Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The neuronal background K2P channels: focus on TREK1

Nature Reviews Neuroscience volume 8, pages 251–261 (2007)Cite this article

Key Points

  • Background K+ channels are dimers of K2P channel subunits, each of which is composed of four transmembrane segments and two P domains arranged in tandem.

  • The Aplysia serotonin-sensitive S-type K+ channel and the Lymnaea anaesthetic-sensitive K(An) channels are classical examples of background K+ channels.

  • Background K+ channels and their regulation by membrane-receptor-coupled second messengers, as well as pharmacological agents, influence neuronal resting membrane potential, action potential duration, membrane input resistance and, consequently, neurotransmitter release.

  • K2P channels diverge from the constant-field Goldman–Hodgkin–Katz (GHK) current formulation and are characterized by complex permeation and gating mechanisms.

  • TREK1 can be activated by mechanical stimulation, intracellular acidosis and warm temperature, thus qualifying as a polymodal sensory ion channel integrating multiple physical and chemical stimuli.

  • Besides its activation by physical stimuli, TREK1 is also upmodulated by various chemical stimuli including cellular lipids and volatile general anaesthetics.

  • Recent evidence suggests that both mechanical and lipid activations of TREK1 may be functionally linked. The proposed model states that a tight dynamic interaction of the cytosolic carboxy-terminal domain of TREK1 with the inner leaflet of the plasma membrane is central to the mechanism of channel gating and regulation by membrane receptors/second messenger pathways.

  • TREK1 is downmodulated by the stimulation of both Gs- and Gq-coupled membrane receptors. Recent studies have identified the second messenger pathways involved in this regulation, including phosphorylation pathways and PtdIns(4,5)P2 hydrolysis.

  • The Trek1−/− mutant mice are healthy, fertile and do not display any visible morphological difference. However, recent studies indicate a central role for TREK1 in anaesthesia, neuroprotection, pain perception and depression.

  • Both the Aplysia S-type K+ channel and mammalian TREK1 are involved in controlling the excitability of presynaptic neurons through the pathway mediated by serotonin, cyclic AMP and protein kinase A. However, in the dorsal raphé neurons, serotonin probably opens TREK1 though the Gi/o pathway, whereas serotonin closes the S-type K+ channel through the Gs pathway in molluscan sensory neurons.

Abstract

Two-pore-domain K+ (K2P) channel subunits are made up of four transmembrane segments and two pore-forming domains that are arranged in tandem and function as either homo- or heterodimeric channels. This structural motif is associated with unusual gating properties, including background channel activity and sensitivity to membrane stretch. Moreover, K2P channels are modulated by a variety of cellular lipids and pharmacological agents, including polyunsaturated fatty acids and volatile general anaesthetics. Recent in vivo studies have demonstrated that TREK1, the most thoroughly studied K2P channel, has a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain and depression.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Diversity and structural properties of the human K2P channels.
Figure 2: Polymodal activation of TREK1 by physical and chemical stimuli.
Figure 3: Modulation of TREK1 by phosphatidylinositol-4,5-bisphosphate.
Figure 4: TREK1 is involved in polymodal pain perception.
Figure 5: Role of TREK1 in general anaesthesia and neuroprotection.
Figure 6: Role of TREK1 in feedback inhibition of serotonergic dorsal raphé neurons and the response to antidepressants.

References

  1. Castellucci, V. & Kandel, E. R. Presynaptic facilitation as a mechanism for behavioral sensitization in Aplysia. Science 194, 1176–1178 (1976). Study of the neural circuit of the gill-withdrawal reflex in the isolated abdominal ganglion of Aplysia , indicating that short-term sensitization is due to presynaptic facilitation.

    CAS  PubMed  Google Scholar 

  2. Siegelbaum, S. A., Camardo, J. S. & Kandel, E. R. Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones. Nature 299, 413–417 (1982). Shows that the application of serotonin to the cell body or intracellular injection of cAMP causes prolonged and complete closure of the S-type background K+ channel, which can account for the increases in transmitter release which underlie behavioural sensitization.

    CAS  PubMed  Google Scholar 

  3. Franks, N. P. & Lieb, W. R. Volatile general anaesthetics activate a novel neuronal K+ current. Nature 333, 662–664 (1988). Shows that, amongst a group of apparently identical molluscan neurons having endogenous firing activity, a single cell displays an unusual sensitivity to volatile agents due to a novel anaesthetic-activated background K+ current IK(An).

    CAS  PubMed  Google Scholar 

  4. Franks, N. P. & Lieb, W. R. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science 254, 427–430 (1991).

    CAS  PubMed  Google Scholar 

  5. Byrne, J. H. & Kandel, E. R. Presynaptic facilitation revisited: state and time dependence. J. Neurosci. 16, 425–435 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Patel, A. J. et al. A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J. 17, 4283–4290 (1998). Demonstrates that TREK1 shares the functional properties of the Aplysia S channel.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  8. Heurteaux, C. et al. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nature Neurosci. 9, 1134–1141 (2006). Shows that TREK1-deficient ( Kcnk2−/−) mice have an increased efficacy of 5-HT neurotransmission and a resistance to depression.

    CAS  PubMed  Google Scholar 

  9. Alloui, A. et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J. 25, 2368–2376 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Heurteaux, C. et al. TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J. 23, 2684–2695 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Patel, A. J. et al. Inhalational anaesthetics activate two-pore-domain background K+ channels. Nature Neurosci. 2, 422–426 (1999). Shows that the K 2P channels TASK and TREK1 are activated by volatile general anaesthetics. Chloroform, diethyl ether, halothane and isoflurane activate TREK1, whereas only halothane and isoflurane activate TASK.

    CAS  PubMed  Google Scholar 

  12. Gruss, M. et al. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol. Pharmacol. 65, 443–452 (2004).

    CAS  PubMed  Google Scholar 

  13. Hervieu, G. J. et al. Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 103, 899–919 (2001).

    CAS  PubMed  Google Scholar 

  14. Medhurst, A. D. et al. Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Mol. Brain Res. 86, 101–114 (2001).

    CAS  PubMed  Google Scholar 

  15. Fink, M. et al. Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J. 15, 6854–6862 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Talley, E. M., Solorzano, G., Lei, Q., Kim, D. & Bayliss, D. A. CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J. Neurosci. 21, 7491–7505 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Patel, A. J. & Honoré, E. Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci. 24, 339–346 (2001).

    CAS  PubMed  Google Scholar 

  18. Lesage, F. & Lazdunski, M. Molecular and functional properties of two-pore-domain potassium channels. Am. J. Physiol. Renal. Physiol. 279, F793–F801 (2000).

    CAS  PubMed  Google Scholar 

  19. Goldstein, S. A. N., Bockenhauer, D., O'Kelly, I. & Zilberg, N. Potassium leak channels and the KCNK family of two-P-domain subunits. Nature Rev. Neurosci. 2, 175–184 (2001).

    CAS  Google Scholar 

  20. Talley, E. M., Sirois, J. E., Lei, Q. & Bayliss, D. A. Two-pore-domain (KCNK) potassium channels: dynamic roles in neuronal function. Neuroscientist 9, 46–56 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998). Uses x-ray analysis to reveal that four identical KcsA subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids.

    CAS  PubMed  Google Scholar 

  23. O''Connell, A. D., Morton, M. J. & Hunter, M. Two-pore domain K+ channels-molecular sensors. Biochim. Biophys. Acta 1566, 152–161 (2002).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  25. Czirjak, G. & Enyedi, P. Formation of functional heterodimers between the TASK-1 and TASK-3 two pore domain potassium channel subunits. J. Biol. Chem. 277, 5436–5432 (2001).

    Google Scholar 

  26. Kang, D., Han, J., Talley, E. M., Bayliss, D. A. & Kim, D. Functional expression of TASK-1/TASK-3 heteromers in cerebellar granule cells. J. Physiol. 554, 64–77 (2004).

    CAS  PubMed  Google Scholar 

  27. Xian Tao, L. et al. The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle. Cardiovasc. Res. 69, 86–97 (2006).

    Google Scholar 

  28. Bockenhauer, D., Zilberberg, N. & Goldstein, S. A. KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nature Neurosci. 4, 486–491 (2001).

    CAS  PubMed  Google Scholar 

  29. Lesage, F. et al. A pH-sensitive yeast outward rectifier K+ channel with two pore domains and novel gating properties. J. Biol. Chem. 271, 4183–4187 (1996).

    CAS  PubMed  Google Scholar 

  30. Reid, J. D. et al. The S. cerevisiae outwardly-rectifying potassium channel (DUK1) identifies a new family of channels with duplicated pore domains. Recept. Channels 4, 51–62 (1996).

    CAS  PubMed  Google Scholar 

  31. Zhou, X. L., Vaillant, B., Loukin, S. H., Kung, C. & Saimi, Y. YKC1 encodes the depolarization-activated K+ channel in the plasma membrane of yeast. FEBS Lett. 373, 170–176 (1995).

    CAS  PubMed  Google Scholar 

  32. Ketchum, K. A., Joiner, W. J., Sellers, A. J., Kaczmarek, L. K. & Goldstein, S. A. N. A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem. Nature 376, 690–695 (1995).

    CAS  PubMed  Google Scholar 

  33. Lesage, F. et al. TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J. 15, 1004–1011 (1996). Cloning of the first mammalian K 2P channel subunit TWIK1.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Duprat, F. et al. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 16, 5464–5471 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Goldstein, S. A., Price, L. A., Rosenthal, D. N. & Pausch, M. H. 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 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Fink, M. et al. A neuronal two P domain K+ channel activated by arachidonic acid and polyunsaturated fatty acid. EMBO J. 17, 3297–3308 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Reyes, R. et al. Cloning and expression of a novel pH-sensitive two pore domain potassium channel from human kidney. J. Biol. Chem. 273, 30863–30869 (1998).

    CAS  PubMed  Google Scholar 

  38. Lesage, F., Terrenoire, C., Romey, G. & Lazdunski, M. 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 (2000).

    CAS  PubMed  Google Scholar 

  39. Hille, B. Ion Channels of Excitable Membranes (Sinauer, Sunderland, Massachusetts, 1992).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  42. Lopes, C. M., Gallagher, P. G., Buck, M. E., Butler, M. H. & Goldstein, S. A. Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3. J. Biol. Chem. 275, 16969–16978 (2000).

    CAS  PubMed  Google Scholar 

  43. Chemin, J. et al. A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO J. 24, 44–53 (2005). Shows that membrane phospholipids, including PtdIns(4,5)P 2 , control channel gating and transform TREK1 into a leak K+ conductance. A C-terminal positively charged cluster is the phospholipid-sensing domain that interacts with the plasma membrane.

    CAS  PubMed  Google Scholar 

  44. Patel, A. J. & Honoré, E. Anesthetic-sensitive 2P domain K+ channels. Anesthesiology 95, 1013–1025 (2001).

    CAS  PubMed  Google Scholar 

  45. Maylie, J. & Adelman, J. P. Beam me up, Scottie! TREK channels swing both ways. Nature Neurosci. 4, 457–458 (2001).

    CAS  PubMed  Google Scholar 

  46. Lopes, C. M. et al. PiP2-Hydrolysis underlies agonist-induced inhibition and regulates voltage-gating of 2-P-Domain K+ Channels. J. Physiol. 564, 117–129 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Maingret, F. et al. TREK-1 is a heat-activated background K+ channel. EMBO J. 19, 2483–2491 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  51. Lauritzen, I. et al. Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep. 6, 642–648 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sandoz, G. et al. AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K+ channels into open leak channels. EMBO J. 25, 5864–5872 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Sheetz, M. P. & Singer, S. J. Biological membranes as bilayer couples. A molecular mechanism of drug-erythocyte interactions. Proc. Natl Acad. Sci. USA 71, 4457–4461 (1974). Shows that membranes whose polar lipids are distributed asymmetrically in the two halves of the membrane bilayer can act as bilayer couples, that is, the two halves can respond differently to a perturbation. This hypothesis is applied to the interactions of amphipathic drugs with human erythrocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Kim, Y., Gnatenco, C., Bang, H. & Kim, D. Localization of TREK-2 K+ channel domains that regulate channel kinetics and sensitivity to pressure, fatty acids and pHi . Pflugers Arch. 2001, 952–960 (2001).

    Google Scholar 

  57. Kim, Y., Bang, H., Gnatenco, C. & Kim, D. Synergistic interaction and the role of C-terminus in the activation of TRAAK K+ channels by pressure, free fatty acids and alkali. Pflugers Arch. 442, 64–72 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Chemin, J. et al. Lysophosphatidic acid-operated K+ channels. J. Biol. Chem. 280, 4415–4421 (2005).

    CAS  PubMed  Google Scholar 

  60. Chemin, J. et al. Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J. 22, 5403–5411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Koh, S. D. et al. TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase. J. Biol. Chem. 47, 44338–44346 (2001).

    Google Scholar 

  62. Kennard, L. E. et al. Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br. J. Pharmacol. 144, 821–829 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Franks, N. P. & Honoré, E. The TREK K2P channels and their role in general anaesthesia and neuroprotection. Trends Pharmacol. Sci. 25, 601–608 (2004).

    CAS  PubMed  Google Scholar 

  64. Franks, N. P. & Lieb, W. R. Background K+ channels: an important target for volatile anesthetics? Nature Neurosci. 2, 395–396 (1999).

    CAS  PubMed  Google Scholar 

  65. Harinath, S. & Sikdar, S. K. Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels. Neuropharmacology 46, 750–760 (2004).

    CAS  PubMed  Google Scholar 

  66. Buckler, K. J. & Honoré, E. The lipid-activated two-pore domain K+ channel TREK-1 is resistant to hypoxia: implication for ischaemic neuroprotection. J. Physiol. 562, 213–222 (2005).

    CAS  PubMed  Google Scholar 

  67. Caley, A. J., Gruss, M. & Franks, N. P. The effects of hypoxia on the modulation of human TREK-1 potassium channels. J. Physiol. 562, 205–212 (2004).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  71. Lauritzen, I. et al. Poly-unsaturated fatty acids are potent neuroprotectors. EMBO J. 19, 1784–1793 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Duprat, F. et al. The neuroprotective agent riluzole activates the two P domain K+ channels TREK-1 and TRAAK. Mol. Pharmacol. 57, 906–912 (2000).

    CAS  PubMed  Google Scholar 

  73. Clapham, D. E. TRP channels as cellular sensors. Nature 426, 517–524 (2003).

    CAS  PubMed  Google Scholar 

  74. Nilius, B., Owsianik, G., Voets, T. & Peters, J. A. Transient receptor potential cation channels in disease. Physiol. Rev. 87, 165–217 (2007).

    CAS  PubMed  Google Scholar 

  75. Gordon, J. A. & Hen, R. TREKing toward new antidepressants. Nature Neurosci. 9, 1081–1083 (2006).

    CAS  PubMed  Google Scholar 

  76. Maingret, F., Fosset, M., Lesage, F., Lazdunski, M. & Honoré, E. TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem. 274, 1381–1387 (1999).

    CAS  PubMed  Google Scholar 

  77. Byrne, J. H. & Kandel, E. R. Presynaptic facilitation revisited: state and time dependence. J. Neurosci. 16, 425–435 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Shuster, M. J., Camardo, J. S., Siegelbaum, S. A. & Kandel, E. R. Cyclic AMP-dependent protein kinase closes the serotonin-sensitive K+ channels of Aplysia sensory neurones in cell-free membrane patches. Nature 313, 392–395 (1985).

    CAS  PubMed  Google Scholar 

  79. Sweatt, D. J. et al. FMRFamide reverses protein phosphorylation produced by 5-HT and cAMP in Aplysia sensory neurons. Nature 342, 275–278 (1989).

    CAS  PubMed  Google Scholar 

  80. Belardetti, F., Kandel, E. R. & Siegelbaum, S. A. Neuronal inhibition by the peptide FMRFamide involves opening of S K+ channels. Nature 325, 153–156 (1987). Demonstrates that FMRFamide produces two actions on the S channel; it increases the probability of opening of the S channels via a cAMP-independent second-messenger system, and it reverses the closures of S channels produced by serotonin or cAMP.

    CAS  PubMed  Google Scholar 

  81. Hamill, O. P. & Martinac, B. Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81, 685–740 (2001).

    CAS  PubMed  Google Scholar 

  82. Sachs, F. & Morris, C. E. Mechanosensitive ion channels in nonspecialized cells. Rev. Physiol. Biochem. Pharmacol. 132, 1–77 (1998).

    CAS  PubMed  Google Scholar 

  83. Kung, C. A possible unifying principle for mechanosensation. Nature 436, 647–654 (2005).

    CAS  PubMed  Google Scholar 

  84. Kloda, A., Ghazi, A. & Martinac, B. C-terminal charged cluster of MscL, RKKEE, functions as a pH sensor. Biophys. J. 90, 1992–1998 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bayliss, D. A., Talley, E. M., Sirois, J. E. & Lei, Q. TASK-1 is a highly modulated pH-sensitive ''leak'' K+ channel expressed in brainstem respiratory neurons. Respir. Physiol. 129, 159–174 (2001).

    CAS  PubMed  Google Scholar 

  88. Talley, E. M., Lei, Q., Sirois, J. E. & Bayliss, D. A. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25, 399–410 (2000).

    CAS  PubMed  Google Scholar 

  89. Talley, E. M. & Bayliss, D. A. 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 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  92. Plant, L. D., Rajan, S. & Goldstein, S. A. K2P channels and their protein partners. Curr. Opin. Neurobiol. 15, 326–333 (2005).

    CAS  PubMed  Google Scholar 

  93. Rajan, S., Plant, L. D., Rabin, M. L., Butler, M. H. & Goldstein, S. A. Sumoylation silences the plasma membrane leak K+ channel K2P1 . Cell 121, 37–47 (2005).

    CAS  PubMed  Google Scholar 

  94. Decressac, S. et al. ARF6-dependent interaction of the TWIK1 K+ channel with EFA6, a GDP/GTP exchange factor for ARF6. EMBO Rep. 5, 1171–1175 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Girard, C. et al. p11, an annexin II subunit, an auxilary protein associated with the background K+ channel, TASK-1. EMBO J. 21, 4439–4448 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Renigunta, V. et al. The retention factor p11 confers an endoplasmic reticulum-localization signal to the potassium channel TASK-1. Traffic 7, 168–181 (2006).

    CAS  PubMed  Google Scholar 

  97. O'Kelly, I., Butler, M. H., Zilberberg, N. & Goldstein, S. A. Forward transport: 14-3-3 binding overcomes retention in endoplasmic reticulum by dibasic signals. Cell 111, 577–588 (2002).

    CAS  PubMed  Google Scholar 

  98. Hsu, K., Seharaseyon, J., Dong, P., Bour, S. & Marban, E. Mutual functional destruction of HIV-1 Vpu and host TASK-1 channel. Mol. Cell 14, 259–267 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I am 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 INSERM and to CNRS for support. I wish to thank A. Patel, S. Siegelbaum and E. Kandel for critical reading of this manuscript. I am grateful to M. Lazdunski and colleagues for helpful and stimulating discussions. Finally, I would like to thank the reviewers of this manuscript for their constructive input.

Author information

Authors and Affiliations

  1. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, Université de Nice-Sophia Antipolis, 660 route des Lucioles, Valbonne, 06560, France

    Eric Honoré

Authors
  1. Eric Honoré
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

Fabrice Duprat's homepage

Glossary

P domain

A short amino acid segment between two transmembrane helices that dips into the membrane without fully crossing it.

Selectivity filter

The sequence that determines K+ selectivity of K+ channels. The primary sequence of the P loop of most K+ channels has the signature sequence Thr–Val–Gly–Tyr–Gly.

Permeability ratio

The relative permeability of an ion channel for a particular monovalent cation. A given ion channel can allow the passage of related ionic species, although not all with the same ease.

Rectification

The property whereby current through a channel does not flow with the same ease from the inside as from the outside.

Inward rectifiers

Channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence upon hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.

Outward rectifiers

Channels that allow current to flow more easily out of the cell. Voltage-gated K+ channels are outward rectifiers that shape the action potential duration.

Intracellular acidosis

A decrease in intracellular pH that occurs, for example, during brain ischaemia.

Cell-attached patch configuration

Recording configuration in which the patch of membrane at the tip of the recording electrode is not excised but remains attached to the cell. This configuration allows the measurement of the current flowing through the ion channels embedded in the electrically isolated membrane patch.

Inside-out patch configuration

Recording configuration in which the patch of membrane at the tip of the patch-clamp electrode is excised from the cell. The intracellular side of the channel is exposed to the bathing solution.

Desensitization

Decrease in the activity of a protein during maintained stimulation.

Inner leaflet

The inner layer of phospholipids in the plasma membrane.

Polar head

Hydrophilic charged groups such as choline, ethanolamine, serine or inositol, bound to glycerol phosphate in membrane phospholipids.

Amphipaths

A molecule with both hydrophobic and hydrophilic surfaces.

Outside-out patch configuration

A variant of the patch-clamp technique, in which a patch of plasma membrane is excised from the cell. The outside of the membrane is exposed to the bathing solution.

Polymodal C-fibres

Non-myelinated axons characterized by a slow conduction. Polymodal nociceptors are activated by high intensity mechanical, chemical and thermal stimuli, involving non-myelinated C-fibres conducting delayed pain.

Allodynia

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

Porsolt forced swim test

A method to estimate behavioural despair in a stressful and inescapable situation. Mice rapidly adopt a characteristic immobile posture when they are forced to swim in a water tank. Immobility is considered to be a state of 'lowered mood' in which the animal has given up hope of finding an exit and is resigned to the stressful situation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Honoré, E. The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8, 251–261 (2007). https://doi.org/10.1038/nrn2117

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2117

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing