S12A5_RAT
ID S12A5_RAT Reviewed; 1139 AA.
AC Q63633; A7Y821;
DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot.
DT 04-DEC-2007, sequence version 2.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Solute carrier family 12 member 5;
DE AltName: Full=Electroneutral potassium-chloride cotransporter 2;
DE AltName: Full=Furosemide-sensitive K-Cl cotransporter;
DE AltName: Full=K-Cl cotransporter 2;
DE Short=rKCC2;
DE AltName: Full=Neuronal K-Cl cotransporter;
GN Name=Slc12a5; Synonyms=Kcc2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=8663311; DOI=10.1074/jbc.271.27.16245;
RA Payne J.A., Stevenson T.J., Donaldson L.F.;
RT "Molecular characterization of a putative K-Cl cotransporter in rat brain.
RT A neuronal-specific isoform.";
RL J. Biol. Chem. 271:16245-16252(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC STRAIN=Wistar; TISSUE=Hippocampus;
RX PubMed=17715129; DOI=10.1074/jbc.m705095200;
RA Uvarov P., Ludwig A., Markkanen M., Pruunsild P., Kaila K., Delpire E.,
RA Timmusk T., Rivera C., Airaksinen M.S.;
RT "A novel N-terminal isoform of the neuron-specific K-Cl cotransporter
RT KCC2.";
RL J. Biol. Chem. 282:30570-30576(2007).
RN [3]
RP FUNCTION.
RX PubMed=9930699; DOI=10.1038/16697;
RA Rivera C., Voipio J., Payne J.A., Ruusuvuori E., Lahtinen H., Lamsa K.,
RA Pirvola U., Saarma M., Kaila K.;
RT "The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during
RT neuronal maturation.";
RL Nature 397:251-255(1999).
RN [4]
RP SUBUNIT.
RX PubMed=11551954; DOI=10.1074/jbc.m107155200;
RA Casula S., Shmukler B.E., Wilhelm S., Stuart-Tilley A.K., Su W.,
RA Chernova M.N., Brugnara C., Alper S.L.;
RT "A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-
RT terminal cytoplasmic domains are required for K-Cl cotransport activity.";
RL J. Biol. Chem. 276:41870-41878(2001).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-57; SER-1045; SER-1048 AND
RP SER-1049, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [6]
RP FUNCTION.
RX PubMed=22345354; DOI=10.1093/cercor/bhs027;
RA Fiumelli H., Briner A., Puskarjov M., Blaesse P., Belem B.J., Dayer A.G.,
RA Kaila K., Martin J.L., Vutskits L.;
RT "An ion transport-independent role for the cation-chloride cotransporter
RT KCC2 in dendritic spinogenesis in vivo.";
RL Cereb. Cortex 23:378-388(2013).
CC -!- FUNCTION: Mediates electroneutral potassium-chloride cotransport in
CC mature neurons and is required for neuronal Cl(-) homeostasis. As major
CC extruder of intracellular chloride, it establishes the low neuronal
CC Cl(-) levels required for chloride influx after binding of GABA-A and
CC glycine to their receptors, with subsequent hyperpolarization and
CC neuronal inhibition (PubMed:9930699). Involved in the regulation of
CC dendritic spine formation and maturation (PubMed:22345354).
CC {ECO:0000269|PubMed:22345354, ECO:0000269|PubMed:9930699}.
CC -!- ACTIVITY REGULATION: Inhibited by WNK3. {ECO:0000250}.
CC -!- SUBUNIT: Homomultimer and heteromultimer with other K-Cl
CC cotransporters. Interacts with AP2A1 (By similarity). {ECO:0000250}.
CC -!- INTERACTION:
CC Q63633; Q7TPH6: Mycbp2; Xeno; NbExp=4; IntAct=EBI-1811510, EBI-1811542;
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=KCC2a;
CC IsoId=Q63633-1; Sequence=Displayed;
CC Name=2; Synonyms=KCC2b;
CC IsoId=Q63633-2; Sequence=VSP_029911;
CC -!- TISSUE SPECIFICITY: Highly expressed in brain. Not detected in other
CC tissues. Highly expressed in pyramidal neurons and in neurons
CC throughout the cortex, hippocampus, the granular layer of the
CC cerebellum and in groups of neurons throughout the brainstem. Barely
CC detectable in dorsal-root ganglions.
CC -!- DEVELOPMENTAL STAGE: Detected in thalamus, but not in hippocampus and
CC neocortex at E20. At birth barely detectable in hippocampus. Expression
CC increases steeply from day 5 to day 9 and then stabilizes at adult
CC levels.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {ECO:0000305}.
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DR EMBL; U55816; AAC52635.1; -; mRNA.
DR EMBL; EF641113; ABV03586.1; -; mRNA.
DR PIR; T31432; T31432.
DR RefSeq; NP_599190.1; NM_134363.1. [Q63633-2]
DR AlphaFoldDB; Q63633; -.
DR SMR; Q63633; -.
DR BioGRID; 251211; 4.
DR ELM; Q63633; -.
DR IntAct; Q63633; 3.
DR MINT; Q63633; -.
DR STRING; 10116.ENSRNOP00000062103; -.
DR BindingDB; Q63633; -.
DR ChEMBL; CHEMBL1075108; -.
DR TCDB; 2.A.30.1.14; the cation-chloride cotransporter (ccc) family.
DR GlyGen; Q63633; 2 sites.
DR iPTMnet; Q63633; -.
DR PhosphoSitePlus; Q63633; -.
DR PaxDb; Q63633; -.
DR PRIDE; Q63633; -.
DR ABCD; Q63633; 1 sequenced antibody.
DR Ensembl; ENSRNOT00000065184; ENSRNOP00000062103; ENSRNOG00000018111. [Q63633-1]
DR Ensembl; ENSRNOT00000114972; ENSRNOP00000093106; ENSRNOG00000018111. [Q63633-2]
DR GeneID; 171373; -.
DR KEGG; rno:171373; -.
DR CTD; 57468; -.
DR RGD; 620811; Slc12a5.
DR eggNOG; KOG2082; Eukaryota.
DR GeneTree; ENSGT00940000160827; -.
DR InParanoid; Q63633; -.
DR OrthoDB; 349744at2759; -.
DR PhylomeDB; Q63633; -.
DR Reactome; R-RNO-426117; Cation-coupled Chloride cotransporters.
DR PRO; PR:Q63633; -.
DR Proteomes; UP000002494; Chromosome 3.
DR GO; GO:0071944; C:cell periphery; ISO:RGD.
DR GO; GO:0032590; C:dendrite membrane; IDA:RGD.
DR GO; GO:0043198; C:dendritic shaft; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:InterPro.
DR GO; GO:0043005; C:neuron projection; ISO:RGD.
DR GO; GO:0043025; C:neuronal cell body; ISO:RGD.
DR GO; GO:0043204; C:perikaryon; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0045202; C:synapse; IEA:GOC.
DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IDA:RGD.
DR GO; GO:0015108; F:chloride transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IDA:RGD.
DR GO; GO:0072488; P:ammonium transmembrane transport; IDA:RGD.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
DR GO; GO:0030644; P:cellular chloride ion homeostasis; ISO:RGD.
DR GO; GO:0006873; P:cellular ion homeostasis; ISO:RGD.
DR GO; GO:0007268; P:chemical synaptic transmission; ISO:RGD.
DR GO; GO:0055064; P:chloride ion homeostasis; IBA:GO_Central.
DR GO; GO:1902476; P:chloride transmembrane transport; IBA:GO_Central.
DR GO; GO:0006821; P:chloride transport; IDA:RGD.
DR GO; GO:0060996; P:dendritic spine development; IDA:UniProtKB.
DR GO; GO:0006971; P:hypotonic response; ISO:RGD.
DR GO; GO:0051452; P:intracellular pH reduction; IDA:RGD.
DR GO; GO:0006811; P:ion transport; ISO:RGD.
DR GO; GO:0007612; P:learning; ISO:RGD.
DR GO; GO:0035264; P:multicellular organism growth; ISO:RGD.
DR GO; GO:0055075; P:potassium ion homeostasis; IBA:GO_Central.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0006813; P:potassium ion transport; IDA:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; ISO:RGD.
DR GO; GO:0040040; P:thermosensory behavior; ISO:RGD.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR030358; KCC2.
DR InterPro; IPR000076; KCL_cotranspt.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR PANTHER; PTHR11827:SF54; PTHR11827:SF54; 1.
DR Pfam; PF00324; AA_permease; 2.
DR Pfam; PF03522; SLC12; 3.
DR PRINTS; PR01081; KCLTRNSPORT.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chloride; Glycoprotein; Ion transport; Membrane;
KW Phosphoprotein; Potassium; Potassium transport; Reference proteome;
KW Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1139
FT /note="Solute carrier family 12 member 5"
FT /id="PRO_0000178036"
FT TOPO_DOM 1..133
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 134..154
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 156..176
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 177..194
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 195..215
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 217..237
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 238..254
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 255..275
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 278..298
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 299..418
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 419..439
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 459..479
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 480..496
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 497..517
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 570..590
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 591..630
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 631..651
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 848..868
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 869..1139
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..62
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 95..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 943..1025
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1033..1052
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 23..44
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 98..112
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 943..966
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 980..996
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 57
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1045
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1048
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1049
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT CARBOHYD 442
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 833
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..40
FT /note="MSRRFTVTSLPPAASAASADPESRRHSVADPRRLPREDVK -> MLNNLTDC
FT EDGDGGANP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8663311"
FT /id="VSP_029911"
SQ SEQUENCE 1139 AA; 126247 MW; 79748F3813EBEFA0 CRC64;
MSRRFTVTSL PPAASAASAD PESRRHSVAD PRRLPREDVK GDGNPKESSP FINSTDTEKG
REYDGRNMAL FEEEMDTSPM VSSLLSGLAN YTNLPQGSKE HEEAENNEGG KKKPVQAPRM
GTFMGVYLPC LQNIFGVILF LRLTWVVGIA GIMESFCMVF ICCSCTMLTA ISMSAIATNG
VVPAGGSYYM ISRSLGPEFG GAVGLCFYLG TTFAGAMYIL GTIEILLAYL FPAMAIFKAE
DASGEAAAML NNMRVYGTCV LTCMATVVFV GVKYVNKFAL VFLGCVILSI LAIYAGVIKS
AFDPPNFPIC LLGNRTLSRH GFDVCAKLAW EGNETVTTRL WGLFCSSRLL NATCDEYFTR
NNVTEIQGIP GAASGLIKEN LWSSYLTKGV IVERRGMPSV GLADGTPVDM DHPYVFSDMT
SYFTLLVGIY FPSVTGIMAG SNRSGDLRDA QKSIPTGTIL AIATTSAVYI SSVVLFGACI
EGVVLRDKFG EAVNGNLVVG TLAWPSPWVI VIGSFFSTCG AGLQSLTGAP RLLQAISRDG
IVPFLQVFGH GKANGEPTWA LLLTACICEI GILIASLDEV APILSMFFLM CYMFVNLACA
VQTLLRTPNW RPRFRYYHWT LSFLGMSLCL ALMFICSWYY ALVAMLIAGL IYKYIEYRGA
EKEWGDGIRG LSLSAARYAL LRLEEGPPHT KNWRPQLLVL VRVDQDQNVV HPQLLSLTSQ
LKAGKGLTIV GSVLEGTFLD NHPQAQRAEE SIRRLMEAEK VKGFCQVVIS SNLRDGVSHL
IQSGGLGGLQ HNTVLVGWPR NWRQKEDHQT WRNFIELVRE TTAGHLALLV TKNVSMFPGN
PERFSEGSID VWWIVHDGGM LMLLPFLLRH HKVWRKCKMR IFTVAQMDDN SIQMKKDLTT
FLYHLRITAE VEVVEMHESD ISAYTYEKTL VMEQRSQILK QMHLTKNERE REIQSITDES
RGSIRRKNPA NTRLRLNVPE ETACDNEEKP EEEVQLIHDQ SAPSCPSSSP SPGEEPEGEG
ETDPEKVHLT WTKDKSAAQK NKGPSPVSSE GIKDFFSMKP EWENLNQSNV RRMHTAVRLN
EVIVNKSRDA KLVLLNMPGP PRNRNGDENY MEFLEVLTEQ LDRVMLVRGG GREVITIYS
