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Target not currently curated in GtoImmuPdb
Target id: 514
Nomenclature: K2P2.1
Abbreviated Name: TREK1
Gene and Protein Information | |||||||
Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 4 | 2 | 426 | 1q41 | KCNK2 | potassium two pore domain channel subfamily K member 2 | 4-5,13 |
Mouse | 4 | 2 | 426 | 1 H6 | Kcnk2 | potassium channel, subfamily K, member 2 | 4 |
Rat | 4 | 2 | 426 | 13q26 | Kcnk2 | potassium two pore domain channel subfamily K member 2 |
Previous and Unofficial Names |
TREK-1 | TPKC1 | arachidonic acid sensitive tandem pore domain potassium channel | potassium channel, two pore domain subfamily K, member 2 | potassium channel |
Database Links | |
Alphafold | O95069 (Hs), P97438 (Mm) |
ChEMBL Target | CHEMBL2321615 (Hs) |
DrugBank Target | O95069 (Hs) |
Ensembl Gene | ENSG00000082482 (Hs), ENSMUSG00000037624 (Mm), ENSRNOG00000002653 (Rn) |
Entrez Gene | 3776 (Hs), 16526 (Mm), 170899 (Rn) |
Human Protein Atlas | ENSG00000082482 (Hs) |
KEGG Gene | hsa:3776 (Hs), mmu:16526 (Mm), rno:170899 (Rn) |
OMIM | 603219 (Hs) |
Pharos | O95069 (Hs) |
RefSeq Nucleotide | NM_001017424 (Hs), NM_010607 (Mm), NM_172042 (Rn) |
RefSeq Protein | NP_001017424 (Hs), NP_034737 (Mm), NP_742038 (Rn) |
UniProtKB | O95069 (Hs), P97438 (Mm) |
Wikipedia | KCNK2 (Hs) |
Associated Proteins | ||||||||||||||||||||||||||||||||
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Associated Protein Comments | ||||||||||||||||||||||||||||||||
Heteromultimers shown to form in vivo: Full length and Δ56-K2P2 can form heteromeric channels in hippocampal neurons [20]. K2P2 has been shown to form heterodimeric channel with K2P1 subunits to mediate the passive conductance in astrocytes [7]. Protein-protein interactions: AKAP150: The A-kinase-anchoring protein AKAP150 binds to the C-terminus of K2P2 to increase the kinetic of K2P2 inactivation by Gs coupled receptors and decrease inhibition by Gq coupled receptors [18]. Mtap2: The microtubule associated protein 2 Mtap2 binds to the C-terminus of K2P2 to increase K2P2 channel surface density [17]. β-COP: β-COP directly binds with N-terminus of K2P2 to increase K2P2 channel surface expression and current density [9]. NTSR3: NTSR3, the neurotensin receptor 3 or sortilin binds K2P2 in the Trans Golgi Network. The association between NTSR3 and K2P2 enhances surface expression and current density of K2P2 [12]. Spadin: Spadin, a polypeptide derived from a short variant of NTSR3, binds to the K2P2-NTSR3 complex and stimulates endocytosis of K2P2 [12]. Gβγ: Gβγ binds to the N-terminus of K2P2 upon Gi-GPCR activation. Binding triggers fast glutamate release in astrocytes and thereby influences the activity of neighboring neurons [21]. PLD2: PLD2, a phosphatidic acid (PA) producing enzyme, binds to the C-terminus of K2P2 to potentiate channel activity in a PA-dependent manner [2]. |
Functional Characteristics | |
Background current |
Ion Selectivity and Conductance | ||||||
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Ion Selectivity and Conductance Comments | ||||||
Phosphorylation of serine 348 regulates reversible inter-conversion between leak and voltage-dependent phenotypes. ‘Activation’ and ‘deactivation’ with voltage steps appear to be instantaneous. The mouse variant may have a smaller conductance [1]. |
Download all structure-activity data for this target as a CSV file
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Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Activator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Volatile anesthetics [19], mechanical stress [11], internal acidification [11] can activate this receptor. |
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Tissue Distribution | ||||||||
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Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||
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Biologically Significant Variant Comments |
A truncated version of K2P2 resulting from alternative translation initiation at methionine 57 has been shown in specific regions of the rat central nervous system during development, demonstrating spatiotemporal regulation of KCNK2 mRNA translation [20]. The permeability ratio of Δ56-K2P2 channels to sodium compared to potassium ions is 0.177; in wild type channels the ratio is 0.022. In addition, the K2P2 gene produces two isoforms of 411 and 426 amino acids via alternative splicing [1,3]. At this time, differences in the biophysical, pharmacological and physiological as well as regulatory properties of these isoforms remain unknown. |
General Comments |
Characterisation of K2P2 knockout mice suggests a loss of sensitivity to general anaesthetics and increased vulnerability to ischemia and reperfusion injury [6]. Phosphorylation of serine 348 regulates reversible inter-conversion between leak and voltage-dependent phenotypes. ‘Activation’ and ‘deactivation’ with voltage steps appear to be instantaneous. The mouse variant may have a smaller conductance [1]. |
1. Bockenhauer D, Zilberberg N, Goldstein SA. (2001) KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci, 4 (5): 486-91. [PMID:11319556]
2. Comoglio Y, Levitz J, Kienzler MA, Lesage F, Isacoff EY, Sandoz G. (2014) Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid. Proc Natl Acad Sci USA, 111 (37): 13547-52. [PMID:25197053]
3. 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 (24): 6854-62. [PMID:9003761]
4. 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]
5. Goldstein SA, Wang KW, Ilan N, Pausch MH. (1998) Sequence and function of the two P domain potassium channels: implications of an emerging superfamily. J Mol Med, 76 (1): 13-20. [PMID:9462864]
6. Heurteaux C, Guy N, Laigle C, Blondeau N, Duprat F, Mazzuca M, Lang-Lazdunski L, Widmann C, Zanzouri M, Romey G et al.. (2004) TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J, 23 (13): 2684-95. [PMID:15175651]
7. Hwang EM, Kim E, Yarishkin O, Woo DH, Han KS, Park N, Bae Y, Woo J, Kim D, Park M et al.. (2014) A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat Commun, 5: 3227. [PMID:24496152]
8. 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]
9. Kim E, Hwang EM, Yarishkin O, Yoo JC, Kim D, Park N, Cho M, Lee YS, Sun CH, Yi GS et al.. (2010) Enhancement of TREK1 channel surface expression by protein-protein interaction with beta-COP. Biochem Biophys Res Commun, 395 (2): 244-50. [PMID:20362547]
10. 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 (K2P ) channel opener, reduces rat dorsal root ganglion neuron excitability. Br J Pharmacol, 175 (12): 2272-2283. [PMID:29150838]
11. 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]
12. Mazella J, Pétrault O, Lucas G, Deval E, Béraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E et al.. (2010) Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol, 8 (4): e1000355. [PMID:20405001]
13. Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C, Medhurst AD, Murdock P, Chapman CG. (2000) Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel. Pflugers Arch, 439 (6): 714-22. [PMID:10784345]
14. 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]
15. 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]
16. 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 K2P Channels. ACS Chem Neurosci, 9 (12): 3153-3165. [PMID:30089357]
17. Sandoz G, Tardy MP, Thümmler S, Feliciangeli S, Lazdunski M, Lesage F. (2008) Mtap2 is a constituent of the protein network that regulates twik-related K+ channel expression and trafficking. J Neurosci, 28 (34): 8545-52. [PMID:18716213]
18. 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 (24): 5864-72. [PMID:17110924]
19. Terrenoire C, Lauritzen I, Lesage F, Romey G, Lazdunski M. (2001) A TREK-1-like potassium channel in atrial cells inhibited by beta-adrenergic stimulation and activated by volatile anesthetics. Circ Res, 89 (4): 336-42. [PMID:11509450]
20. 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 (6): 859-70. [PMID:18579077]
21. Woo DH, Han KS, Shim JW, Yoon BE, Kim E, Bae JY, Oh SJ, Hwang EM, Marmorstein AD, Bae YC et al.. (2012) TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell, 151 (1): 25-40. [PMID:23021213]