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Protein

Solute carrier family 12 member 5

Gene

SLC12A5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl- homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl- levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262).By similarity1 Publication

Enzyme regulationi

Inhibited by WNK3.1 Publication

GO - Molecular functioni

  • chloride transmembrane transporter activity Source: UniProtKB
  • potassium:chloride symporter activity Source: UniProtKB
  • potassium ion symporter activity Source: GO_Central
  • protein kinase binding Source: ParkinsonsUK-UCL

GO - Biological processi

  • cellular chloride ion homeostasis Source: UniProtKB
  • cellular ion homeostasis Source: UniProtKB
  • chemical synaptic transmission Source: GO_Central
  • dendritic spine development Source: UniProtKB
  • ion transport Source: Reactome
  • learning Source: Ensembl
  • multicellular organism growth Source: Ensembl
  • response to drug Source: Ensembl
  • thermosensory behavior Source: Ensembl
  • transport Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Ion transport, Potassium transport, Symport, Transport

Keywords - Ligandi

Potassium

Enzyme and pathway databases

BioCyciZFISH:ENSG00000124140-MONOMER.
ReactomeiR-HSA-426117. Cation-coupled Chloride cotransporters.

Protein family/group databases

TCDBi2.A.30.5.6. the cation-chloride cotransporter (ccc) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Solute carrier family 12 member 5
Alternative name(s):
Electroneutral potassium-chloride cotransporter 2
K-Cl cotransporter 2
Short name:
hKCC2
Neuronal K-Cl cotransporter
Gene namesi
Name:SLC12A5
Synonyms:KCC2, KIAA1176
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

HGNCiHGNC:13818. SLC12A5.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 133CytoplasmicSequence analysisAdd BLAST133
Transmembranei134 – 154HelicalSequence analysisAdd BLAST21
Transmembranei156 – 176HelicalSequence analysisAdd BLAST21
Topological domaini177 – 194CytoplasmicSequence analysisAdd BLAST18
Transmembranei195 – 215HelicalSequence analysisAdd BLAST21
Transmembranei217 – 237HelicalSequence analysisAdd BLAST21
Topological domaini238 – 254CytoplasmicSequence analysisAdd BLAST17
Transmembranei255 – 275HelicalSequence analysisAdd BLAST21
Transmembranei278 – 298HelicalSequence analysisAdd BLAST21
Topological domaini299 – 418CytoplasmicSequence analysisAdd BLAST120
Transmembranei419 – 439HelicalSequence analysisAdd BLAST21
Transmembranei459 – 479HelicalSequence analysisAdd BLAST21
Topological domaini480 – 496CytoplasmicSequence analysisAdd BLAST17
Transmembranei497 – 517HelicalSequence analysisAdd BLAST21
Transmembranei570 – 590HelicalSequence analysisAdd BLAST21
Topological domaini591 – 630CytoplasmicSequence analysisAdd BLAST40
Transmembranei631 – 651HelicalSequence analysisAdd BLAST21
Transmembranei848 – 868HelicalSequence analysisAdd BLAST21
Topological domaini869 – 1139CytoplasmicSequence analysisAdd BLAST271

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Involvement in diseasei

Epileptic encephalopathy, early infantile, 34 (EIEE34)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE34 is characterized by onset of refractory migrating focal seizures in infancy. Affected children show developmental regression and are severely impaired globally.
See also OMIM:616645
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075078311L → H in EIEE34; results in reduced chloride transport; decreased localization at the cell surface. 1 Publication1
Natural variantiVAR_075079426L → P in EIEE34; results in loss of chloride transport; decreased localization at the cell surface. 1 Publication1
Natural variantiVAR_075080551G → D in EIEE34; results in loss of chloride transport; decreased localization at the cell surface. 1 Publication1
Epilepsy, idiopathic generalized 14 (EIG14)3 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant form of idiopathic generalized epilepsy, a disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures.
See also OMIM:616685
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075081975R → H in EIG14; rare variant associated with disease susceptibility; results in reduced chloride transport; decreased localization at the cell surface; unable to induce cortical dendritic spines formation. 3 PublicationsCorresponds to variant rs142740233dbSNPEnsembl.1
Natural variantiVAR_0750831072R → C in EIG14; rare variant associated with disease susceptibility; results in reduced chloride transport. 2 PublicationsCorresponds to variant rs548424453dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation, Epilepsy

Organism-specific databases

DisGeNETi57468.
MIMi616645. phenotype.
616685. phenotype.
OpenTargetsiENSG00000124140.
PharmGKBiPA37814.

Chemistry databases

ChEMBLiCHEMBL1615384.
DrugBankiDB00887. Bumetanide.
DB00761. Potassium Chloride.
GuidetoPHARMACOLOGYi972.

Polymorphism and mutation databases

BioMutaiSLC12A5.
DMDMi161784306.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001780341 – 1139Solute carrier family 12 member 5Add BLAST1139

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei57PhosphothreonineBy similarity1
Glycosylationi442N-linked (GlcNAc...)Sequence analysis1
Glycosylationi833N-linked (GlcNAc...)Sequence analysis1
Modified residuei1045PhosphoserineBy similarity1
Modified residuei1048PhosphoserineBy similarity1
Modified residuei1049PhosphoserineBy similarity1

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiQ9H2X9.
PaxDbiQ9H2X9.
PeptideAtlasiQ9H2X9.
PRIDEiQ9H2X9.

PTM databases

iPTMnetiQ9H2X9.
PhosphoSitePlusiQ9H2X9.
SwissPalmiQ9H2X9.

Expressioni

Tissue specificityi

Brain specific. Detected in neuronal cells.

Gene expression databases

BgeeiENSG00000124140.
CleanExiHS_SLC12A5.
ExpressionAtlasiQ9H2X9. baseline and differential.
GenevisibleiQ9H2X9. HS.

Organism-specific databases

HPAiHPA072058.

Interactioni

Subunit structurei

Homomultimer and heteromultimer with other K-Cl cotransporters. Interacts with AP2A1 (By similarity).By similarity

GO - Molecular functioni

  • protein kinase binding Source: ParkinsonsUK-UCL

Protein-protein interaction databases

BioGridi121538. 2 interactors.
STRINGi9606.ENSP00000387694.

Chemistry databases

BindingDBiQ9H2X9.

Structurei

3D structure databases

ProteinModelPortaliQ9H2X9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the SLC12A transporter family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2082. Eukaryota.
COG0531. LUCA.
GeneTreeiENSGT00760000119053.
HOGENOMiHOG000092644.
HOVERGENiHBG052852.
InParanoidiQ9H2X9.
KOiK14427.
OMAiGWPRNWR.
OrthoDBiEOG091G0WB4.
PhylomeDBiQ9H2X9.
TreeFamiTF313657.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR030358. KCC2.
IPR000076. KCL_cotranspt.
IPR018491. SLC12_C.
IPR004842. SLC12A_fam.
[Graphical view]
PANTHERiPTHR11827:SF54. PTHR11827:SF54. 4 hits.
PfamiPF00324. AA_permease. 2 hits.
PF03522. SLC12. 3 hits.
[Graphical view]
PRINTSiPR01081. KCLTRNSPORT.
TIGRFAMsiTIGR00930. 2a30. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9H2X9-1) [UniParc]FASTAAdd to basket
Also known as: KCC2a

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSRRFTVTSL PPAGPARSPD PESRRHSVAD PRHLPGEDVK GDGNPKESSP
60 70 80 90 100
FINSTDTEKG KEYDGKNMAL FEEEMDTSPM VSSLLSGLAN YTNLPQGSRE
110 120 130 140 150
HEEAENNEGG KKKPVQAPRM GTFMGVYLPC LQNIFGVILF LRLTWVVGIA
160 170 180 190 200
GIMESFCMVF ICCSCTMLTA ISMSAIATNG VVPAGGSYYM ISRSLGPEFG
210 220 230 240 250
GAVGLCFYLG TTFAGAMYIL GTIEILLAYL FPAMAIFKAE DASGEAAAML
260 270 280 290 300
NNMRVYGTCV LTCMATVVFV GVKYVNKFAL VFLGCVILSI LAIYAGVIKS
310 320 330 340 350
AFDPPNFPIC LLGNRTLSRH GFDVCAKLAW EGNETVTTRL WGLFCSSRFL
360 370 380 390 400
NATCDEYFTR NNVTEIQGIP GAASGLIKEN LWSSYLTKGV IVERSGMTSV
410 420 430 440 450
GLADGTPIDM DHPYVFSDMT SYFTLLVGIY FPSVTGIMAG SNRSGDLRDA
460 470 480 490 500
QKSIPTGTIL AIATTSAVYI SSVVLFGACI EGVVLRDKFG EAVNGNLVVG
510 520 530 540 550
TLAWPSPWVI VIGSFFSTCG AGLQSLTGAP RLLQAISRDG IVPFLQVFGH
560 570 580 590 600
GKANGEPTWA LLLTACICEI GILIASLDEV APILSMFFLM CYMFVNLACA
610 620 630 640 650
VQTLLRTPNW RPRFRYYHWT LSFLGMSLCL ALMFICSWYY ALVAMLIAGL
660 670 680 690 700
IYKYIEYRGA EKEWGDGIRG LSLSAARYAL LRLEEGPPHT KNWRPQLLVL
710 720 730 740 750
VRVDQDQNVV HPQLLSLTSQ LKAGKGLTIV GSVLEGTFLE NHPQAQRAEE
760 770 780 790 800
SIRRLMEAEK VKGFCQVVIS SNLRDGVSHL IQSGGLGGLQ HNTVLVGWPR
810 820 830 840 850
NWRQKEDHQT WRNFIELVRE TTAGHLALLV TKNVSMFPGN PERFSEGSID
860 870 880 890 900
VWWIVHDGGM LMLLPFLLRH HKVWRKCKMR IFTVAQMDDN SIQMKKDLTT
910 920 930 940 950
FLYHLRITAE VEVVEMHESD ISAYTYEKTL VMEQRSQILK QMHLTKNERE
960 970 980 990 1000
REIQSITDES RGSIRRKNPA NTRLRLNVPE ETAGDSEEKP EEEVQLIHDQ
1010 1020 1030 1040 1050
SAPSCPSSSP SPGEEPEGEG ETDPEKVHLT WTKDKSVAEK NKGPSPVSSE
1060 1070 1080 1090 1100
GIKDFFSMKP EWENLNQSNV RRMHTAVRLN EVIVKKSRDA KLVLLNMPGP
1110 1120 1130
PRNRNGDENY MEFLEVLTEH LDRVMLVRGG GREVITIYS
Length:1,139
Mass (Da):126,184
Last modified:December 4, 2007 - v3
Checksum:i100C097AF1FD4B3E
GO
Isoform 2 (identifier: Q9H2X9-2) [UniParc]FASTAAdd to basket
Also known as: KCC2b

The sequence of this isoform differs from the canonical sequence as follows:
     1-40: MSRRFTVTSLPPAGPARSPDPESRRHSVADPRHLPGEDVK → MLNNLTDCEDGDGGANP

Show »
Length:1,116
Mass (Da):123,511
Checksum:i68D46DECF8592FCF
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Isoform 2 (identifier: Q9H2X9-2)
Sequence conflicti2L → P in AAG43493 (PubMed:12106695).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075078311L → H in EIEE34; results in reduced chloride transport; decreased localization at the cell surface. 1 Publication1
Natural variantiVAR_027414407P → A.Corresponds to variant rs16985442dbSNPEnsembl.1
Natural variantiVAR_075079426L → P in EIEE34; results in loss of chloride transport; decreased localization at the cell surface. 1 Publication1
Natural variantiVAR_075080551G → D in EIEE34; results in loss of chloride transport; decreased localization at the cell surface. 1 Publication1
Natural variantiVAR_036557847G → D in a colorectal cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_075081975R → H in EIG14; rare variant associated with disease susceptibility; results in reduced chloride transport; decreased localization at the cell surface; unable to induce cortical dendritic spines formation. 3 PublicationsCorresponds to variant rs142740233dbSNPEnsembl.1
Natural variantiVAR_0750821071R → W.1 PublicationCorresponds to variant rs369042030dbSNPEnsembl.1
Natural variantiVAR_0750831072R → C in EIG14; rare variant associated with disease susceptibility; results in reduced chloride transport. 2 PublicationsCorresponds to variant rs548424453dbSNPEnsembl.1
Natural variantiVAR_0249941100P → L.1 PublicationCorresponds to variant rs17297532dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0299091 – 40MSRRF…GEDVK → MLNNLTDCEDGDGGANP in isoform 2. 3 PublicationsAdd BLAST40

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF208159 mRNA. Translation: AAG43493.1.
AL162458 Genomic DNA. Translation: CAH74054.2.
BC132668 mRNA. Translation: AAI32669.1.
BC132670 mRNA. Translation: AAI32671.1.
AB033002 mRNA. Translation: BAA86490.1.
DA102113 mRNA. No translation available.
DA328785 mRNA. No translation available.
CCDSiCCDS13391.1. [Q9H2X9-2]
CCDS46610.1. [Q9H2X9-1]
RefSeqiNP_001128243.1. NM_001134771.1. [Q9H2X9-1]
NP_065759.1. NM_020708.4. [Q9H2X9-2]
UniGeneiHs.21413.

Genome annotation databases

EnsembliENST00000243964; ENSP00000243964; ENSG00000124140. [Q9H2X9-2]
ENST00000454036; ENSP00000387694; ENSG00000124140. [Q9H2X9-1]
GeneIDi57468.
KEGGihsa:57468.
UCSCiuc002xrb.3. human. [Q9H2X9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF208159 mRNA. Translation: AAG43493.1.
AL162458 Genomic DNA. Translation: CAH74054.2.
BC132668 mRNA. Translation: AAI32669.1.
BC132670 mRNA. Translation: AAI32671.1.
AB033002 mRNA. Translation: BAA86490.1.
DA102113 mRNA. No translation available.
DA328785 mRNA. No translation available.
CCDSiCCDS13391.1. [Q9H2X9-2]
CCDS46610.1. [Q9H2X9-1]
RefSeqiNP_001128243.1. NM_001134771.1. [Q9H2X9-1]
NP_065759.1. NM_020708.4. [Q9H2X9-2]
UniGeneiHs.21413.

3D structure databases

ProteinModelPortaliQ9H2X9.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121538. 2 interactors.
STRINGi9606.ENSP00000387694.

Chemistry databases

BindingDBiQ9H2X9.
ChEMBLiCHEMBL1615384.
DrugBankiDB00887. Bumetanide.
DB00761. Potassium Chloride.
GuidetoPHARMACOLOGYi972.

Protein family/group databases

TCDBi2.A.30.5.6. the cation-chloride cotransporter (ccc) family.

PTM databases

iPTMnetiQ9H2X9.
PhosphoSitePlusiQ9H2X9.
SwissPalmiQ9H2X9.

Polymorphism and mutation databases

BioMutaiSLC12A5.
DMDMi161784306.

Proteomic databases

MaxQBiQ9H2X9.
PaxDbiQ9H2X9.
PeptideAtlasiQ9H2X9.
PRIDEiQ9H2X9.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000243964; ENSP00000243964; ENSG00000124140. [Q9H2X9-2]
ENST00000454036; ENSP00000387694; ENSG00000124140. [Q9H2X9-1]
GeneIDi57468.
KEGGihsa:57468.
UCSCiuc002xrb.3. human. [Q9H2X9-1]

Organism-specific databases

CTDi57468.
DisGeNETi57468.
GeneCardsiSLC12A5.
HGNCiHGNC:13818. SLC12A5.
HPAiHPA072058.
MIMi606726. gene.
616645. phenotype.
616685. phenotype.
neXtProtiNX_Q9H2X9.
OpenTargetsiENSG00000124140.
PharmGKBiPA37814.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2082. Eukaryota.
COG0531. LUCA.
GeneTreeiENSGT00760000119053.
HOGENOMiHOG000092644.
HOVERGENiHBG052852.
InParanoidiQ9H2X9.
KOiK14427.
OMAiGWPRNWR.
OrthoDBiEOG091G0WB4.
PhylomeDBiQ9H2X9.
TreeFamiTF313657.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000124140-MONOMER.
ReactomeiR-HSA-426117. Cation-coupled Chloride cotransporters.

Miscellaneous databases

GeneWikiiChloride_potassium_symporter_5.
GenomeRNAii57468.
PROiQ9H2X9.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000124140.
CleanExiHS_SLC12A5.
ExpressionAtlasiQ9H2X9. baseline and differential.
GenevisibleiQ9H2X9. HS.

Family and domain databases

InterProiIPR004841. AA-permease/SLC12A_dom.
IPR030358. KCC2.
IPR000076. KCL_cotranspt.
IPR018491. SLC12_C.
IPR004842. SLC12A_fam.
[Graphical view]
PANTHERiPTHR11827:SF54. PTHR11827:SF54. 4 hits.
PfamiPF00324. AA_permease. 2 hits.
PF03522. SLC12. 3 hits.
[Graphical view]
PRINTSiPR01081. KCLTRNSPORT.
TIGRFAMsiTIGR00930. 2a30. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiS12A5_HUMAN
AccessioniPrimary (citable) accession number: Q9H2X9
Secondary accession number(s): A2RTX2
, Q5VZ41, Q9H4Z0, Q9ULP4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 13, 2002
Last sequence update: December 4, 2007
Last modified: November 2, 2016
This is version 136 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Miscellaneous

Inhibited by furosemide and bumetanide.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.