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K2P2.1

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Target id: 514

Nomenclature: K2P2.1

Abbreviated Name: TREK1

Family: Two-pore domain potassium channels (K2P)

Contents:

Gene and Protein Information Click here for help
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 Click here for help
TREK-1 | TPKC1 | arachidonic acid sensitive tandem pore domain potassium channel | potassium channel, two pore domain subfamily K, member 2 | potassium channel
Database Links Click here for help
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 Click here for help
Heteromeric Pore-forming Subunits
Name References
K2P1.1 7
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
AKAP150 18
Mtap2 17
β-COP 9
NTSR3 12
Spadin 12
Gβγ 21
PLD2 2
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 Click here for help
Background current
Ion Selectivity and Conductance Click here for help
Species:  Rat
Rank order:  K+ [85.0 pS]
References:  1
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 go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
chloroform Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - - - 8x10-3 - 14
⤷ Conc range: 8x10-3 M studied at 1-5 mM [14]
GI‐530159 Small molecule or natural product Click here for species-specific activity table Hs - 6.1 – 6.1 pEC50 - - 10
⤷ pEC50 6.1 (EC50 7.6x10-7 M) [10]
Description: Measuring 86Rb efflux by TREK1 induced by GI‐530159 at 70 mM potassium.
pEC50 6.1 (EC50 8.9x10-7 M) [10]
Description: Measuring GI‐530139-induced enhanced current via single hTREK1 channels measured at +60 mV in the inside‐out manual patch configuration, in a concentration–response experiment.
BL-1249 Small molecule or natural product Click here for species-specific activity table Hs - 5.3 pEC50 - - 16
⤷ pEC50 5.3 (EC50 5.5x10-6 M) [16]
arachidonic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Activation 5.0 pEC50 - - 15
⤷ pEC50 5.0 (EC50 1x10-5 M) studied at 1-10 µM [15]
riluzole Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - - - - -
⤷
halothane Small molecule or natural product Approved drug Click here for species-specific activity table Hs - - - - - 14
⤷ studied at 1-5 mM [14]
isoflurane Small molecule or natural product Approved drug Click here for species-specific activity table Hs - - - - - 14
⤷ studied at 1-5 mM [14]
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
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
norfluoxetine Small molecule or natural product Click here for species-specific activity table Hs - 5.1 pIC50 - - 8
⤷ pIC50 5.1 (IC50 9x10-6 M) [8]
Tissue Distribution Click here for help
CNS
Species:  Human
Technique:  Northern Blot, TaqMan
References:  13
Heart, lungs and brain
Species:  Mouse
Technique:  In situ hybridisation
References:  3
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0003075 altered response to CNS ischemic injury PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0009747 impaired behavioral response to xenobiotic PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0009763 increased sensitivity to induced morbidity/mortality PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0009766 increased sensitivity to xenobiotic induced morbidity/mortality PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0003076 increased susceptibility to ischemic brain injury PMID: 15175651 
Kcnk2tm1Lzd Kcnk2tm1Lzd/Kcnk2tm1Lzd
involves: 129 * C57BL/6J		 MGI:109366  MP:0002906 increased susceptibility to pharmacologically induced seizures PMID: 15175651 
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].

References

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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]

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