerLink
Log in

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Acosta C, Djouhri L, Watkins R, Berry C, Bromage K, Lawson SN (2014) TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain. J Neurosci 34:1494–1509

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Alloui A, Zimmermann K, Mamet J, Duprat F, Noël 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) TREK1, a K+ channel involved in polymodal pain perception. EMBO J 25:2368–2376

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafrenière RG, Roy B, Griffiths LR, Rouleau GA, Ebers GC, Cader ZM, Tucker SJ (2012) Functional analysis of missense variants in the TRESK (KCNK18) K channel. Sci Rep 2:237

    PubMed Central  PubMed  Google Scholar 

  4. Bagriantsev SN, Ang KH, Gallardo-Godoy A, Clark KA, Arkin MR, Renslo AR, Minor DL Jr (2013) A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels. ACS Chem Biol 8:1841–1851

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Bagriantsev SN, Clark KA, Minor DL Jr (2012) Metabolic and thermal stimuli control K(2P)2.1 (TREK1) through modular sensory and gating domains. EMBO J 31:3297–3308

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Bagriantsev SN, Peyronnet R, Clark KA, Honore E, Minor DL Jr (2011) Multiple modalities converge on a common gate to control K2P channel function. EMBO J 30:3594–3606

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Basbaum AI, Jessell T (2000) The perception of pain. In: Kandel ER, Schwartz J, Jessell T (eds) Principles of neuroscience. Appleton and Lange, New York, pp 472–491

    Google Scholar 

  9. Bautista DM, Sigal YM, Milstein AD, Garrison JL, Zorn JA, Tsuruda PR, Nicoll RA, Julius D (2008) Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels. Nat Neurosci 11:772–779

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Bayliss DA, Barrett PQ (2008) Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci 29:566–575

    PubMed Central  CAS  PubMed  Google Scholar 

  11. 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

    CAS  PubMed  Google Scholar 

  12. Brohawn SG, Campbell EB, MacKinnon R (2013) Domain-swapped chain connectivity and gated membrane access in a Fab-mediated crystal of the human TRAAK K+ channel. Proc Natl Acad Sci U S A 110:2129–2134

    PubMed Central  CAS  PubMed  Google Scholar 

  13. Brohawn SG, del Marmol J, MacKinnon R (2012) Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335:436–441

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Bruner JK, Zou B, Zhang H, Zhang Y, Schmidt K, Li M (2014) Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel. Eur J Pharmacol 740:603–610

    CAS  PubMed  Google Scholar 

  15. Cain SM, Meadows HJ, Dunlop J, Bushell TJ (2008) mGlu4 potentiation of K(2P)2.1 is dependant on C-terminal dephosphorylation. Mol Cell Neurosci 37:32–39

    CAS  PubMed  Google Scholar 

  16. Cao L, Veale EL, Mathie A, Stevens E (2010) Differential modulation of TREK-1, TASK-3 and TRESK K2P ion channels by BL-1249. Program No. 174.6/KK13. 2010 Neuroscience Meeting Planner. Society for Neuroscience Online, San Diego, CA

  17. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Cohen A, Ben-Abu Y, Zilberberg N (2009) Gating the pore of potassium leak channels. Eur Biophys J 39:61–73

    CAS  PubMed  Google Scholar 

  19. Cohen A, Sagron R, Somech E, Segal-Hayoun Y, Zilberberg N (2009) Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K(2P)2.1 channel. Mol Cell Neurosci 40:382–389

    CAS  PubMed  Google Scholar 

  20. Czirják G, Enyedi P (2006) Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK. J Biol Chem 281:14677–14682

    PubMed  Google Scholar 

  21. Czirják G, Enyedi P (2014) The LQLP calcineurin-docking site is a major determinant of the calcium-dependent activation of human TRESK background K+ channel. J Biol Chem 289:29506–29518

  22. Czirják G, Tóth ZE, 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

    PubMed  Google Scholar 

  23. Czirják G, Vuity D, Enyedi P (2008) Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. J Biol Chem 283:15672–15680

    PubMed Central  PubMed  Google Scholar 

  24. Danthi S, Enyeart JA, Enyeart JJ (2004) Caffeic acid esters activate TREK-1 potassium channels and inhibit depolarization-dependent secretion. Mol Pharmacol 65:599–610

    CAS  PubMed  Google Scholar 

  25. Dedman A, Sharif-Naeini R, Folgering JH, Duprat F, Patel A, Honoré E (2009) The mechano-gated K(2P) channel TREK-1. Eur Biophys J 38:293–303

    CAS  PubMed  Google Scholar 

  26. Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E (2011) Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol Med 3:266–278

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Devilliers M, Busserolles J, Lolignier S, Deval E, Pereira V, Alloui A, Christin M, Mazet B, Delmas P, Noel J, Lazdunski M, Eschalier A (2013) Activation of TREK-1 by morphine results in analgesia without adverse side effects. Nat Commun 4:2941

    PubMed  Google Scholar 

  28. Dobler T, Springauf A, Tovornik S, Weber M, Schmitt A, Sedlmeier R, Wischmeyer E, Döring F (2007) TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J Physiol 585:867–879

    PubMed Central  CAS  PubMed  Google Scholar 

  29. Du X, Gamper N (2013) Potassium channels in peripheral pain pathways: expression, function and therapeutic potential. Curr Neuropharmacol 11:621–640

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Du X, Hao H, Gigout S, Huang D, Yang Y, Li L, Wang C, Sundt D, Jaffe DB, Zhang H, Gamper N (2014) Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission. Pain. doi:10.1016/j.pain.2014.08.025

    PubMed Central  PubMed  Google Scholar 

  31. Duprat F, Lesage F, Patel AJ, Fink M, Romey G, Lazdunski M (2000) The neuroprotective agent riluzole activates the two P domain K(+) channels TREK1 and TRAAK. Mol Pharmacol 57:906–912

    CAS  PubMed  Google Scholar 

  32. Eckert M, Egenberger B, Döring F, Wischmeyer E (2011) TREK1 isoforms generated by alternative translation initiation display different susceptibility to the antidepressant fluoxetine. Neuropharmacology 61:918–923

    CAS  PubMed  Google Scholar 

  33. Enyedi P, Czirjak G (2010) Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev 90:559–605

    CAS  PubMed  Google Scholar 

  34. 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 Central  CAS  PubMed  Google Scholar 

  35. Gohlke BO, Preissner R, Preissner S (2014) SuperPain—a resource on pain-relieving compounds targeting ion channels. Nucleic Acids Res 42:D1107–D1112

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S (2005) International union of pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacol Rev 57:527–540

    CAS  PubMed  Google Scholar 

  37. 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

    CAS  PubMed  Google Scholar 

  38. Guinamard R, Simard C, Del Negro C (2013) Flufenamic acid as an ion channel modulator. Pharmacol Ther 138:272–284

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Guo Z, Cao YQ (2014) Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors. PLoS One 9:e87029

    PubMed Central  PubMed  Google Scholar 

  40. Guo Z, Liu P, Ren F, Cao YQ (2014) Non-migraine associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons. J Neurophysiol 112:568–579

  41. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G, Lazdunski M (2004) TREK1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J 23:2684–2695

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thümmler 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 TREK1 results in a depression-resistant phenotype. Nat Neurosci 9:1134–1141

    CAS  PubMed  Google Scholar 

  43. Honoré E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8:251–261

    PubMed  Google Scholar 

  44. Honoré E, Maingret F, Lazdunski M, Patel AJ (2002) An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK1. EMBO J 21:2968–2976

    PubMed Central  PubMed  Google Scholar 

  45. Huang DY, Yu BW, Fan QW (2008) Roles of TRESK, a novel two-pore domain K+ channel, in pain pathway and general anesthesia. Neurosci Bull 24:166–172

    CAS  PubMed  Google Scholar 

  46. Hwang EM, Kim E, Yarishkin O, Woo DH, Han KS, Park N, Bae Y, Woo J, Kim D, Park M, Lee CJ, Park JY (2014) A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat Commun 5:3227

    PubMed  Google Scholar 

  47. Kang D, Choe C, Kim D (2005) Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol 564:103–116

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Kang D, Kim D (2006) TREK-2 (K2P10.1) and TRESK (K2P18.1) are major background K+ channels in dorsal root ganglion neurons. Am J Physiol Cell Physiol 291:C138–C146

    CAS  PubMed  Google Scholar 

  49. Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005) Inhibition of the human two-pore domain potassium channel, TREK1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144:821–829

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Kim EJ, Kang D, Han J (2011) Baicelein and wogonin are activators of rat TREK-2 two-pore domain K+ channel. Acta Physiol 202:185–192

    CAS  Google Scholar 

  51. Kim EJ, Ryu HW, Curtis-Long MJ, Han J, Kim JY, Cho JK, Kang D, Park KH (2010) Chemoselective regulation of TREK2 channel: activation by sulfonate chalcones and inhibition by sulfonamide chalcones. Bioorg Med Chem Lett 20:4237–4239

    CAS  PubMed  Google Scholar 

  52. Kim S, Lee Y, Tak HM, Park HJ, Sohn YS, Hwang S, Han J, Kang D, Lee KW (2013) Identification of blocker binding site in mouse TRESK by molecular modeling and mutational studies. Biochim Biophys Acta 1828:1131–1142

    CAS  PubMed  Google Scholar 

  53. Koh SD, Monaghan K, Sergeant GP, Ro S, Walker RL, Sanders KM, Horowitz B (2001) TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase. An essential role in smooth muscle inhibitory neurotransmission. J Biol Chem 276:44338–44346

    CAS  PubMed  Google Scholar 

  54. La JH, Gebhart GF (2011) Colitis decreases mechanosensitive K2P channel expression and function in mouse colon sensory neurons. Am J Physiol Gastrointest Liver Physiol 301:G165–G174

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, McLaughlan S, Dubé MP, Marcinkiewicz MM, Ramagopalan S, Ansorge O, Brais B, Sequeiros J, Pereira-Monteiro JM, Griffiths LR, Tucker SJ, Ebers G, Rouleau GA (2010) A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med 16:1157–1160

    PubMed  Google Scholar 

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

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Lee J, Kim T, Hong J, Woo J, Min H, Hwang E, Lee SJ, Lee CJ (2012) Imiquimod enhances excitability of dorsal root ganglion neurons by inhibiting background (K(2P)) and voltage-gated (K(v)1.1 and K(v)1.2) potassium channels. Mol Pain 8:2

    PubMed Central  CAS  PubMed  Google Scholar 

  58. Lennertz RC, Tsunozaki M, Bautista DM, Stucky CL (2010) Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool. J Neurosci 30:4353–4361

    PubMed Central  CAS  PubMed  Google Scholar 

  59. Lotshaw DP (2007) Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels. Cell Biochem Biophys 47:209–256

    CAS  PubMed  Google Scholar 

  60. Liu P, Xiao Z, Ren F, Guo Z, Chen Z, Zhao H, Cao YQ (2013) Functional analysis of a migraine-associated TRESK K+ channel mutation. J Neurosci 33:12810–12824

    PubMed Central  CAS  PubMed  Google Scholar 

  61. Ma XY, Yu JM, Zhang SZ, Liu XY, Wu BH, Wei XL, Yan JQ, Sun HL, Yan HT, Zheng JQ (2011) External Ba2+ block of the two-pore domain potassium channel TREK1 defines conformational transition in its selectivity filter. J Biol Chem 286:39813–39822

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Maher BH, Taylor M, Stuart S, Okolicsanyi RK, Roy B, Sutherland HG, Haupt LM, Griffiths LR (2013) Analysis of 3 common polymorphisms in the KCNK18 gene in an Australian Migraine case–control cohort. Gene 528:343–346

    CAS  PubMed  Google Scholar 

  63. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honoré E (2000) TREK1 is a heat-activated background K(+) channel. EMBO J 19:2483–2491

    PubMed Central  CAS  PubMed  Google Scholar 

  64. Maingret F, Patel AJ, Lesage F, Lazdunski M, Honoré E (2000) Lysophospholipids open the two-pore domain mechano-gated K(+) channels TREK1 and TRAAK. J Biol Chem 275:10128–10133

    CAS  PubMed  Google Scholar 

  65. Marsh B, Acosta C, Djouhri L, Lawson SN (2012) Leak K+ channel mRNAs in dorsal root ganglia: relation to inflammation and spontaneous pain behaviour. Mol Cell Neurosci 49:375–386

    CAS  PubMed  Google Scholar 

  66. Mathie A (2007) Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J Physiol 578:377–385

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Mathie A (2010) Ion channels as novel therapeutic targets in the treatment of pain. J Pharm Pharmacol 62:1089–1095

    CAS  PubMed  Google Scholar 

  68. Mathie A, Al-Moubarak E, Veale EL (2010) Gating of two pore domain potassium channels. J Physiol 588:3149–3156

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Mathie A, Veale EL (2007) Therapeutic potential of neuronal two-pore domain potassium-channel modulators. Curr Opin Investig Drugs 8:555–562

    CAS  PubMed  Google Scholar 

  70. 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. Brain Res Mol Brain Res 86:101–114

    CAS  PubMed  Google Scholar 

  71. Miller AN, Long SB (2012) Crystal structure of the human two-pore domain potassium channel K2P1. Science 335:432–436

    CAS  PubMed  Google Scholar 

  72. Morenilla-Palao C, Luis E, Fernández-Peña C, Quintero E, Weaver JL, Bayliss DA, Viana F (2014) Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep 8:1571–1582

    CAS  PubMed  Google Scholar 

  73. Murbartián 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

    PubMed  Google Scholar 

  74. Noël J, Sandoz G, Lesage F (2011) Molecular regulations governing TREK and TRAAK channel functions. Channels 5:402–409

    PubMed Central  PubMed  Google Scholar 

  75. Noël J, Zimmermann K, Busserolles J, Deval E, Alloui A, Diochot S, Guy N, Borsotto M, Reeh P, Eschalier A, Lazdunski M (2009) The mechano-activated K+ channels TRAAK and TREK1 control both warm and cold perception. EMBO J 28:1308–1318

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  77. 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

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Pereira V, Busserolles J, Christin M, Devilliers M, Poupon L, Legha W, Alloui A, Aissouni Y, Bourinet E, Lesage F, Eschalier A, Lazdunski M, Noël J (2014) Role of the TREK2 potassium channel in cold and warm thermosensation and in pain perception. Pain. doi:10.1016/j.pain.2014.09.013

    Google Scholar 

  79. Piechotta PL, Rapedius M, Stansfeld PJ, Bollepalli MK, Erhlich G, Andres-Enguix I, Fritzenshaft H, Decher N, Sansom MS, Tucker SJ, Baukrowitz T (2011) The pore structure and gating mechanism of K2P channels. EMBO J 30:3607–3619

    PubMed Central  CAS  PubMed  Google Scholar 

  80. Plant LD (2012) A role for K2P channels in the operation of somatosensory nociceptors. Front Mol Neurosci 5:21

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Pollema-Mays SL, Centeno MV, Ashford CJ, Apkarian AV, Martina M (2013) Expression of background potassium channels in rat DRG is cell-specific and down-regulated in a neuropathic pain model. Mol Cell Neurosci 57:1–9

    CAS  PubMed  Google Scholar 

  82. Rahm AK, Gierten J, Kisselbach J, Staudacher I, Staudacher K, Schweizer PA, Becker R, Katus HA, Thomas D (2012) PKC-dependent activation of human K(2P) 18.1 K(+) channels. Br J Pharmacol 166:764–773

    PubMed Central  CAS  PubMed  Google Scholar 

  83. Rapedius M, Schmidt MR, Sharma C, Stansfeld PJ, Sansom MS, Baukrowitz T, Tucker SJ (2012) State-independent intracellular access of quaternary ammonium blockers to the pore of TREK-1. Channels 6:473–478

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Rodrigues N, Bennis K, Vivier D, Pereira V, Chatelain FC, Chapuy E, Deokar H, Busserolles J, Lesage F, Eschalier A, Ducki S (2014) Synthesis and structure–activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel. Eur J Med Chem 75:391–402

    CAS  PubMed  Google Scholar 

  85. Sandoz G, Douguet D, Chatelain F, Lazdunski M, Lesage F (2009) Extracellular acidification exerts opposite actions on TREK1 and TREK2 potassium channels via a single conserved histidine residue. Proc Natl Acad Sci U S A 106:14628–14633

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Sandoz G, Levitz J, Kramer RH, Isacoff EY (2012) Optical control of endogenous proteins with a photoswitchable conditional subunit reveals a role for TREK1 in GABA(B) signaling. Neuron 74:1005–1014

    PubMed Central  CAS  PubMed  Google Scholar 

  87. Sandoz G, Thümmler 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

    PubMed Central  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. Sawyer CM, Carstens MI, Simons CT, Slack J, McCluskey TS, Furrer S, Carstens E (2009) Activation of lumbar spinal wide-dynamic range neurons by a sanshool derivative. J Neurophysiol 101:1742–1748

    PubMed Central  PubMed  Google Scholar 

  90. Sehgal SA, Hassan M, Rashid S (2014) Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18. Drug Des Dev Ther 8:571–581

    CAS  Google Scholar 

  91. Takahira M, Sakurai M, Sakurada N, Sugiyama K (2005) Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels. Pflugers Arch 451:474–478

    CAS  PubMed  Google Scholar 

  92. 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

    CAS  PubMed  Google Scholar 

  93. Tertyshnikova S, Knox RJ, Plym MJ, Thalody G, Griffin C, Neelands T, Harden DG, Signor L, Weaver D, Myers RA, Lodge NJ (2005) BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: a putative potassium channel opener with bladder-relaxant properties. J Pharmacol Exp Ther 313:250–259

    CAS  PubMed  Google Scholar 

  94. Thomas D, Plant LD, Wilkens CM, McCrossan ZA, Goldstein SA (2008) Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron 58:859–870

    PubMed Central  CAS  PubMed  Google Scholar 

  95. Tsantoulas C, McMahon SB (2014) Opening paths to novel analgesics: the role of potassium channels in chronic pain. Trends Neurosci 37:146–158

    PubMed Central  CAS  PubMed  Google Scholar 

  96. Tsunozaki M, Bautista DM (2009) Mammalian somatosensory mechanotransduction. Curr Opin Neurobiol 19:362–369

    CAS  PubMed  Google Scholar 

  97. Tsunozaki M, Lennertz RC, Vilceanu D, Katta S, Stucky CL, Bautista DM (2013) A ‘toothache tree’ alkylamide inhibits Aδ mechanonociceptors to alleviate mechanical pain. J Physiol 591:3325–3340

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Tulleuda A, Cokic B, Callejo G, Saiani B, Serra J, Gasull X (2011) TRESK channel contribution to nociceptive sensory neurons excitability: modulation by nerve injury. Mol Pain 7:30

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Veale EL, Al-Moubarak E, Bajaria N, Omoto K, Cao L, Tucker SJ, Stevens EB, Mathie A (2014) Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels. Mol Pharmacol 85:671–681

    PubMed  Google Scholar 

  100. Veale EL, Rees KA, Mathie A, Trapp S (2010) Dominant negative effects of a non-conducting TREK1 splice variant expressed in brain. J Biol Chem 285:29295–29304

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Waxman SG, Zamponi GW (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci 17:153–163

    CAS  PubMed  Google Scholar 

  102. Woolf CJ, Ma Q (2007) Nociceptors-noxious stimulus detectors. Neuron 55:353–364

    CAS  PubMed  Google Scholar 

  103. Wright PD, Weir G, Cartland J, Tickle D, Kettleborough C, Cader MZ, Jerman J (2013) Cloxyquin (5-chloroquinolin-8-ol) is an activator of the two-pore domain potassium channel TRESK. Biochem Biophys Res Commun 441:463–468

    CAS  PubMed  Google Scholar 

  104. Yamamoto Y, Hatakeyama T, Taniguchi K (2009) Immunohistochemical colocalization of TREK-1, TREK-2 and TRAAK with TRP channels in the trigeminal ganglion cells. Neurosci Lett 454:129–133

    CAS  PubMed  Google Scholar 

  105. Yang SB, Jan LY (2008) Thrilling moment of an inhibitory channel. Neuron 58:823–824

    CAS  PubMed  Google Scholar 

  106. Yoo S, Liu J, Sabbadini M, Au P, Xie GX, Yost CS (2009) Regional expression of the anesthetic-activated potassium channel TRESK in the rat nervous system. Neurosci Lett 465:79–84

    PubMed Central  CAS  PubMed  Google Scholar 

  107. Zhou J, Yang CX, Zhong JY, Wang HB (2013) Intrathecal TRESK gene recombinant adenovirus attenuates spared nerve injury-induced neuropathic pain in rats. Neuroreport 24:131–136

    CAS  PubMed  Google Scholar 

  108. Zhou J, Yao SL, Yang CX, Zhong JY, Wang HB, Zhang Y (2012) TRESK gene recombinant adenovirus vector inhibits capsaicin-mediated substance P release from cultured rat dorsal root ganglion neurons. Mol Med Rep 5:1049–1052

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Biotechnology and Biological Sciences Research Council (UK) [BB/J000930/1] and Pfizer. Thanks to Ehab Al-Moubarak for homology modelling of the TREK1 channel on TRAAK (Fig. 2) and to Madeleine Mathie for help with Fig. 1.

Author information

Authors and Affiliations

  1. Medway School of Pharmacy, University of Kent, Central Avenue, Chatham Maritime, Kent, ME4 4TB, UK

    Alistair Mathie & Emma L. Veale

Authors
  1. Alistair Mathie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emma L. Veale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alistair Mathie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mathie, A., Veale, E.L. Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain. Pflugers Arch - Eur J Physiol 467, 931–943 (2015). https://doi.org/10.1007/s00424-014-1655-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-014-1655-3

Keywords

Search

Navigation