Q7Z418 (KCNKI_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Potassium channel subfamily K member 18

Alternative name(s):
TWIK-related individual potassium channel
TWIK-related spinal cord potassium channel

Gene names

Name:	KCNK18
Synonyms:	TRESK, TRIK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	384 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 By similarity. Ref.1 Ref.3
Subunit structure	Interacts with calcineurin By similarity. Interacts with YWHAH, in a phosphorylation-dependent manner By similarity.
Subcellular location	Cell membrane; Multi-pass membrane protein Ref.5.
Tissue specificity	Expressed specifically in dorsal root ganglion and trigeminal ganglion neurons. Detected at low levels in spinal cord. Ref.1 Ref.3 Ref.6
Post-translational modification	Phosphorylation of Ser-252 is required for the binding of 14-3-3eta/YWHAH. Calcineurin-mediated dephosphorylation of Ser-264 enhances channel activity By similarity. N-glycosylated. Ref.5
Involvement in disease	Migraine with or without aura 13 (MGR13) [MIM:613656]: A form of migraine trasmitted in an autosomal dominant pattern. Migraine is a disabling symptom complex of periodic headaches, usually temporal and unilateral. Headaches are often accompanied by irritability, nausea, vomiting and photobia, preceded by constriction of the cranial arteries. The two major subtypes are common migraine (migraine without aura) and classic migraine (migraine with aura). Classic migraine is characterized by recurrent attacks of reversible neurological symptoms (aura) that precede or accompany the headache. Aura may include a combination of sensory disturbances, such as blurred vision, hallucinations, vertigo, numbness and difficulty in concentrating and speaking. Note: The disease is caused by mutations affecting the gene represented in this entry. Susceptibility to migraine has been shown to be conferred by a frameshift mutation that segregates with the disorder in a large multigenerational family. Migraine was associated with sensitivity to lights, sounds, and smells, as well as nausea and occasional vomiting. Triggers included fatigue, alcohol and bright lights. Mutations in KCNK18 are a rare cause of migraine. Ref.6
Miscellaneous	In contrast to its mouse ortholog, it is not regulated by extracellular protons.
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
Coding sequence diversity	Polymorphism
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 direct assay Ref.1. Source: BHF-UCL potassium ion export Inferred from direct assay Ref.1. Source: BHF-UCL synaptic transmission Traceable author statement. Source: Reactome
Cellular_component	integral to plasma membrane Inferred by curator Ref.1. Source: BHF-UCL
Molecular_function	calcium-activated potassium channel activity Inferred from electronic annotation. Source: Compara outward rectifier potassium channel activity Inferred from direct assay Ref.1. Source: BHF-UCL
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 384	384	Potassium channel subfamily K member 18		PRO_0000312500
Regions
	Topological domain	1 – 23	23	Cytoplasmic Potential
	Transmembrane	24 – 44	21	Helical; Potential
	Intramembrane	103 – 129	27	Pore-forming; Name=Pore-forming 1; Potential
	Transmembrane	130 – 148	19	Helical; Potential
	Topological domain	149 – 280	132	Cytoplasmic Potential
	Transmembrane	281 – 301	21	Helical; Potential
	Intramembrane	314 – 328	15	Pore-forming; Name=Pore-forming 2; Potential
	Transmembrane	335 – 355	21	Helical; Potential
	Topological domain	356 – 384	29	Cytoplasmic Potential
	Region	200 – 205	6	Interaction with calcineurin By similarity
	Region	249 – 254	6	Interaction with YWHAH By similarity
Sites
	Site	96	1	Not glycosylated
Amino acid modifications
	Modified residue	252	1	Phosphoserine By similarity
	Glycosylation	70	1	N-linked (GlcNAc...) Ref.5
Natural variations
	Natural variant	34	1	A → V. Ref.6		VAR_064027
	Natural variant	58	1	F → Y. Corresponds to variant rs3909165 [ dbSNP | Ensembl ].		VAR_037521
	Natural variant	198	1	A → G. Corresponds to variant rs363359 [ dbSNP | Ensembl ].		VAR_037522
	Natural variant	231	1	S → P. Corresponds to variant rs363315 [ dbSNP | Ensembl ].		VAR_037523
	Natural variant	233	1	A → V. Ref.6 Corresponds to variant rs363360 [ dbSNP | Ensembl ].		VAR_037524
	Natural variant	255	1	E → K. Corresponds to variant rs3026042 [ dbSNP | Ensembl ].		VAR_037525
	Natural variant	346	1	V → I. Corresponds to variant rs12247136 [ dbSNP | Ensembl ].		VAR_037526
Experimental info
	Mutagenesis	70	1	N → Q: Strongly reduced current amplitude and localization to cell membrane. Strongly reduced current amplitude and localization to cell membrane; when associated with Q-96. Ref.5
	Mutagenesis	96	1	N → Q: Strongly reduced current amplitude and localization to cell membrane. Strongly reduced current amplitude and localization to cell membrane; when associated with Q-70. Ref.5
	Mutagenesis	121	1	Y → H: Restores sensitivity to extracellular protons. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Q7Z418 [UniParc]. Last modified October 1, 2003. Version 1. Checksum: 5D0B544F815ACB1C	FASTA	384	43,671
	10 20 30 40 50 60 MEVSGHPQAR RCCPEALGKL FPGLCFLCFL VTYALVGAVV FSAIEDGQVL VAADDGEFEK 70 80 90 100 110 120 FLEELCRILN CSETVVEDRK QDLQGHLQKV KPQWFNRTTH WSFLSSLFFC CTVFSTVGYG 130 140 150 160 170 180 YIYPVTRLGK YLCMLYALFG IPLMFLVLTD TGDILATILS TSYNRFRKFP FFTRPLLSKW 190 200 210 220 230 240 CPKSLFKKKP DPKPADEAVP QIIISAEELP GPKLGTCPSR PSCSMELFER SHALEKQNTL 250 260 270 280 290 300 QLPPQAMERS NSCPELVLGR LSYSIISNLD EVGQQVERLD IPLPIIALIV FAYISCAAAI 310 320 330 340 350 360 LPFWETQLDF ENAFYFCFVT LTTIGFGDTV LEHPNFFLFF SIYIIVGMEI VFIAFKLVQN 370 380 RLIDIYKNVM LFFAKGKFYH LVKK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel two-pore domain K+ channel, TRESK, is localized in the spinal cord." Sano Y., Inamura K., Miyake A., Mochizuki S., Kitada C., Yokoi H., Nozawa K., Okada H., Matsushime H., Furuichi K. J. Biol. Chem. 278:27406-27412(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY. Tissue: Spinal cord.
[2]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"Potent activation of the human tandem pore domain K channel TRESK with clinical concentrations of volatile anesthetics." Liu C., Au J.D., Zou H.L., Cotten J.F., Yost C.S. Anesth. Analg. 99:1715-1722(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[4]	"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: MUTAGENESIS OF TYR-121.
[5]	"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-70, MUTAGENESIS OF ASN-70 AND ASN-96.
[6]	"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, INVOLVEMENT IN MGR13, VARIANTS VAL-34 AND VAL-233.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Throb - Issue 124 of December 2010

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB087138 mRNA. Translation: BAC78527.1. AL731557 Genomic DNA. Translation: CAI14827.2.
IPI	IPI00375859.
RefSeq	NP_862823.1. NM_181840.1.
UniGene	Hs.449650.
3D structure databases
ProteinModelPortal	Q7Z418.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000334650.
PTM databases
PhosphoSite	Q7Z418.
Polymorphism databases
DMDM	74750072.
Proteomic databases
PaxDb	Q7Z418.
PRIDE	Q7Z418.
Protocols and materials databases
DNASU	338567.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000334549; ENSP00000334650; ENSG00000186795.
GeneID	338567.
KEGG	hsa:338567.
UCSC	uc010qsr.2. human.
Organism-specific databases
CTD	338567.
GeneCards	GC10P118947.
HGNC	HGNC:19439. KCNK18.
HPA	HPA044739.
MIM	613655. gene. 613656. phenotype.
neXtProt	NX_Q7Z418.
PharmGKB	PA134985465.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG311880.
HOGENOM	HOG000074045.
HOVERGEN	HBG104673.
InParanoid	Q7Z418.
OMA	AFKLVQN.
OrthoDB	EOG4ZCT4M.
PhylomeDB	Q7Z418.
Enzyme and pathway databases
Reactome	REACT_13685. Neuronal System.
Gene expression databases
CleanEx	HS_KCNK18.
Genevestigator	Q7Z418.
Family and domain databases
InterPro	IPR003280. 2pore_dom_K_chnl. IPR013099. Ion_trans_2. [Graphical view]
Pfam	PF07885. Ion_trans_2. 2 hits. [Graphical view]
PRINTS	PR01333. 2POREKCHANEL.
ProtoNet	Search...
Other
GenomeRNAi	338567.
NextBio	97036.
SOURCE	Search...

Entry information

Entry name

KCNKI_HUMAN

Accession

Primary (citable) accession number: Q7Z418
Secondary accession number(s): Q5SQQ8

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 4, 2007
Last sequence update:	October 1, 2003
Last modified:	May 1, 2013
This is version 82 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.