Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

SLC12A3

contributors: mct/np - updated : 14-09-2015

HGNC name	solute carrier family 12 (sodium/chloride transporters), member 3
HGNC id	10912

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	GTMS1 Gitelman syndrome 1
Location	16q13      Physical location : 56.899.118 - 56.949.760
Synonym name	thiazide-sensitive Na-Cl co-transporter
	Na-Cl symporter
Synonym symbol(s)	NCCT, TSC, NCC

DNA

TYPE	functioning gene
STRUCTURE	50.64 kb     26 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter (TATA box)
	Binding site
text structure	2 Sp binding sites, one potential E box and binding site for NF-1/CTF of NY-I/CP1

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000339 26 - 5582 NP_000330 - 1030 - 2008 18270262 NM_001126107 26 splicing 5579 NP_001119579 - 1029 kidney 2008 18270262 NM_001126108 26 - 5555 NP_001119580 - 1021 - 2008 18270262

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Reproductive female system uterus cervix       male system prostate     moderately Urinary kidney tubule convoluted tubule distal tubule   Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	twelve transmembrane segments (12TM)
	intracytoplasmic N and C termini

HOMOLOGY

interspecies

homolog to murine Slc12a3

Homologene

FAMILY

solute carrier family 12, sodium/chloride

CATEGORY

transport carrier

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
text	decreased ubiquitination may be a major mechanism for accumulation of phosphorylated SLC12A3 in the plasma membranes

basic FUNCTION	principal mediator of sodium and chloride reabsorption in the kidney, distal convoluted tubule
	having function in renal salt reabsorption (Hebert 2004)
	involved in mediation of blood pressure levels, but not involved in determining blood pressure levels (Aoi 2007)
	SLC12A3 of distal convoluted tubule (DCT) is activated by luminal trafficking and phosphorylation at conserved NH2-terminal residues
	mediates salt reabsorption in the distal nephron of the kidney and is the target of thiazide diuretics, which are commonly prescribed to treat hypertension
	ubiquitination of SLC12A3 may be an important determinant of SLC12A3 protein abundance and plasma membrane localization within cells
	plays a major role in renal electrolyte balance
	controls ion homeostasis and arterial blood pressure
	SLC12A3 inhibition stimulates duodenal Ca(2+) absorption as well as osteoblast differentiation and bone Ca(2+) storage, possibly through a PTK2/ERK dependent mechanism

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	WNK4 promotes SLC12A3 targeting to the lysosome for degradation via a mechanism involving sortilin
	cytoplasmic HSPA4 plays a critical role in selecting immature forms of SLC12A3 for ERAD
	SLC12A3 phosphorylation decreased SLC12A3 ubiquitination, which may contribute to the increase of SLC12A3 abundance mostly on plasma membranes
	STK39 and OSR1 regulate sodium-chloride co-transporters SLC12A3, and SLC12A1 in a nephron-specific manner
	WNK4 inhibits plasma membrane targeting of SLC12A3 through regulation of STX12 SNARE formation
	WNK3 is an activator of SLC12A3, and NEDD4L is an inhibitor
	potential role for WNK3 on SLC12A3 expression at the plasma membrane, an effect apparently independent of the STK39 and the aldosterone-SGK1 pathway
	KCNJ10 is a main contributor to the basolateral K conductance in the early distal convoluted tubule (DCT1) and determines the expression of the apical SLC12A3 in the DCT
	STK39 is an important mediator of the increased SLC12A3 activation by phosphorylation that occurs in the distal convoluted tubule in response to a low-K(+) diet
	proline-rich exons are modular cassettes that convert WNK1 into a NEDD4L substrate, thereby linking aldosterone and other NEDD4L-suppressing antinatriuretic hormones to SLC12A3 phosphorylation status

cell & other

REGULATION

inhibited by

PRKWNK4

repressed by

acidification

Other	thiazide-sensitive
	signalling pathway plays a key role in controlling the phosphorylation and activity of SLC12A3 (Richardson 2008)
	SLC12A3 phosphorylation by OSR1 and SPAK kinases and ubiquitination are coordinated and involved in the regulation of SLC12A3 under various pathophysiological conditions

ASSOCIATED DISORDERS

corresponding disease(s)

GTMS1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation     gain of function gain-of-function mutation in SLC12A3 causes pseudohypoaldosteronism type II

Susceptibility

to primary hypertension to end-stage renal disease in diabetic nephropathy

Variant & Polymorphism SNP	increasing the risk of end-stage renal disease in diabetic nephropathy

Candidate gene
Marker
Therapy target	inhibitors of STK39/OXSR1 might be of use in reducing blood pressure by suppressing phosphorylation and hence activity of SLC12A3 (Richardson 2008)

ANIMAL & CELL MODELS