S12A1_HUMAN
ID S12A1_HUMAN Reviewed; 1099 AA.
AC Q13621; A8JYA2; E9PDW4;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 04-NOV-2008, sequence version 2.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Solute carrier family 12 member 1;
DE AltName: Full=Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2;
DE AltName: Full=Kidney-specific Na-K-Cl symporter;
GN Name=SLC12A1; Synonyms=NKCC2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM F), VARIANTS BARTS1 PHE-272 AND
RP ASN-648, VARIANT ALA-958, AND ALTERNATIVE SPLICING.
RX PubMed=8640224; DOI=10.1038/ng0696-183;
RA Simon D.B., Karet F.E., Hamdan J.M., Di Pietro A., Sanjad S.A.,
RA Lifton R.P.;
RT "Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused
RT by mutations in the Na-K-2Cl cotransporter NKCC2.";
RL Nat. Genet. 13:183-188(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), AND VARIANT ALA-958.
RC TISSUE=Spinal ganglion;
RA Di Fulvio M., Garzon-Muvdi T., Alvarez-Leefmans F.J.;
RT "Molecular cloning and characterization of NKCC2A in non-renal tissues.";
RL Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [4]
RP ACTIVITY REGULATION.
RX PubMed=21613606; DOI=10.1152/ajpcell.00070.2011;
RA Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A.,
RA Pasantes-Morales H., Gamba G., Mercado A.;
RT "Similar Effects of all WNK3 Variants upon SLC12 Cotransporters.";
RL Am. J. Physiol. 301:C601-C608(2011).
RN [5]
RP TISSUE SPECIFICITY.
RX PubMed=29993276; DOI=10.1152/ajprenal.00539.2017;
RA Frische S., Chambrey R., Trepiccione F., Zamani R., Marcussen N.,
RA Alexander R.T., Skjoedt K., Svenningsen P., Dimke H.;
RT "H+-ATPase B1 subunit localizes to thick ascending limb and distal
RT convoluted tubule of rodent and human kidney.";
RL Am. J. Physiol. 315:F429-F444(2018).
CC -!- FUNCTION: Renal sodium, potassium and chloride ion cotransporter that
CC mediates the transepithelial NaCl reabsorption in the thick ascending
CC limb and plays an essential role in the urinary concentration and
CC volume regulation. Electrically silent transporter system.
CC {ECO:0000250|UniProtKB:P55016}.
CC -!- ACTIVITY REGULATION: Activated by WNK3. {ECO:0000269|PubMed:21613606}.
CC -!- SUBUNIT: When phosphorylated, interacts with PPP3CB.
CC {ECO:0000250|UniProtKB:P55016}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000250|UniProtKB:P55014}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A;
CC IsoId=Q13621-1; Sequence=Displayed;
CC Name=B;
CC IsoId=Q13621-2; Sequence=Not described;
CC Name=F;
CC IsoId=Q13621-3; Sequence=VSP_035701;
CC -!- TISSUE SPECIFICITY: Kidney; localizes to the thick ascending limbs (at
CC protein level). {ECO:0000269|PubMed:29993276}.
CC -!- DISEASE: Bartter syndrome 1, antenatal (BARTS1) [MIM:601678]: A form of
CC Bartter syndrome, an autosomal recessive disorder characterized by
CC impaired salt reabsorption in the thick ascending loop of Henle with
CC pronounced salt wasting, hypokalemic metabolic alkalosis, and varying
CC degrees of hypercalciuria. BARTS1 is a life-threatening condition
CC beginning in utero, with marked fetal polyuria that leads to
CC polyhydramnios and premature delivery. Another hallmark is a marked
CC hypercalciuria and, as a secondary consequence, the development of
CC nephrocalcinosis and osteopenia. {ECO:0000269|PubMed:8640224}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {ECO:0000305}.
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DR EMBL; U58130; AAB07364.1; -; mRNA.
DR EMBL; EF559316; ABU69043.2; -; mRNA.
DR EMBL; AC023355; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC066612; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS10129.2; -. [Q13621-1]
DR CCDS; CCDS53940.1; -. [Q13621-3]
DR RefSeq; NP_000329.2; NM_000338.2. [Q13621-1]
DR RefSeq; NP_001171761.1; NM_001184832.1. [Q13621-3]
DR AlphaFoldDB; Q13621; -.
DR SMR; Q13621; -.
DR BioGRID; 112446; 3.
DR IntAct; Q13621; 4.
DR STRING; 9606.ENSP00000379822; -.
DR ChEMBL; CHEMBL1874; -.
DR DrugBank; DB00887; Bumetanide.
DR DrugBank; DB00534; Chlormerodrin.
DR DrugBank; DB00310; Chlorthalidone.
DR DrugBank; DB00903; Etacrynic acid.
DR DrugBank; DB00695; Furosemide.
DR DrugBank; DB00774; Hydroflumethiazide.
DR DrugBank; DB00232; Methyclothiazide.
DR DrugBank; DB02925; Piretanide.
DR DrugBank; DB14500; Potassium.
DR DrugBank; DB11098; Potassium bicarbonate.
DR DrugBank; DB00761; Potassium chloride.
DR DrugBank; DB13620; Potassium gluconate.
DR DrugBank; DB01325; Quinethazone.
DR DrugBank; DB00214; Torasemide.
DR DrugCentral; Q13621; -.
DR GuidetoPHARMACOLOGY; 968; -.
DR TCDB; 2.A.30.1.2; the cation-chloride cotransporter (ccc) family.
DR GlyGen; Q13621; 2 sites.
DR iPTMnet; Q13621; -.
DR PhosphoSitePlus; Q13621; -.
DR BioMuta; SLC12A1; -.
DR DMDM; 212276464; -.
DR EPD; Q13621; -.
DR jPOST; Q13621; -.
DR MassIVE; Q13621; -.
DR MaxQB; Q13621; -.
DR PaxDb; Q13621; -.
DR PeptideAtlas; Q13621; -.
DR PRIDE; Q13621; -.
DR ProteomicsDB; 19762; -.
DR ProteomicsDB; 59614; -. [Q13621-1]
DR ProteomicsDB; 59615; -. [Q13621-3]
DR Antibodypedia; 11970; 245 antibodies from 35 providers.
DR DNASU; 6557; -.
DR Ensembl; ENST00000380993.8; ENSP00000370381.3; ENSG00000074803.21. [Q13621-1]
DR Ensembl; ENST00000396577.7; ENSP00000379822.3; ENSG00000074803.21. [Q13621-3]
DR Ensembl; ENST00000647232.1; ENSP00000493875.1; ENSG00000074803.21. [Q13621-3]
DR Ensembl; ENST00000647546.1; ENSP00000495332.1; ENSG00000074803.21. [Q13621-1]
DR GeneID; 6557; -.
DR KEGG; hsa:6557; -.
DR MANE-Select; ENST00000380993.8; ENSP00000370381.3; NM_000338.3; NP_000329.2.
DR UCSC; uc001zwn.5; human. [Q13621-1]
DR CTD; 6557; -.
DR DisGeNET; 6557; -.
DR GeneCards; SLC12A1; -.
DR HGNC; HGNC:10910; SLC12A1.
DR HPA; ENSG00000074803; Tissue enriched (kidney).
DR MalaCards; SLC12A1; -.
DR MIM; 600839; gene.
DR MIM; 601678; phenotype.
DR neXtProt; NX_Q13621; -.
DR OpenTargets; ENSG00000074803; -.
DR PharmGKB; PA320; -.
DR VEuPathDB; HostDB:ENSG00000074803; -.
DR eggNOG; KOG2083; Eukaryota.
DR GeneTree; ENSGT00940000158030; -.
DR HOGENOM; CLU_001883_0_0_1; -.
DR InParanoid; Q13621; -.
DR OMA; TRFQVNV; -.
DR OrthoDB; 254933at2759; -.
DR PhylomeDB; Q13621; -.
DR TreeFam; TF313191; -.
DR PathwayCommons; Q13621; -.
DR Reactome; R-HSA-426117; Cation-coupled Chloride cotransporters.
DR Reactome; R-HSA-5619104; Defective SLC12A1 causes Bartter syndrome 1 (BS1).
DR SignaLink; Q13621; -.
DR SIGNOR; Q13621; -.
DR BioGRID-ORCS; 6557; 8 hits in 1064 CRISPR screens.
DR ChiTaRS; SLC12A1; human.
DR GenomeRNAi; 6557; -.
DR Pharos; Q13621; Tclin.
DR PRO; PR:Q13621; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q13621; protein.
DR Bgee; ENSG00000074803; Expressed in renal medulla and 147 other tissues.
DR ExpressionAtlas; Q13621; baseline and differential.
DR Genevisible; Q13621; HS.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0015379; F:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0008511; F:sodium:potassium:chloride symporter activity; IBA:GO_Central.
DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central.
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:0034220; P:ion transmembrane transport; ISS:BHF-UCL.
DR GO; GO:0006811; P:ion transport; TAS:Reactome.
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:0055078; P:sodium ion homeostasis; IBA:GO_Central.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central.
DR InterPro; IPR004841; AA-permease/SLC12A_dom.
DR InterPro; IPR013612; AA_permease_N.
DR InterPro; IPR018491; SLC12_C.
DR InterPro; IPR002445; Slc12a1.
DR InterPro; IPR002443; SLC12A1/SLC12A2.
DR InterPro; IPR004842; SLC12A_fam.
DR PANTHER; PTHR11827; PTHR11827; 1.
DR Pfam; PF00324; AA_permease; 1.
DR Pfam; PF08403; AA_permease_N; 1.
DR Pfam; PF03522; SLC12; 1.
DR PRINTS; PR01207; NAKCLTRNSPRT.
DR PRINTS; PR01209; NAKCLTRSPRT2.
DR TIGRFAMs; TIGR00930; 2a30; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Bartter syndrome; Cell membrane; Chloride;
KW Disease variant; Glycoprotein; Ion transport; Membrane; Neurodegeneration;
KW Phosphoprotein; Potassium; Potassium transport; Reference proteome; Sodium;
KW Sodium transport; Symport; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1099
FT /note="Solute carrier family 12 member 1"
FT /id="PRO_0000178018"
FT TOPO_DOM 1..177
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 178..198
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 202..222
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 223..259
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 260..280
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 303..323
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 324..327
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 328..348
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 380..400
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 401..417
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 418..438
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 485..505
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 506..550
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 551..571
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 572..592
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 593..609
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 610..630
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 793..813
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 814..1099
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 31..53
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 34..53
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 61
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55014"
FT MOD_RES 100
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P55014"
FT MOD_RES 105
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P55014"
FT MOD_RES 118
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 120
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 130
FT /note="Phosphoserine; by AMPK"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT MOD_RES 148
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55016"
FT CARBOHYD 446
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 456
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 214..238
FT /note="LIILLSTMVTSITGLSTSAIATNGF -> IIIGLSVVVTTLTGISMSAICTN
FT GV (in isoform F)"
FT /evidence="ECO:0000303|PubMed:8640224"
FT /id="VSP_035701"
FT VARIANT 272
FT /note="V -> F (in BARTS1; dbSNP:rs137853158)"
FT /evidence="ECO:0000269|PubMed:8640224"
FT /id="VAR_010223"
FT VARIANT 648
FT /note="D -> N (in BARTS1; dbSNP:rs137853157)"
FT /evidence="ECO:0000269|PubMed:8640224"
FT /id="VAR_010224"
FT VARIANT 958
FT /note="V -> A (in dbSNP:rs1552311)"
FT /evidence="ECO:0000269|PubMed:8640224, ECO:0000269|Ref.2"
FT /id="VAR_047257"
FT CONFLICT 75
FT /note="Q -> H (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
FT CONFLICT Q13621-3:220..221
FT /note="VV -> TI (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
FT CONFLICT Q13621-3:225
FT /note="L -> I (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
FT CONFLICT Q13621-3:228
FT /note="I -> M (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
FT CONFLICT Q13621-3:230
FT /note="M -> T (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
FT CONFLICT Q13621-3:234
FT /note="C -> A (in Ref. 1; AAB07364)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1099 AA; 121450 MW; C1C868B7F8B563AC CRC64;
MSLNNSSNVF LDSVPSNTNR FQVSVINENH ESSAAADDNT DPPHYEETSF GDEAQKRLRI
SFRPGNQECY DNFLQSGETA KTDASFHAYD SHTNTYYLQT FGHNTMDAVP KIEYYRNTGS
ISGPKVNRPS LLEIHEQLAK NVAVTPSSAD RVANGDGIPG DEQAENKEDD QAGVVKFGWV
KGVLVRCMLN IWGVMLFIRL SWIVGEAGIG LGVLIILLST MVTSITGLST SAIATNGFVR
GGGAYYLISR SLGPEFGGSI GLIFAFANAV AVAMYVVGFA ETVVDLLKES DSMMVDPTND
IRIIGSITVV ILLGISVAGM EWEAKAQVIL LVILLIAIAN FFIGTVIPSN NEKKSRGFFN
YQASIFAENF GPRFTKGEGF FSVFAIFFPA ATGILAGANI SGDLEDPQDA IPRGTMLAIF
ITTVAYLGVA ICVGACVVRD ATGNMNDTII SGMNCNGSAA CGLGYDFSRC RHEPCQYGLM
NNFQVMSMVS GFGPLITAGI FSATLSSALA SLVSAPKVFQ ALCKDNIYKA LQFFAKGYGK
NNEPLRGYIL TFLIAMAFIL IAELNTIAPI ISNFFLASYA LINFSCFHAS YAKSPGWRPA
YGIYNMWVSL FGAVLCCAVM FVINWWAAVI TYVIEFFLYV YVTCKKPDVN WGSSTQALSY
VSALDNALEL TTVEDHVKNF RPQCIVLTGG PMTRPALLDI THAFTKNSGL CICCEVFVGP
RKLCVKEMNS GMAKKQAWLI KNKIKAFYAA VAADCFRDGV RSLLQASGLG RMKPNTLVIG
YKKNWRKAPL TEIENYVGII HDAFDFEIGV VIVRISQGFD ISQVLQVQEE LERLEQERLA
LEATIKDNEC EEESGGIRGL FKKAGKLNIT KTTPKKDGSI NTSQSMHVGE FNQKLVEAST
QFKKKQEKGT IDVWWLFDDG GLTLLIPYIL TLRKKWKDCK LRIYVGGKIN RIEEEKIVMA
SLLSKFRIKF ADIHIIGDIN IRPNKESWKV FEEMIEPYRL HESCKDLTTA EKLKRETPWK
ITDAELEAVK EKSYRQVRLN ELLQEHSRAA NLIVLSLPVA RKGSISDLLY MAWLEILTKN
LPPVLLVRGN HKNVLTFYS
