Q6VV64 (KCNKI_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Potassium channel subfamily K member 18

Alternative name(s):
Two-pore-domain potassium channel TRESK

Gene names

Name:	Kcnk18
Synonyms:	Tresk-2, Tresk2

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	394 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Outward rectifying potassium channel. Produces rapidly activating outward rectifier K+ currents. May function as background potassium channel that sets the resting membrane potential. Channel activity is directly activated by calcium signal. Activated by the G(q)-protein coupled receptor pathway. The calcium signal robustly activates the channel via calcineurin, whereas the anchoring of 14-3-3/YWHAH interferes with the return of the current to the resting state after activation. Inhibited also by arachidonic acid and other naturally occurring unsaturated free fatty acids. Channel activity is also enhanced by volatile anesthetics, such as isoflurane. Appears to be the primary target of hydroxy-alpha-sanshool, an ingredient of Schezuan pepper. May be involved in the somatosensory function with special respect to pain sensation. Ref.1 Ref.2 Ref.8
Subunit structure	Interacts with calcineurin. Interacts with YWHAH, in a phosphorylation-dependent manner. Ref.5 Ref.7
Subcellular location	Cell membrane; Multi-pass membrane protein Ref.9.
Tissue specificity	Detected in brain cortex, cerebellum, dorsal root ganglion, spinal cord and testis. High expression in trigeminal ganglion, also expressed in autonomic nervous system ganglia such as the stellate ganglion and paravertebral sympathetic ganglia. Expressed in all adult spinal cord and brain regions, with slightly higher expression in thalamus, hypothalamus, hippocampus and posterior corte (at protein level). In non-neuronal tissues, substantial expression found in lung and heart and weal expression in liver, testis, kidney, small intestine and spleen. Ref.1 Ref.2 Ref.6 Ref.10
Developmental stage	Expression appears in trigeminal ganglion and dorsal root ganglia from E15.5 and increased through E18 to reach a peak in newborn mouse postnatal day 1. Ref.10
Post-translational modification	Phosphorylation of Ser-264 is required for the binding of 14-3-3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-276 enhances channel activity. N-glycosylated. Ref.9
Miscellaneous	Regulated by extracellular protons whereas human ortholog is not. His-132 is responsible for proton-dependent specific activity.
Sequence similarities	Belongs to the two pore domain potassium channel (TC 1.A.1.8) family. [View classification]

Ontologies

Keywords
Biological process	Ion transport Potassium transport Transport
Cellular component	Cell membrane Membrane
Domain	Transmembrane Transmembrane helix
Ligand	Potassium
Molecular function	Ion channel Potassium channel
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular response to pH Inferred from electronic annotation. Source: Ensembl potassium ion export Inferred from electronic annotation. Source: Ensembl potassium ion transport Inferred from direct assay Ref.9. Source: UniProtKB
Cellular_component	integral component of membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	calcium-activated potassium channel activity Inferred from direct assay Ref.9. Source: UniProtKB outward rectifier potassium channel activity Inferred from electronic annotation. Source: Ensembl protein binding Inferred from physical interaction Ref.7. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 394	394	Potassium channel subfamily K member 18		PRO_0000312501
Regions
	Topological domain	1 – 31	31	Cytoplasmic Potential
	Transmembrane	32 – 52	21	Helical; Potential
	Intramembrane	114 – 140	27	Pore-forming; Name=Pore-forming 1; Potential
	Transmembrane	142 – 162	21	Helical; Potential
	Topological domain	163 – 292	130	Cytoplasmic Potential
	Transmembrane	293 – 313	21	Helical; Potential
	Intramembrane	326 – 340	15	Pore-forming; Name=Pore-forming 2; Potential
	Transmembrane	347 – 367	21	Helical; Potential
	Topological domain	368 – 394	27	Cytoplasmic Potential
	Region	210 – 215	6	Interaction with calcineurin
	Region	261 – 266	6	Interaction with YWHAH
Amino acid modifications
	Modified residue	264	1	Phosphoserine Ref.7
	Modified residue	276	1	Phosphoserine Probable
	Glycosylation	83	1	N-linked (GlcNAc...) Ref.9
Experimental info
	Mutagenesis	83	1	N → Q: Strongly reduced current amplitude and localization to cell membrane. Ref.9
	Mutagenesis	132	1	H → N: Insensitive to extracellular protons. Ref.6
	Mutagenesis	212	1	I → A: Loss of interaction with calcineurin and activation by elevated intracellular calcium; when associated with A-214.
	Mutagenesis	214	1	I → A: Strongly reduced activation by elevated intracellular calcium. Loss of interaction with calcineurin and activation by elevated intracellular calcium; when associated with A-212.
	Mutagenesis	264	1	S → A: Loss of interaction with YWHAH. Ref.7
	Mutagenesis	276	1	S → A: Enhances basal channel activity and abolishes stimulation by calcineurin. Ref.1
	Sequence conflict	228	1	K → R in AAI15706. Ref.4
	Sequence conflict	228	1	K → R in AAI04133. Ref.4
	Sequence conflict	251	1	K → E in AAI15706. Ref.4
	Sequence conflict	251	1	K → E in AAI04133. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Q6VV64 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 82D03F7D7F0D5591	FASTA	394	44,403
	10 20 30 40 50 60 MEAEEPPEAR RCCPEALGKA RGCCPEALGK LLPGLCFLCC LVTYALVGAA LFSAVEGRPD 70 80 90 100 110 120 PEAEENPELK KFLDDLCNIL KCNLTVVEGS RKNLCEHLQH LKPQWLKAPQ DWSFLSALFF 130 140 150 160 170 180 CCTVFSTVGY GHMYPVTRLG KFLCMLYALF GIPLMFLVLT DIGDILATIL SRAYSRFQAL 190 200 210 220 230 240 LCLPHDIFKW RSLPLCRKQP DSKPVEEAIP QIVIDAGVDE LLNPQPSKDP PSPSCNVELF 250 260 270 280 290 300 ERLVAREKKN KLQPPTRPVE RSNSCPELVL GRLSCSILSN LDEVGQQVER LDIPLPVIAL 310 320 330 340 350 360 VVFAYISCAA AILPFWETEL GFEDAFYFCF VTLTTIGFGD IVLVHPHFFL FFSIYIIVGM 370 380 390 EILFIAFKLM QNRLLHTYKT LMLFVCQREV SLPW

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin." Czirjak G., Toth Z.E., Enyedi P. J. Biol. Chem. 279:18550-18558(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, MUTAGENESIS OF SER-276, PHOSPHORYLATION AT SER-276, TISSUE SPECIFICITY. Strain: NMRI. Tissue: Cerebellum.
[2]	"Species-specific differences in response to anesthetics and other modulators by the K2P channel TRESK." Keshavaprasad B., Liu C., Au J.D., Kindler C.H., Cotten J.F., Yost C.S. Anesth. Analg. 101:1042-1049(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, FUNCTION. Strain: BALB/c. Tissue: Spinal cord.
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Egg.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"Targeting of calcineurin to an NFAT-like docking site is required for the calcium-dependent activation of the background K+ channel, TRESK." Czirjak G., Enyedi P. J. Biol. Chem. 281:14677-14682(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CALCINEURIN.
[6]	"TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones." Dobler T., Springauf A., Tovornik S., Weber M., Schmitt A., Sedlmeier R., Wischmeyer E., Doring F. J. Physiol. (Lond.) 585:867-879(2007) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, MUTAGENESIS OF HIS-132.
[7]	"Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation." Czirjak G., Vuity D., Enyedi P. J. Biol. Chem. 283:15672-15680(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH YWHAH, MUTAGENESIS OF SER-264, PHOSPHORYLATION AT SER-264.
[8]	"Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels." Bautista D.M., Sigal Y.M., Milstein A.D., Garrison J.L., Zorn J.A., Tsuruda P.R., Nicoll R.A., Julius D. Nat. Neurosci. 11:772-779(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"N-linked glycosylation determines cell surface expression of two-pore-domain K+ channel TRESK." Egenberger B., Polleichtner G., Wischmeyer E., Doring F. Biochem. Biophys. Res. Commun. 391:1262-1267(2010) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-83, MUTAGENESIS OF ASN-83.
[10]	"A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura." Lafreniere R.G., Cader M.Z., Poulin J.F., Andres-Enguix I., Simoneau M., Gupta N., Boisvert K., Lafreniere F., McLaughlan S., Dube M.P., Marcinkiewicz M.M., Ramagopalan S., Ansorge O., Brais B., Sequeiros J., Pereira-Monteiro J.M., Griffiths L.R., Tucker S.J., Ebers G., Rouleau G.A. Nat. Med. 16:1157-1160(2010) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Throb - Issue 124 of December 2010

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY325301 mRNA. Translation: AAQ91836.1. AY542902 mRNA. Translation: AAS48426.1. AK139600 mRNA. Translation: BAE24080.1. AK162136 mRNA. Translation: BAE36746.1. BC104132 mRNA. Translation: AAI04133.1. BC104133 mRNA. Translation: AAI04134.1. BC115705 mRNA. Translation: AAI15706.1. BC115887 mRNA. Translation: AAI15888.1. BC127136 mRNA. Translation: AAI27137.1. BC127137 mRNA. Translation: AAI27138.1.
CCDS	CCDS29934.1.
RefSeq	NP_997144.1. NM_207261.3.
UniGene	Mm.329947.
3D structure databases
ProteinModelPortal	Q6VV64.
SMR	Q6VV64. Positions 44-181.
ModBase	Search...
MobiDB	Search...
Protein-protein interaction databases
IntAct	Q6VV64. 1 interaction.
MINT	MINT-7997383.
STRING	10090.ENSMUSP00000065713.
Protein family/group databases
TCDB	1.A.1.18.1. the voltage-gated ion channel (vic) superfamily.
PTM databases
PhosphoSite	Q6VV64.
Proteomic databases
PRIDE	Q6VV64.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000065204; ENSMUSP00000065713; ENSMUSG00000040901.
GeneID	332396.
KEGG	mmu:332396.
UCSC	uc008ibh.1. mouse.
Organism-specific databases
CTD	338567.
MGI	MGI:2685627. Kcnk18.
Phylogenomic databases
eggNOG	NOG311880.
GeneTree	ENSGT00700000104522.
HOGENOM	HOG000074045.
HOVERGEN	HBG104673.
InParanoid	Q6VV64.
OMA	AFKLVQN.
OrthoDB	EOG7MPRDX.
PhylomeDB	Q6VV64.
TreeFam	TF316115.
Gene expression databases
Bgee	Q6VV64.
CleanEx	MM_KCNK18.
Genevestigator	Q6VV64.
Family and domain databases
InterPro	IPR003280. 2pore_dom_K_chnl. IPR013099. 2pore_dom_K_chnl_dom. IPR003092. 2pore_dom_K_chnl_TASK. [Graphical view]
Pfam	PF07885. Ion_trans_2. 2 hits. [Graphical view]
PRINTS	PR01333. 2POREKCHANEL. PR01095. TASKCHANNEL.
ProtoNet	Search...
Other
NextBio	399876.
PRO	Q6VV64.
SOURCE	Search...

Entry information

Entry name

KCNKI_MOUSE

Accession

Primary (citable) accession number: Q6VV64
Secondary accession number(s): Q1LZJ5 , Q1LZM8, Q3MI50, Q3MI51

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 4, 2007
Last sequence update:	July 5, 2004
Last modified:	July 9, 2014
This is version 90 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program