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FLASH GENE
Symbol SLC12A1 contributors: mct/pgu - updated : 10-05-2016
HGNC name solute carrier family 12 (sodium/potassium/chloride transporters), member 1
HGNC id 10910
Corresponding disease
BSND1 Bartter syndrome, antenatal type 1
NHPT1 Neonatal Primary Hyperparathyroidism 1
Location 15q21.1      Physical location : 48.498.497 - 48.596.273
Synonym name
  • Na-K-2Cl cotransporter
  • NKCC2A variant A
  • kidney-specific Na-K-Cl symporter
  • Synonym symbol(s) NKCC2, BSC1, MGC48843
    DNA
    TYPE functioning gene
    STRUCTURE 97.78 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    Map cen - D15S118 - D15S214 - [D15S132 - D15S161 - D15S209 ] - D15S117 - qter
    Text [SLC12A1 ]
    Physical map
    SLC30A4 15q15-q21.1 solute carrier family 30 (zinc transporter), member 4 FLJ39426 15q15.1 hypothetical protein FLJ39426 PLDN 15q14 pallidin homolog (mouse) SQRDL 15q15 sulfide quinone reductase-like (yeast) LOC145660 15q15.1 hypothetical LOC145660 SEMA6D 15q15.2 sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D LOC283652 MYEF2 15q15.1 myelin expression factor 2 SLC12A1 15q15-q21 solute carrier family 12 (sodium/potassium/chloride transporters), member 1 DUT 15q21.1 dUTP pyrophosphatase FBN1 15q21.1 fibrillin 1 (Marfan syndrome) LOC388119 15 similar to Oxr1 protein KIAA0912 15q15.3 KIAA0912 protein CRI1 15q21.1-q21.2 CREBBP/EP300 inhibitory protein 1 LOC390582 15 similar to keratin 8; cytokeratin 8; keratin, type II cytoskeletal 8 KIAA0256 15q15.3 KIAA0256 gene product TRIP15 15q21.2 KIAA0256 gene product LOC390583 15 similar to Protein C6orf66 (HSPC125) (My013 protein) GALK2 15q21.1 galactokinase 2 FLJ32800 15q15.3 hypothetical protein FLJ32800 LOC390584 15 similar to putative intramembrane cleaving protease; presenilin-like protein 2; intramembrane protease 3 FGF7 15q15-q21.1 fibroblast growth factor 7 (keratinocyte growth factor) MDS009 15q15.3 x 009 protein LOC388120 15 hypothetical gene supported by BC013357; NM_016120 ATP8B4 15q15.3 ATPase, Class I, type 8B, member 4 SLC27A2 15q21.2 solute carrier family 27 (fatty acid transporter), member 2 HDC 15q15-q21 histidine decarboxylase GABPB2 15q15.2 GA binding protein transcription factor, beta subunit 2, 47kDa FLJ10038 15q15.3 hypothetical protein FLJ10038 USP8 6p21.3 ubiquitin specific protease 8 TRPM7 15q21 transient receptor potential cation channel, subfamily M, member 7 SPPL2A 15q15.3 putative intramembrane cleaving protease AP4E1 15q15.2 adaptor-related protein complex 4, epsilon 1 subunit
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    26 - 4717 121.3 1099 in medullary thick ascending limbs (MAL) and cortical thick ascending limbs (CAL) 2009 19535327
    NKCC2f
    27 - 4717 121.3 1099 in the cortical thick ascending limbs (CAL) and the distal convoluted tubules (DCT) but not in the medullary thick ascending limbs (MAL), and in pancreatic beta-cells 2009 19535327
  • NKCC2a
  • since NKCC2a expression is restricted to the TAL, NKCC2a-dependent activation of NFAT5 is part of a pathway by which the TAL produces TNF in response to hypertonic NaCl intake
  • EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon   Mus musculus
    Nervousbraindiencephalonhypothalamus   Homo sapiens
    UrinarykidneytubuleHenles loopHL ascending limb  Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestiveepithelial cell Mus musculus
    Urinaryepithelial cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES Hydrophobic
    STRUCTURE
    motifs/domains
  • twelve transmembrane segments (12TM) receptor
  • intracytoplasmic N and C termini
  • aminoacid permease domain
  • a Py motif
  • coiled-coil dimerization domain
  • cytoplasmic tail containing at least two distinct major motifs, LLV motif controls ER export and cell surface expression levels, whereas another independent motif present in the region determines its polarized surface expression in epithelial cells
  • a 150-AA stretch of SLC12A1 C-terminal tail is involved in the interaction with MAL
  • trihydrophobic motif in the distal C-terminus that was required for endoplasmic reticulum (ER) exit and surface expression of the co-transporter ; in the C-terminus, only motifs required for ER exit and surface expression of SLC12A1 are evolutionarily conserved in all members of the SLC12A family, a group of cation-chloride co-transporters
  • HOMOLOGY
    interspecies homolog to rattus slc12a1
    intraspecies homolog to SLC12A2
    Homologene
    FAMILY
  • SLC12A transporter family
  • SLC12 gene family of electroneutral cation-chloride cotransporters
  • CATEGORY transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
    text
  • located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL)
  • basic FUNCTION
  • Na+ : K+ : 2Cl cotransporter 2, bumetanide-sensitive
  • primary mediator of sodium and chloride reabsorption in the apical membrane thick ascending limb of the loop of Henle
  • having function in renal salt reabsorption
  • major route for sodium/chloride transport across the apical plasma membrane of the thick ascending limb (TAL)3 of the kidney
  • Na-K-Cl cotransporter that mediates active reabsorption of sodium-chloride in the thick ascending limb of the loop of Henle in the kidney
  • evidence of SLC12A1 expression in pancreatic beta-cells where it may play a role in insulin secretion
  • couples the movement of Na(+), K(+), and Cl(-) ions across the plasma membrane of most cells and thus plays a central role in cellular homeostasis
  • furosemide-sensitive, and responsible for urine concentration and helps maintain systemic salt homeostasis
  • is one of the transport proteins with the highest overall reabsorptive capacity in the kidney
  • sodium reabsorption via SL C12A1 in the thick ascending limbs has a major role for medullary osmotic gradient and subsequent water reabsorption in the collecting ducts
  • osmoregulation requires brain expression of SLC12A1
  • involved in insulin secretion and a single SLC12A2 allele may protect beta-cells from failure due to increased homeostatic expression of SLC12A1
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS electron transport
    text small molecule transport
    PATHWAY
    metabolism
    signaling
    major salt transport pathway of the apical membrane of the mammalian thick ascending limb (TAL) of Henle's loop
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with STK39 and WNK3 (the chloride-sensitive activation of NKCC2 requires this interaction)
  • interacting with MAL (MAL increases the cell surface retention of SLC12A1 by attenuating its internalization, and this coincides with an increase in cotransporter phosphorylation)
  • STK39 and OSR1 regulate sodium-chloride co-transporters SLC12A3, and SLC12A1 in a nephron-specific manner
  • ANXA2 is a lipid raft-associated trafficking factor for SLC12A1
  • vasopressin plays an important role in the colonic epithelia by stimulating NKCC2 trafficking to the apical membrane and inducing SLC12A1-mediated ion transport
  • VAMP3 interacts with SLC12A1 and mediates its constitutive exocytic delivery to the apical surface, and VAMP3 is required for normal SLC12A1 expression, renal function, and blood pressure
  • cell & other
    REGULATION
    activated by intracellular chloride depletion by a mechanism that involves WNK3 and SPAK kinases
    Other regulation by intracellular chloride depletion requires interaction between WNK3 and SPAK, in a pathway in which WNK3 lies upstream of SPAK
    ASSOCIATED DISORDERS
    corresponding disease(s) BSND1 , NHPT1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion      
    with LEO1 in gliomas
    constitutional     --low  
    through inhibitory factors for SLC12A1 expression in dehydration
    constitutional       gain of function
    is linked with inherited hypertension
    Susceptibility to essential hypertension
    Variant & Polymorphism other rare alleles protecting against essential hypertension
    Candidate gene
    Marker
    Therapy target target of loop diuretic drugs used worldwide for the treatment of edematous states
    SystemTypeDisorderPubmed
    miscelleaneousurinary 
    target of loop diuretic drugs used worldwide for the treatment of edematous states
    ANIMAL & CELL MODELS