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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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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 P domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, below, is based on similarities in both structural and functional properties within subfamilies.
K2P1.1
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K2P2.1
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K2P3.1
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K2P4.1
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K2P5.1
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K2P6.1
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K2P7.1
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K2P9.1
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K2P10.1
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K2P12.1
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K2P13.1
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K2P15.1
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K2P16.1
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K2P17.1
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K2P18.1
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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. U.S.A., 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. 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]
15. 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. U.S.A., 113 (15): 4194-9. [PMID:27035963]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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]
22. 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]
23. 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. U.S.A., 107 (23): 10743-8. [PMID:20498050]
24. 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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]
31. Warth R, Barrière H, Meneton P, Bloch M, Thomas J, Tauc M, Heitzmann D, Romeo E, Verrey F, Mengual R, Guy N, Bendahhou S, Lesage F, Poujeol P, Barhanin J. (2004) Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc. Natl. Acad. Sci. U.S.A., 101 (21): 8215-20. [PMID:15141089]
Subcommittee members:
Steve A.N. Goldstein (Chairperson)
Leigh D. Plant |
Other contributors:
Douglas A. Bayliss
Gábor Czirják
Péter Enyedi
Florian Lesage
Daniel L. Minor, Jr.
Francisco Sepúlveda |
Database page citation:
Douglas A. Bayliss, Gábor Czirják, Péter Enyedi, Steve A.N. Goldstein, Florian Lesage, Daniel L. Minor, Jr., Leigh D. Plant, Francisco Sepúlveda. Two P domain potassium channels. Accessed on 17/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=79.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Striessnig J, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Voltage-gated ion channels. Br J Pharmacol. 174 Suppl 1: S160-S194.
The K2P6, K2P7.1, K2P15.1 and K2P12.1 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.