SLC12A3
entrez
6559
canonical
uniprot
P55017
canonical
ensembl
ENSG00000070915
resolver
ensp
ENSP00000262502
resolver
ensp
ENSP00000402152
resolver
ensp
ENSP00000456149
resolver
ensp
ENSP00000457552
resolver
enst
ENST00000262502
resolver
genesymbol
SLC12A3
resolver
genesymbol_syn
NCC
resolver
genesymbol_syn
TSC
resolver
hgnc
HGNC:10912
resolver
uniprot
A8MSJ2
resolver
uniprot
C9JNN9
resolver
uniprot
J3QSS1
resolver
uniprot_entry
J3QSS1_HUMAN
resolver
uniprot_entry
S12A3_HUMAN
resolver
uniprot_sec
A8MSJ2
resolver
uniprot_sec
C9JNN9
resolver
activity_regulation
ACTIVITY REGULATION: Phosphorylation by OXSR1/OSR1 and STK39/SPAK in kidney distal convoluted tubules downstream of WNK4 promotes its activity (PubMed:18270262). Also activated by OXSR1/OSR1 and STK39/SPAK downstream of WNK3 (PubMed:21613606). Target of thiazide diuretics used in the treatment of high blood pressure (PubMed:36792826, PubMed:8528245). Thiazide drugs, such as polythiazide, specifically inhibit SLC12A3/NCC transporter activity by competing with chloride for binding and by locking SLC12A3/NCC in an outward-facing conformation (PubMed:36792826). {ECO:0000269|PubMed:18270262, ECO:0000269|PubMed:21613606, ECO:0000269|PubMed:36792826, ECO:0000269|PubMed:8528245}.
uniprot
proteins
amino_acid_sequence
MAELPTTETPGDATLCSGRFTISTLLSSDEPSPPAAYDSSHPSHLTHSSTFCMRTFGYNTIDVVPTYEHYANSTQPGEPRKVRPTLADLHSFLKQEGRHLHALAFDSRPSHEMTDGLVEGEAGTSSEKNPEEPVRFGWVKGVMIRCMLNIWGVILYLRLPWITAQAGIVLTWIIILLSVTVTSITGLSISAISTNGKVKSGGTYFLISRSLGPELGGSIGLIFAFANAVGVAMHTVGFAETVRDLLQEYGAPIVDPINDIRIIAVVSVTVLLAISLAGMEWESKAQVLFFLVIMVSFANYLVGTLIPPSEDKASKGFFSYRADIFVQNLVPDWRGPDGTFFGMFSIFFPSATGILAGANISGDLKDPAIAIPKGTLMAIFWTTISYLAISATIGSCVVRDASGVLNDTVTPGWGACEGLACSYGWNFTECTQQHSCHYGLINYYQTMSMVSGFAPLITAGIFGATLSSALACLVSAAKVFQCLCEDQLYPLIGFFGKGYGKNKEPVRGYLLAYAIAVAFIIIAELNTIAPIISNFFLCSYALINFSCFHASITNSPGWRPSFQYYNKWAALFGAIISVVIMFLLTWWAALIAIGVVLFLLLYVIYKKPEVNWGSSVQAGSYNLALSYSVGLNEVEDHIKNYRPQCLVLTGPPNFRPALVDFVGTFTRNLSLMICGHVLIGPHKQRMPELQLIANGHTKWLNKRKIKAFYSDVIAEDLRRGVQILMQAAGLGRMKPNILVVGFKKNWQSAHPATVEDYIGILHDAFDFNYGVCVMRMREGLNVSKMMQAHINPVFDPAEDGKEASARVDPKALVKEEQATTIFQSEQGKKTIDIYWLFDDGGLTLLIPYLLGRKRRWSKCKIRVFVGGQINRMDQERKAIISLLSKFRLGFHEVHILPDINQNPRAEHTKRFEDMIAPFRLNDGFKDEATVNEMRRDCPWKISDEEITKNRVKSLRQVRLNEIVLDYSRDAALIVITLPIGRKGKCPSSLYMAWLETLSQDLRPPVILIRGNQENVLTFYCQ
uniprot
proteins
disease_involvement
DISEASE: Gitelman syndrome (GTLMNS) [MIM:263800]: An autosomal recessive disorder characterized by hypokalemic alkalosis in combination with hypomagnesemia, low urinary calcium, and increased renin activity associated with normal blood pressure. Patients are often asymptomatic or present transient periods of muscular weakness and tetany, usually accompanied by abdominal pain, vomiting and fever. The phenotype is highly heterogeneous in terms of age at onset and severity. Cardinal features such as hypocalciuria and hypomagnesemia might also change during the life cycle of a given patient. It has overlapping features with Bartter syndrome. {ECO:0000269|PubMed:10616841, ECO:0000269|PubMed:10988270, ECO:0000269|PubMed:11168953, ECO:0000269|PubMed:11940055, ECO:0000269|PubMed:12008755, ECO:0000269|PubMed:12112667, ECO:0000269|PubMed:15069170, ECO:0000269|PubMed:15687331, ECO:0000269|PubMed:16429844, ECO:0000269|PubMed:17654016, ECO:0000269|PubMed:17873326, ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:26099046, ECO:0000269|PubMed:33462018, ECO:0000269|PubMed:33772578, ECO:0000269|PubMed:34079339, ECO:0000269|PubMed:34657521, ECO:0000269|PubMed:35693921, ECO:0000269|PubMed:36370249, ECO:0000269|PubMed:36460433, ECO:0000269|PubMed:8528245, ECO:0000269|PubMed:8900229, ECO:0000269|PubMed:8954067, ECO:0000269|PubMed:9734597}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
function
FUNCTION: Electroneutral sodium and chloride ion cotransporter, which acts as a key mediator of sodium and chloride reabsorption in kidney distal convoluted tubules (PubMed:18270262, PubMed:21613606, PubMed:22009145, PubMed:36351028, PubMed:36792826). Also acts as a receptor for the pro-inflammatory cytokine IL18, thereby contributing to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2 (By similarity). May act either independently of IL18R1, or in a complex with IL18R1 (By similarity). {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:18270262, ECO:0000269|PubMed:21613606, ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826}.
uniprot
proteins
mass_dalton
113139
uniprot
proteins
mutagenesis
MUTAGEN 19; /note="R->A: Abolished interaction with OXSR1/OSR1 and STK39/SPAK, preventing phosphorylation and activation."; /evidence="ECO:0000269|PubMed:18270262"; MUTAGEN 46; /note="T->A: Decreased phosphorylation by OXSR1/OSR1 and STK39/SPAK."; /evidence="ECO:0000269|PubMed:18270262"; MUTAGEN 55; /note="T->A: Decreased phosphorylation by OXSR1/OSR1 and STK39/SPAK."; /evidence="ECO:0000269|PubMed:18270262"; MUTAGEN 60; /note="T->A: Decreased phosphorylation by OXSR1/OSR1 and STK39/SPAK."; /evidence="ECO:0000269|PubMed:18270262"; MUTAGEN 62; /note="D->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 70; /note="Y->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 83; /note="R->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 86; /note="L->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 91; /note="S->A: Decreased phosphorylation by OXSR1/OSR1 and STK39/SPAK."; /evidence="ECO:0000269|PubMed:18270262"; MUTAGEN 149; /note="N->A: Reduced sensitivity to thiazide diuretics. Reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826"; MUTAGEN 158; /note="R->A: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 223; /note="F->A: Reduced sensitivity to thiazide diuretics."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 227; /note="N->A: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028"; MUTAGEN 234; /note="H->A,Y: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028"; MUTAGEN 240; /note="E->A: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 386; /note="Y->A: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028"; MUTAGEN 467; /note="S->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826"; MUTAGEN 468; /note="S->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826"; MUTAGEN 526; /note="N->A: Strongly reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 540; /note="Y->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826"; MUTAGEN 765; /note="F->A: Reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 838; /note="D->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 886; /note="F->A: Reduced sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826"; MUTAGEN 1009; /note="R->A: Abolished sodium and chloride ion cotransporter activity."; /evidence="ECO:0000269|PubMed:36792826
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3 (PubMed:22406640). However, it was later shown that it is not the case. {ECO:0000269|PubMed:22406640}.; PTM: Phosphorylated at Thr-46, Thr-55, Thr-60 and Ser-91 by OXSR1/OSR1 and STK39/SPAK downstream of WNK4, promoting its activity (PubMed:18270262). Phosphorylated in response to IL18 (By similarity). {ECO:0000250|UniProtKB:P59158, ECO:0000269|PubMed:18270262}.
uniprot
proteins
protein_family
SLC12A transporter family
uniprot
proteins
pubmed
10616841
uniprot
proteins
pubmed
10988270
uniprot
proteins
pubmed
11168953
uniprot
proteins
pubmed
11940055
uniprot
proteins
pubmed
12008755
uniprot
proteins
pubmed
12112667
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15069170
uniprot
proteins
pubmed
15616553
uniprot
proteins
pubmed
15687331
uniprot
proteins
pubmed
16429844
uniprot
proteins
pubmed
17654016
uniprot
proteins
pubmed
17873326
uniprot
proteins
pubmed
17885550
uniprot
proteins
pubmed
18270262
uniprot
proteins
pubmed
21613606
uniprot
proteins
pubmed
22009145
uniprot
proteins
pubmed
22406640
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
26099046
uniprot
proteins
pubmed
29993276
uniprot
proteins
pubmed
33462018
uniprot
proteins
pubmed
33772578
uniprot
proteins
pubmed
34079339
uniprot
proteins
pubmed
34657521
uniprot
proteins
pubmed
35693921
uniprot
proteins
pubmed
36351028
uniprot
proteins
pubmed
36370249
uniprot
proteins
pubmed
36460433
uniprot
proteins
pubmed
36792826
uniprot
proteins
pubmed
8528245
uniprot
proteins
pubmed
8812482
uniprot
proteins
pubmed
8900229
uniprot
proteins
pubmed
8954067
uniprot
proteins
pubmed
9734597
uniprot
proteins
sequence_length
1021
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:22009145, ECO:0000269|PubMed:36370249}; Multi-pass membrane protein {ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826}. Apical cell membrane {ECO:0000250|UniProtKB:P59158}; Multi-pass membrane protein {ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826}.
uniprot
proteins
transmembrane_region
TRANSMEM 138..167; /note="Discontinuously helical; Name=1"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 168..189; /note="Helical; Name=2"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 221..243; /note="Helical; Name=3"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 256..280; /note="Helical; Name=4"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 281..303; /note="Helical; Name=5"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 339..360; /note="Discontinuously helical; Name=6"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 372..393; /note="Helical; Name=7"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 454..477; /note="Helical; Name=8"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 508..522; /note="Helical; Name=9"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 528..544; /note="Helical; Name=10"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 568..587; /note="Helical; Name=11"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT"; TRANSMEM 588..599; /note="Helical; Name=12"; /evidence="ECO:0000269|PubMed:36351028, ECO:0000269|PubMed:36792826, ECO:0007744|PDB:7Y6I, ECO:0007744|PDB:8FHO, ECO:0007744|PDB:8FHP, ECO:0007744|PDB:8FHQ, ECO:0007744|PDB:8FHR, ECO:0007744|PDB:8FHT
uniprot
proteins