Abstract
TWIK-related spinal cord K+ channel (TRESK) is the gene product of KCNK18, the last discovered leak potassium K2P channel gene. Under resting conditions, TRESK is constitutively phosphorylated at two regulatory regions. Protein kinase A (PKA) and microtubule affinity-regulating (MARK) kinases can be applied in experiments to phosphorylate these sites of TRESK expressed in Xenopus oocytes, respectively. Upon generation of a calcium signal, TRESK is dephosphorylated and thereby activated by calcineurin. In this process, the binding of calcineurin to the channel by non-catalytic interacting sites is essential. The phosphorylation/dephosphorylation regulatory process is modified by 14-3-3 proteins. Human, but not murine TRESK is also activated by protein kinase C. TRESK is expressed most abundantly in sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia, and the channel modifies certain forms of nociceptive afferentation. In a large pedigree, a dominant negative mutant TRESK allele was found to co-segregate perfectly with migraine phenotype. While this genetic defect may be responsible only for a very small fraction of migraine cases, specific TRESK activation is expected to exert beneficial effect in common forms of the disease.
Similar content being viewed by others
References
Albin KC, Simons CT (2010) Psychophysical evaluation of a sanshool derivative (alkylamide) and the elucidation of mechanisms subserving tingle. PLoS One 5:e9520
Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafreniere 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 2:237–243
Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, Kallela M, Malik R, De VB, Terwindt G, Medland SE, Todt U, McArdle WL, Quaye L, Koiranen M, Ikram MA, Lehtimaki T, Stam AH, Ligthart L, Wedenoja J, Dunham I, Neale BM, Palta P, Hamalainen E, Schurks M, Rose LM, Buring JE, Ridker PM, Steinberg S, Stefansson H, Jakobsson F, Lawlor DA, Evans DM, Ring SM, Farkkila M, Artto V, Kaunisto MA, Freilinger T, Schoenen J, Frants RR, Pelzer N, Weller CM, Zielman R, Heath AC, Madden PA, Montgomery GW, Martin NG, Borck G, Gobel H, Heinze A, Heinze-Kuhn K, Williams FM, Hartikainen AL, Pouta A, van den Ende J, Uitterlinden AG, Hofman A, Amin N, Hottenga JJ, Vink JM, Heikkila K, Alexander M, Muller-Myhsok B, Schreiber S, Meitinger T, Wichmann HE, Aromaa A, Eriksson JG, Traynor BJ, Trabzuni D, Rossin E, Lage K, Jacobs SB, Gibbs JR, Birney E, Kaprio J, Penninx BW, Boomsma DI, Van DC, Raitakari O, Jarvelin MR, Zwart JA, Cherkas L, Strachan DP, Kubisch C, Ferrari MD, Van den Maagdenberg AM, Dichgans M, Wessman M, Smith GD, Stefansson K, Daly MJ, Nyholt DR, Chasman DI, Palotie A (2013) Genome-wide meta-analysis identifies new susceptibility loci for migraine. Nat Genet 45:912–917
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
Bobak N, Bittner S, Andronic J, Hartmann S, Muhlpfordt F, Schneider-Hohendorf T, Wolf K, Schmelter C, Gobel K, Meuth P, Zimmermann H, Doring F, Wischmeyer E, Budde T, Wiendl H, Meuth SG, Sukhorukov VL (2011) Volume regulation of murine T lymphocytes relies on voltage-dependent and two-pore domain potassium channels. Biochim Biophys Acta 1808:2036–2044
Braun G, Nemcsics B, Enyedi P, Czirják G (2011) TRESK background K+ channel is inhibited by PAR-1/MARK microtubule affinity-regulating kinases in xenopus oocytes. PLoS One 6:e28119
Brohawn SG, Del MJ, MacKinnon R (2012) Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335:436–441
Bruner JK, Zou B, Zhang H, Zhang Y, Schmidt K, Li M (2014) Identification of novel small molecule modulators of K18.1 two-pore potassium channel. Eur J Pharmacol 740:603–610
Cadaveira-Mosquera A, Perez M, Reboreda A, Rivas-Ramirez P, Fernandez-Fernandez D, Lamas JA (2012) Expression of K2P channels in sensory and motor neurons of the autonomic nervous system. J Mol Neurosci 48:86–96
Chae YJ, Zhang J, Au P, Sabbadini M, Xie GX, Yost CS (2010) Discrete change in volatile anesthetic sensitivity in mice with inactivated tandem pore potassium ion channel TRESK. Anesthesiology 113:1326–1337
Cooper BY, Johnson RD, Rau KK (2004) Characterization and function of TWIK-related acid sensing K+ channels in a rat nociceptive cell. Neuroscience 129:209–224
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
Czirják G, Enyedi P (2006) Zinc and mercuric ions distinguish TRESK from the other two-pore-domain K+ channels. Mol Pharmacol 69:1024–1032
Czirják G, Enyedi P (2010) Tresk background K+ channel is inhibited by phosphorylation via two distinct pathways. J Biol Chem 285:14549–14557
Czirják, G. and 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
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
Czirják G, Vuity D, Enyedi P (2008) Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. J Biol Chem 283:15672–15680
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
Enyedi P, Veres I, Braun G, Czirják G (2014) Tubulin binds to the cytoplasmic loop of TRESK background K+ channel in vitro. PLoS One 9:e97854
Gohlke, B. O., Preissner, R., and Preissner, S. (2013) SuperPain—a resource on pain-relieving compounds targeting ion channels. Nucleic Acids Res 42:D1107–1112
Guo Z, Cao YQ (2014) Over-expression of TRESK K+ channels reduces the excitability of trigeminal ganglion nociceptors. PLoS One 9:e87029
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
Han J, Kang D (2009) TRESK channel as a potential target to treat T-cell mediated immune dysfunction. Biochem Biophys Res Commun 390:1102–1105
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
Kang D, Kim GT, Kim EJ, La JH, Lee JS, Lee ES, Park JY, Hong SG, Han J (2008) Lamotrigine inhibits TRESK regulated by G-protein coupled receptor agonists. Biochem Biophys Res Commun 367:609–615
Kang D, Mariash E, Kim D (2004) Functional expression of TRESK-2, a new member of the tandem-pore K+ channel family. J Biol Chem 279:28063–28070
Keshavaprasad B, Liu C, Au JD, Kindler CH, Cotten JF, Yost CS (2005) Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK. Anesth Analg 101:1042–1049
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
Koo JY, Jang Y, Cho H, Lee CH, Jang KH, Chang YH, Shin J, Oh U (2007) Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons. Eur J Neurosci 26:1139–1147
Lafreniere RG, Cader MZ, Poulin JF, Andres-Enguix I, Simoneau M, Gupta N, Boisvert K, Lafreniere F, McLaughlan S, Dube 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
Lennertz RC, Tsunozaki M, Bautista DM, Stucky CL (2010) Physiological basis of tingling paresthesia evoked by hydroxy-alpha-sanshool. J Neurosci 30:4353–4361
Liu C, Au JD, Zou HL, Cotten JF, Yost CS (2004) Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics. Anesth Analg 99:1715–1722
Liu J, Masuda ES, Tsuruta L, Arai N, Arai K (1999) Two independent calcineurin-binding regions in the N-terminal domain of murine NF-ATx1 recruit calcineurin to murine NF-ATx1. J Immunol 162:4755–4761
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
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
Manteniotis S, Lehmann R, Flegel C, Vogel F, Hofreuter A, Schreiner BS, Altmuller J, Becker C, Schobel N, Hatt H, Gisselmann G (2013) Comprehensive RNA-Seq expression analysis of sensory ganglia with a focus on ion channels and GPCRs in Trigeminal ganglia. PLoS One 8:e79523
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
Matenia D, Mandelkow EM (2009) The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci 34:332–342
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
Menozzi-Smarrito C, Riera CE, Munari C, le Coutre J, Robert F (2009) Synthesis and evaluation of new alkylamides derived from alpha-hydroxysanshool, the pungent molecule in szechuan pepper. J Agric Food Chem 57:1982–1989
Miller AN, Long SB (2012) Crystal structure of the human two-pore domain potassium channel K2P1. Science 335:432–436
Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Farkkila M, Hamalainen E, Kaprio J, Kaunisto MA, Heath AC, Montgomery GW, Gobel H, Todt U, Ferrari MD, Launer LJ, Frants RR, Terwindt GM, De VB, Verschuren WM, Brand J, Freilinger T, Pfaffenrath V, Straube A, Ballinger DG, Zhan Y, Daly MJ, Cox DR, Dichgans M, Van den Maagdenberg AM, Kubisch C, Martin NG, Wessman M, Peltonen L, Palotie A (2008) A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet 17:3318–3331
Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M (1999) Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 2:422–426
Pike A.C.W., Dong Y.Y., Dong L., Quigley A., Shrestha L., Mukhopadhyay S., Strain-Damerell C., Goubin S., Grieben M., Shintre C.A., Mackenzie A., Vollmar M., Von Delft F., Arrowsmith C.H., Edwards A.M., Bountra C., Burgess-Brown N., Carpenter E.P. (2013) Crystal structure of human two pore domain potassium ion channel Trek2 (K2p10.1). PDB database: 4bw5, MMDB database:112180
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
Pottosin II, Bonales-Alatorre E, Valencia-Cruz G, Mendoza-Magana ML, Dobrovinskaya OR (2008) TRESK-like potassium channels in leukemic T cells. Pflugers Arch 456:1037–1048
Rahm AK, Gierten J, Kisselbach J, Staudacher I, Staudacher K, Schweizer PA, Becker R, Katus HA, Thomas D (2011) Protein kinase C-dependent activation of human K(2P) 18.1 K+ channels. Br J Pharmacol 166:764–773
Rahm AK, Wiedmann F, Gierten J, Schmidt C, Schweizer PA, Becker R, Katus HA, Thomas D (2013) Functional characterization of zebrafish K18.1 (TRESK) two-pore-domain K channels. Naunyn Schmiedebergs Arch. Pharmacol 387:291–300
Rajan S, Preisig-Müller R, Wischmeyer E, Nehring R, Hanley PJ, Renigunta V, Musset B, Schlichthorl G, Derst C, Karschin A, Daut J (2002) Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3. J Physiol 545:13–26
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 276:7302–7311
Rajan S, Wischmeyer E, Xin LG, Preisig-Müller R, Daut J, Karschin A, Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histidine as pH sensor. J Biol Chem 275:16650–16657
Riera CE, Menozzi-Smarrito C, Affolter M, Michlig S, Munari C, Robert F, Vogel H, Simon SA, le Coutre J (2009) Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Br J Pharmacol 157:1398–1409
Sanchez-Miguel DS, Garcia-Dolores F, Rosa Flores-Marquez M, Delgado-Enciso I, Pottosin I, Dobrovinskaya O (2013) TRESK potassium channel in human T lymphoblasts. Biochem Biophys Res Commun 434:273–279
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
Silberstein SD, Dodick DW (2013) Migraine genetics: part II. Headache 53:1218–1229
Tsunozaki M, Lennertz RC, Vilceanu D, Katta S, Stucky CL, Bautista DM (2013) A ‘toothache tree’ alkylamide inhibits Adelta mechanonociceptors to alleviate mechanical pain. J Physiol 591:3325–3340
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 7:30–46
Valencia-Cruz G, Shabala L, Delgado-Enciso I, Shabala S, Bonales-Alatorre E, Pottosin II, Dobrovinskaya OR (2009) Kbg and Kv1.3 channels mediate potassium efflux in the early phase of apoptosis in Jurkat T lymphocytes. Am JPhysiol Cell Physiol 285:14549–14557
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
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 465:78–84
Yost CS (2000) Tandem pore domain K channels: an important site of volatile anesthetic action? Curr. Drug Targets 1:207–217
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
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
Zhu W, Oxford GS (2011) Differential gene expression of neonatal and adult DRG neurons correlates with the differential sensitization of TRPV1 responses to nerve growth factor. Neurosci Lett 500:192–196
Acknowledgment
This work was supported by the Hungarian National Research Fund (OTKA K108496).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Enyedi, P., Czirják, G. Properties, regulation, pharmacology, and functions of the K2P channel, TRESK. Pflugers Arch - Eur J Physiol 467, 945–958 (2015). https://doi.org/10.1007/s00424-014-1634-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-014-1634-8