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FLASH GENE
Symbol SLC12A2 contributors: mct/npt/pgu - updated : 09-05-2016
HGNC name solute carrier family 12 (sodium/potassium/chloride transporters), member 2
HGNC id 10911
Location 5q23.3      Physical location : 127.419.482 - 127.525.379
Synonym name
  • bumetanide-sensitive sodium-(potassium)-chloride cotransporter 1
  • basolateral Na-K-Cl symporter
  • protein phosphatase 1, regulatory subunit 141
  • Synonym symbol(s) NKCC1, BSC2, BSC, MGC104233, PPP1R141
    DNA
    TYPE functioning gene
    STRUCTURE 105.90 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked   status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 6891 - 1212 - 2014 24695712
  • NKCC1a
  • 26 - 6843 - 1196 - 2014 24695712
  • NKCC1b, lacking exon 21
  • expression of NKCC1b was associated with SLC12A2 polymorphism rs3087889
  • - - - - - . expressed preferentially in the fetus 2014 24695712
  • ultra-short transcript (1-2a)
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Olfactory (smell)olfactory bulb     Homo sapiens
    Reproductivefemale systembreastmammary gland  
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period perinatal
    Text highly expressed in cerebral cortex in early postnatal days but decreasing during postnatal development
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminus not required for dimerization
  • twelve transmembrane segments (12TM), with role of TM3 in the binding and translocation of ions as well as in the binding of loop diuretic inhibitors
  • a large extracellular loop
  • C-terminus plays an essential role in dimerization that exhibits definite homologue-specificity
  • intracytoplasmic N and C termini
  • mono polymer homomer , dimer
    HOMOLOGY
    Homologene
    FAMILY
  • SLC12A transporter family
  • SLC12 gene family of electroneutral cation-chloride cotransporters
  • CATEGORY secretory , transport carrier
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule
    text
  • expressed in the ciliary membrane, where it mediates chloride accumulation into the ciliary lumen
  • most of SLC12A2 in the plasma membrane is core/hybrid-type N-glycosylated, and the minimal proportion of complex N-glycosylated NKCC1 is functionally active
  • basic FUNCTION
  • regulating transcellular movement of chloride in colon
  • maybe involved in endolymph secretion and in regulating cell volume
  • facilitating seizures in the developing hippocampus
  • plays a key role in epithelial salt secretion and cell volume regulation
  • major pathway for Cl- accumulation in glioma cells, and genetic or pharmacologic inhibition of SLC12A2 is associated with a marked reduction in glioma cell invasion
  • regulates intracellular Cl- concentration in many cell types and is a critical part of the Cl- secretory pathway in salt secreting epithelia
  • in the brain is critically involved in maintaining chloride homeostasis and in neuronal responses mediated by GABA(A) receptors
  • SLC12A2 co-transporter is involved in the maintenance of a high intracellular chloride concentration [Cl(-)] in beta-cells and its inhibition with BTD blocks glucose-induced insulin secretion
  • play important roles in Na(+) and K(+) concentrations in key physiological systems, including cardiac, vascular, renal, nervous, and sensory systems
  • 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
  • involved in cell volume/ion regulation
  • 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
    PATHWAY
    metabolism
    signaling
    a component
  • exist as homodimers in the membrane, suggesting that this may be a common feature of the CCCs
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with HSP90 (binding of HSP90 may be required for Na(+)-K(+)-Cl(-) cotransport to occur at the cell surface and it could play an important role in ion-dependent signaling mechanisms)
  • SIX1 and SIX4 regulate SLC12A2
  • WNK2 promotes Cl- accumulation by reciprocally activating SLC12A2 and inhibiting SLC12A5 in a kinase-dependent manner
  • FOXA1 regulates sweat secretion through BEST2 anion channel and SLC12A2
  • STK39 and OXSR1 entering cells through exosomes are preferentially expressed at the plasma membrane and the kinases in exosomes are functional and maintain SLC12A2 in a phosphorylated state
  • WNK1 is a negative regulator of integrin-mediated adhesion, whereas it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2
  • cell & other
    REGULATION
    activated by EGFR (role for EGFR in the chronic regulation of epithelial secretory capacity through upregulation of SLC12A2 expression)
    WNK2 that might activate SLC12A2 indirectly via STK39
    by hypertonicity and inactivated by hypotonicity
    Other bumetanide-sensitive,
    aldosterone can regulate SLC12A2 protein expression, quite sensitively and rapidly, independent of mRNA expression changes
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    reduced SLC12A5/SLC12A2 ratio in the cerebrospinal fluid of Rett Syndrome patients, suggesting a disturbed process of GABAergic neuronal maturation
    constitutional       loss of function
    affects not only secretion, but also goblet cell function and chemosensing of intestinal contents via G-protein coupled chemosensory receptors
    constitutional     --over  
    in endometriosis, positively correlated with endometrioma size
    Susceptibility to schizophrenia
    Variant & Polymorphism other variation in SLC12A2 may increase risk for schizophrenia via alterations of mRNA expression at the molecular level and impairment of optimal prefrontal function
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneoushypertension 
    increased SLC12A2 activity and glycosylation disrupt chloride homeostasis and impair synaptic inhibition in the hypothalamic paraventricular nucleus (PVN) to augment the sympathetic drive in hypertension
    ANIMAL & CELL MODELS
  • Nkcc1-deficient mice exhibit significant defects in perception of a complex odorant mixture in both air-phase and submerged approaches