K<sub>2P</sub>18.1 | Two P domain potassium channels | IUPHAR/BPS Guide to PHARMACOLOGY

K2P18.1

Target id: 527

Nomenclature: K2P18.1

Family: Two P domain potassium channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for K2P18.1 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 4 2 384 10q25.3 KCNK18 potassium two pore domain channel subfamily K member 18 8
Mouse 4 2 394 19 D3 Kcnk18 potassium channel, subfamily K, member 18
Rat 4 2 405 1q55 Kcnk18 potassium two pore domain channel subfamily K member 18
Previous and Unofficial Names
TRESK-1/TRESK-2 | TRIK | TWIK related spinal cord K+ channel | tandem-pore K+ (K(2P)) channel | two-pore-domain potassium channel TRESK | potassium channel, two pore domain subfamily K, member 18 | potassium channel
Database Links
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Calcineurin 2-3
14-3-3 proteins 5
Tubulin 6
Associated Protein Comments
Protein-protein interactions: Calcineurin binds to the intracellular loop of human K2P18 at two non-catalytic interacting motifs (PQIIIS and LQLP). The binding is necessary for the phosphatase to dephosphorylate and activate the channel [2-3]. 14-3-3 proteins bind to the RSNpSCP mode I motif of the intracellular loop of human K2P18. The binding is phosphorylation dependent and contributes to the inhibition of the channel after phosphorylation [5]. Tubulin binds in vitro to the intracellular loop of TRESK. The significance of this interaction is unknown [6].
Functional Characteristics
Background current

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Activator Comments
The Two-pore Domain K+ Channel, K2P18.1, is activated by cytoplasmic calcium via calcineurin [4] and some volatile anasthetics.
Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
arachidonic acid Hs - - - - - 8
studied at 10-50 µM [8]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
Ba2+ N/A - - - 2.5x10-3 - 3x10-3 -
Conc range: 2.5x10-3 - 3x10-3 M
quinidine N/A - - - 1x10-4 - 2x10-4 -
Conc range: 1x10-4 - 2x10-4 M
quinine N/A - - - 1x10-4 - 2x10-4 -
Conc range: 1x10-4 - 2x10-4 M
Channel Blocker Comments
Free fatty acids and external acidic pH have been demonstrated to act as K2p18.1 pore blockers.
Tissue Distribution
Cerebrum, cerebellum, brain stem, spinal cord, testis.
Species:  Mouse
Technique:  RT-PCR
References:  4
Clinically-Relevant Mutations and Pathophysiology
Disease:  Migraine, with or without aura, susceptibility to, 13
Disease Ontology: DOID:6364
OMIM: 613656
References:  1,7
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Frameshift Human F139WfsX24 Results in a truncated channel which suppresses full length K2P18 in a dominant negative manner. Cosegregates in a large family with migraine with aura. 7
Missense Human A34V Found in one migraine proband; dominant negative effect 1
General Comments
Activation is instantaneous, single channel currents are non-inactivating and time dependent. TRESK2 was cloned from mouse testis and shares 65% homology with human K2P18. As study continues it will become clear if this is the true correlate of the human channel or a distinct gene (K2P19). It is suspected that distinct cDNAs for both TRESK-1 and TRESK-2 are present in human tissues.

References

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1. Andres-Enguix I, Shang L, Stansfeld PJ, Morahan JM, Sansom MS, Lafrenière RG, Roy B, Griffiths LR, Rouleau GA, Ebers GC et al.. (2012) Functional analysis of missense variants in the TRESK (KCNK18) K channel. Sci Rep, 2: 237. [PMID:22355750]

2. 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 (21): 14677-82. [PMID:16569637]

3. Czirják G, 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 (43): 29506-18. [PMID:25202008]

4. 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 (18): 18550-8. [PMID:14981085]

5. Czirják G, Vuity D, Enyedi P. (2008) Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. J. Biol. Chem., 283 (23): 15672-80. [PMID:18397886]

6. 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 (5): e97854. [PMID:24830385]

7. 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]

8. 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]

Contributors

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How to cite this page

Leigh D. Plant, Douglas A. Bayliss, Daniel L. Minor, Jr., Gábor Czirják, Péter Enyedi, Florian Lesage, Francisco Sepúlveda, Steve A.N. Goldstein.
Two P domain potassium channels: K2P18.1. Last modified on 09/03/2017. Accessed on 13/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=527.