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2.A.30.1.12 Electroneutral NaCl symporter, NCC (Gitelman syndrome transporter) (Correia et al. 2022; Bi et al. 2023). NCC is also an Interleukin-18 (IL18)-binding protein that collaborates with the IL18 receptor in cell signaling, inflammatory molecule expression, and experimental atherogenesis (Wang et al. 2015). NCC and the α- and γ-subunits of the epithelial Na⁺ channel, which together determine salt balance and blood pressure, directly interact with each other with functional consequences (Mistry et al. 2016). The cryo-EM structure of the human sodium-chloride cotransporter, NCC, has been solved (Nan et al. 2022). NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. The full-length structure of human NCC, with 2.9 Å resolution for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain, has been solved. In this structure, NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na₂ site are observed in the structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na₁ and Cl₁ and might also mediate the coordination of Na₂ through a Ser residue. Putative observed water molecules may participate in the coordination of ions and TM coupling. Together with transport activity assays, this structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC (Nan et al. 2022). NCC drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Zhao et al. 2024 determined NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension. Zhao et al. 2024 showed that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation. A missense variant in the SLC12A3 gene enhances aberrant splicing causing Gitelman syndrome (Law et al. 2025). Finerenone provides a novel treatment for Gitelman syndrome (Jiang et al. 2024). Upregulation of SLC12A3 and SLC12A9 confers aggressiveness and unfavorable prognosis in uveal melanoma (Yan et al. 2023).
Accession Number:	P55017
Protein Name:	NaCl Symporter aka SLC12A3
Length:	1021
Molecular Weight:	113125.00
Species:	Homo sapiens (Human) [9606]
Number of TMSs:	11
Location¹ / Topology² / Orientation³:	Membrane¹ / Multi-pass membrane protein²
Substrate	chloride, sodium(1+)

RefSeq:	NP_000330.2 NP_001119579.1 NP_001119580.1
Entrez Gene ID:	6559
Pfam:	PF00324 PF08403
OMIM:	263800 phenotype 600968 gene
KEGG:	hsa:6559 hsa:6559
Gene Ontology GO:0016324 C:apical plasma membrane GO:0005887 C:integral to plasma membrane GO:0005624 C:membrane fraction GO:0015378 F:sodium:chloride symporter activity GO:0006821 P:chloride transport GO:0006814 P:sodium ion transport GO:0055085 P:transmembrane transport GO:0035725 P:sodium ion transmembrane transport
References (39) [1] “Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.” Simon D.B.et.al. 8528245 [2] “Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3).” Mastroianni N.et.al. 8812482 [3] “The sequence and analysis of duplication-rich human chromosome 16.” Martin J.et.al. 15616553 [4] “Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome.” Mastroianni N.et.al. 8900229 [5] “Association of a mutation in thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome.” Takeuchi K.et.al. 8954067 [6] “Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain.” Lemmink H.H.et.al. 9734597 [7] “Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension.” Melander O.et.al. 10988270 [8] “Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome.” Monkawa T.et.al. 10616841 [9] “Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.” Cruz D.N.et.al. 11168953 [10] “Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman's syndrome.” Pantanetti P.et.al. 11940055 [11] “Two novel mutations of thiazide-sensitive Na-Cl cotrans porter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome.” Tajima T.et.al. 12008755 [12] “Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome.” Syren M.-L.et.al. 12112667 [13] “Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.” Maki N.et.al. 15069170 [14] “Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome.” Lin S.-H.et.al. 15687331 [15] “A novel mutation of the thiazide-sensitive sodium chloride cotransporter gene in a Japanese family with Gitelman syndrome.” Terui K.et.al. 16429844 [16] “Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.” Fava C.et.al. 17654016 [17] “Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome.” Aoi N.et.al. 17873326 [18] “Molecular variants of the thiazide-sensitive Na+-Cl- cotransporter in hypertensive families.” Keszei A.P.et.al. 17885550 [19] “Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.” Simon D.B.et.al. 8528245 [20] “Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3).” Mastroianni N.et.al. 8812482 [21] “Complete sequencing and characterization of 21,243 full-length human cDNAs.” Ota T.et.al. 14702039 [22] “The sequence and analysis of duplication-rich human chromosome 16.” Martin J.et.al. 15616553 [23] “Similar Effects of all WNK3 Variants upon SLC12 Cotransporters.” Cruz-Rangel S.et.al. 21613606 [24] “Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome.” Mastroianni N.et.al. 8900229 [25] “KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.” Louis-Dit-Picard H.et.al. 22406640 [26] “Association of a mutation in thiazide-sensitive Na-Cl cotransporter with familial Gitelman's syndrome.” Takeuchi K.et.al. 8954067 [27] “Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain.” Lemmink H.H.et.al. 9734597 [28] “Genetic variants of thiazide-sensitive NaCl-cotransporter in Gitelman's syndrome and primary hypertension.” Melander O.et.al. 10988270 [29] “Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome.” Monkawa T.et.al. 10616841 [30] “Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.” Cruz D.N.et.al. 11168953 [31] “Severe hypomagnesaemia-induced hypocalcaemia in a patient with Gitelman's syndrome.” Pantanetti P.et.al. 11940055 [32] “Two novel mutations of thiazide-sensitive Na-Cl cotrans porter (TSC) gene in two sporadic Japanese patients with Gitelman syndrome.” Tajima T.et.al. 12008755 [33] “Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome.” Syren M.-L.et.al. 12112667 [34] “Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.” Maki N.et.al. 15069170 [35] “Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome.” Lin S.-H.et.al. 15687331 [36] “A novel mutation of the thiazide-sensitive sodium chloride cotransporter gene in a Japanese family with Gitelman syndrome.” Terui K.et.al. 16429844 [37] “Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.” Fava C.et.al. 17654016 [38] “Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome.” Aoi N.et.al. 17873326 [39] “Molecular variants of the thiazide-sensitive Na+-Cl- cotransporter in hypertensive families.” Keszei A.P.et.al. 17885550

UniProt (Universal Protein Resource)
CDD Search (Conserved Domain Database)

Predict TMSs (Predict number of transmembrane segments)

FASTA formatted sequence

1:	MAELPTTETP GDATLCSGRF TISTLLSSDE PSPPAAYDSS HPSHLTHSST FCMRTFGYNT 
61:	IDVVPTYEHY ANSTQPGEPR KVRPTLADLH SFLKQEGRHL HALAFDSRPS HEMTDGLVEG 
121:	EAGTSSEKNP EEPVRFGWVK GVMIRCMLNI WGVILYLRLP WITAQAGIVL TWIIILLSVT 
181:	VTSITGLSIS AISTNGKVKS GGTYFLISRS LGPELGGSIG LIFAFANAVG VAMHTVGFAE 
241:	TVRDLLQEYG APIVDPINDI RIIGVVSVTV LLAISLAGME WESKAQVLFF LVIMVSFANY 
301:	LVGTLIPPSE DKASKGFFSY RADIFVQNLV PDWRGPDGTF FGMFSIFFPS ATGILAGANI 
361:	SGDLKDPAIA IPKGTLMAIF WTTISYLAIS ATIGSCVVRD ASGVLNDTVT PGWGACEGLA 
421:	CSYGWNFTEC TQQHSCHYGL INYYQTMSMV SGFAPLITAG IFGATLSSAL ACLVSAAKVF 
481:	QCLCEDQLYP LIGFFGKGYG KNKEPVRGYL LAYAIAVAFI IIAELNTIAP IISNFFLCSY 
541:	ALINFSCFHA SITNSPGWRP SFQYYNKWAA LFGAIISVVI MFLLTWWAAL IAIGVVLFLL 
601:	LYVIYKKPEV NWGSSVQAGS YNLALSYSVG LNEVEDHIKN YRPQCLVLTG PPNFRPALVD 
661:	FVGTFTRNLS LMICGHVLIG PHKQRMPELQ LIANGHTKWL NKRKIKAFYS DVIAEDLRRG 
721:	VQILMQAAGL GRMKPNILVV GFKKNWQSAH PATVEDYIGI LHDAFDFNYG VCVMRMREGL 
781:	NVSKMMQAHI NPVFDPAEDG KEASARVDPK ALVKEEQATT IFQSEQGKKT IDIYWLFDDG 
841:	GLTLLIPYLL GRKRRWSKCK IRVFVGGQIN RMDQERKAII SLLSKFRLGF HEVHILPDIN 
901:	QNPRAEHTKR FEDMIAPFRL NDGFKDEATV NEMRRDCPWK ISDEEITKNR VKSLRQVRLN 
961:	EIVLDYSRDA ALIVITLPIG RKGKCPSSLY MAWLETLSQD LRPPVILIRG NQENVLTFYC 
1021:	Q

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Gene Ontology

References (39)

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