The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K_2P channels (and not two-pore channels). Some of the K_2P subunits can form heterodimers across subfamilies (e.g. K_2P3.1 with K_2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

The K_2P6, K_2P7.1, K_2P15.1 and K_2P12.1 subtypes, when expressed in isolation, are nonfunctional. All 4TM channels are insensitive to the classical potassium channel blockers tetraethylammonium and fampridine, but are blocked to varying degrees by Ba²⁺ ions.

* Key recommended reading is highlighted with an asterisk

* Gada K, Plant LD. (2019) Two-pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26. Br J Pharmacol, 176 (2): 256-266. [PMID:30325008]

* Jin X, Zhang Y, Alharbi A, Hanbashi A, Alhoshani A, Parrington J. (2020) Targeting Two-Pore Channels: Current Progress and Future Challenges. Trends Pharmacol Sci, 41 (8): 582-594. [PMID:32679067]

* Mathie A, Veale EL, Cunningham KP, Holden RG, Wright PD. (2021) Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond. Annu Rev Pharmacol Toxicol, 61: 401-420. [PMID:32679007]

1. Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N et al.. (2008) Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet, 83 (2): 193-9. [PMID:18678320]

2. Blin S, Ben Soussia I, Kim EJ, Brau F, Kang D, Lesage F, Bichet D. (2016) Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties. Proc Natl Acad Sci USA, 113 (15): 4200-5. [PMID:27035965]

3. Blin S, Chatelain FC, Feliciangeli S, Kang D, Lesage F, Bichet D. (2014) Tandem pore domain halothane-inhibited K+ channel subunits THIK1 and THIK2 assemble and form active channels. J Biol Chem, 289 (41): 28202-12. [PMID:25148687]

4. Cazals Y, Bévengut M, Zanella S, Brocard F, Barhanin J, Gestreau C. (2015) KCNK5 channels mostly expressed in cochlear outer sulcus cells are indispensable for hearing. Nat Commun, 6: 8780. [PMID:26549439]

5. Czirják G, Enyedi P. (2002) Formation of functional heterodimers between the TASK-1 and TASK-3 two-pore domain potassium channel subunits. J Biol Chem, 277 (7): 5426-32. [PMID:11733509]

6. Decher N, Wemhöner K, Rinné S, Netter MF, Zuzarte M, Aller MI, Kaufmann SG, Li XT, Meuth SG, Daut J et al.. (2011) Knock-out of the potassium channel TASK-1 leads to a prolonged QT interval and a disturbed QRS complex. Cell Physiol Biochem, 28 (1): 77-86. [PMID:21865850]

7. 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 (5): 906-12. [PMID:10779373]

8. Fink M, Lesage F, Duprat F, Heurteaux C, Reyes R, Fosset M, Lazdunski M. (1998) A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J, 17 (12): 3297-308. [PMID:9628867]

9. Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El Wakil A, Lalli E, Guy N, Mengual R et al.. (2008) Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. EMBO J, 27 (1): 179-87. [PMID:18034154]

10. Kang D, Choe C, Kim D. (2005) Thermosensitivity of the two-pore domain K+ channels TREK-2 and TRAAK. J Physiol (Lond.), 564 (Pt 1): 103-16. [PMID:15677687]

11. Kang D, Kim D. (2004) Single-channel properties and pH sensitivity of two-pore domain K+ channels of the TALK family. Biochem Biophys Res Commun, 315 (4): 836-44. [PMID:14985088]

12. 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 (6): 821-9. [PMID:15685212]

13. Lafrenière RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafrenière F, McLaughlan S, Dubé MP et al.. (2010) A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura. Nat Med, 16 (10): 1157-60. [PMID:20871611]

14. Lazarenko RM, Willcox SC, Shu S, Berg AP, Jevtovic-Todorovic V, Talley EM, Chen X, Bayliss DA. (2010) Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics. J Neurosci, 30 (22): 7691-704. [PMID:20519544]

15. 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 (37): 28398-405. [PMID:10880510]

16. Levitz J, Royal P, Comoglio Y, Wdziekonski B, Schaub S, Clemens DM, Isacoff EY, Sandoz G. (2016) Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels. Proc Natl Acad Sci USA, 113 (15): 4194-9. [PMID:27035963]

17. 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 (22): 16969-78. [PMID:10748056]

18. Loucif AJC, Saintot PP, Liu J, Antonio BM, Zellmer SG, Yoger K, Veale EL, Wilbrey A, Omoto K, Cao L et al.. (2018) GI-530159, a novel, selective, mechanosensitive two-pore-domain potassium (K_2P ) channel opener, reduces rat dorsal root ganglion neuron excitability. Br J Pharmacol, 175 (12): 2272-2283. [PMID:29150838]

19. Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E. (1999) TRAAK is a mammalian neuronal mechano-gated K+ channel. J Biol Chem, 274 (3): 1381-7. [PMID:9880510]

20. Maingret F, Lauritzen I, Patel AJ, Heurteaux C, Reyes R, Lesage F, Lazdunski M, Honoré E. (2000) TREK-1 is a heat-activated background K(+) channel. EMBO J, 19 (11): 2483-91. [PMID:10835347]

21. Maingret F, Patel AJ, Lazdunski M, Honoré E. (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J, 20 (1-2): 47-54. [PMID:11226154]

22. 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 (38): 26691-6. [PMID:10480871]

23. 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 (5): 422-6. [PMID:10321245]

24. 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 (15): 4283-90. [PMID:9687497]

25. Plant LD, Dementieva IS, Kollewe A, Olikara S, Marks JD, Goldstein SA. (2010) One SUMO is sufficient to silence the dimeric potassium channel K2P1. Proc Natl Acad Sci USA, 107 (23): 10743-8. [PMID:20498050]

26. Plant LD, Zuniga L, Araki D, Marks JD, Goldstein SA. (2012) SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons. Sci Signal, 5 (251): ra84. [PMID:23169818]

27. Pope L, Arrigoni C, Lou H, Bryant C, Gallardo-Godoy A, Renslo AR, Minor Jr DL. (2018) Protein and Chemical Determinants of BL-1249 Action and Selectivity for K_2P Channels. ACS Chem Neurosci, 9 (12): 3153-3165. [PMID:30089357]

28. Rajan S, Wischmeyer E, Karschin C, Preisig-Müller R, Grzeschik KH, Daut J, Karschin A, Derst C. (2001) THIK-1 and THIK-2, a novel subfamily of tandem pore domain K+ channels. J Biol Chem, 276 (10): 7302-11. [PMID:11060316]

29. Rajan S, Wischmeyer E, Xin Liu G, Preisig-Müller R, Daut J, Karschin A, Derst C. (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem, 275 (22): 16650-7. [PMID:10747866]

30. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M. (1998) Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J Biol Chem, 273 (47): 30863-9. [PMID:9812978]

31. 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 (30): 27406-12. [PMID:12754259]

32. 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 (20): 17733-42. [PMID:11886861]

33. Toncheva D, Mihailova-Hristova M, Vazharova R, Staneva R, Karachanak S, Dimitrov P, Simeonov V, Ivanov S, Balabanski L, Serbezov D et al.. (2014) NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy. Biomed Res Int, 2014: 920723. [PMID:24949484]

34. Warth R, Barrière 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 (21): 8215-20. [PMID:15141089]

Subcommittee members: Steve A.N. Goldstein (Chairperson) Departments of Pediatrics, Physiology & Biophysics, and Pharmaceutical Sciences University of California, Irvine 1001 Health Sciences Road Irvine Hall 265 Irvine, CA 92697-3950 USA Leigh D. Plant Research Associate Professor Department of Pharmaceutical Sciences Northeastern University, School of Pharmacy Bouvé College of Health Sciences 360 Huntington Avenue Boston, MA 02115 USA

Other contributors: Austin M. Baggetta Department of Pharmaceutical Sciences Northeastern University, School of Pharmacy Bouvé College of Health Sciences 360 Huntington Avenue Boston, MA 02115 USA Douglas A. Bayliss Department of Pharmacology University of Virginia Health System Charlottesville VA 22908 USA Gábor Czirják Department of Physiology Semmelweis University Budapest Hungary Péter Enyedi Department of Physiology Semmelweis University Budapest Hungary Florian Lesage CNRS UMR 7275 Université de Nice Valbonne France Daniel L. Minor, Jr. Cardiovascular Research Institute Departments of Biochemistry & Biophysics and Cellular & Molecular Pharmacology California Institute for Quantitative Biomedical Research Kavli Institute for Fundamental Neuroscience University of California, San Francisco CA, U.S.A. Francisco Sepúlveda Centro de Estudios Científicos Valdivia Chile