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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
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
    Physical map
    MT4 16q13 metallothionein IV MT3 16q13 metallothionein 3 (growth inhibitory factor (neurotrophic)) MT2A 16q13 metallothionein 2A MT1L 16q13 metallothionein 1L MT1E 16q13 metallothionein 1E (functional) MT1K 16q13 metallothionein 1K MT1J 16q13 metallothionein 1J MT1A 16q13 metallothionein 1A (functional) LOC390733 16 similar to MTM MT1B 16q13 metallothionein 1B (functional) MT1F 16q13 metallothionein 1F (functional) MT1G 16q13 metallothionein 1G MT1H 16q13 metallothionein 1H MT1X 16q13 metallothionein 1X KIAA0095 16q13 metallothionein 1X SLC12A3 16q13 solute carrier family 12 (sodium/chloride transporters), member 3 HERPUD1 16q12.2-13 homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 CETP 16q13 cholesteryl ester transfer protein, plasma NOD27 16q13 nucleotide-binding oligomerization domains 27
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    26 - 5582 - 1030 - 2008 18270262
    26 splicing 5579 - 1029 kidney 2008 18270262
    26 - 5555 - 1021 - 2008 18270262
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivefemale systemuteruscervix  
     male systemprostate  moderately
    Urinarykidneytubuleconvoluted tubuledistal 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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