Affinage

SLC12A1

Solute carrier family 12 member 1 · UniProt Q13621

Length
1099 aa
Mass
121.5 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC12A1 encodes NKCC2, the apical Na⁺-K⁺-2Cl⁻ cotransporter of the thick ascending limb (TAL) that mediates a major fraction of renal NaCl reabsorption, and loss-of-function mutations cause Bartter syndrome type I (PMID:8640224, PMID:12761241). NKCC2 transport activity is regulated by phosphorylation of conserved N-terminal threonines (T95/T100/T105) through a WNK3–SPAK/OSR1 kinase cascade activated by intracellular chloride depletion, and independently at Ser126 by AMPK, with alternative splicing of exon 4 (variants A, B, F) determining ion affinity via residues in transmembrane domain 2 and intracellular loop 1 (PMID:18550832, PMID:17341212, PMID:17186942). Apical surface abundance is dynamically controlled by vasopressin/cAMP/PKA-stimulated exocytic insertion via VAMP2, constitutive clathrin- and lipid-raft-mediated endocytosis through dynamin-2, and modulatory protein interactions including aldolase B, SCAMP2, MAL/VIP17, and Tamm-Horsfall protein that shift the balance between surface retention and internalization (PMID:25008321, PMID:22977238, PMID:17848580, PMID:21737451). ER quality control of NKCC2 biogenesis depends on conserved C-terminal di-leucine motifs for ER exit and OS9-mediated ERAD of immature forms, while Nedd4-2-dependent ubiquitination promotes proteasomal degradation of the mature transporter (PMID:19535327, PMID:26721884, PMID:23104236).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Identification of SLC12A1 loss-of-function mutations in Bartter syndrome type I families established NKCC2 as the essential apical cotransporter for NaCl reabsorption in the TAL, resolving the molecular identity of the furosemide-sensitive transporter in this nephron segment.

    Evidence Genetic linkage analysis and mutation identification in affected families; concurrent immunohistochemistry localizing NKCC2 to the apical membrane of TAL cells

    PMID:8640224 PMID:8853424

    Open questions at the time
    • No structure–function analysis of identified mutations
    • Mechanism of NaCl reabsorption coupling not defined at molecular level
  2. 1998 High

    Functional reconstitution of NKCC2A in mammalian cells revealed distinct kinetic properties from NKCC1, including lower K⁺ affinity, higher bumetanide sensitivity, and higher resting activity, establishing that NKCC2 has unique transport characteristics adapted for the renal concentrating mechanism.

    Evidence Stable expression of NKCC1/NKCC2 chimera in HEK-293 cells with ion affinity measurements and volume response assays

    PMID:9556622

    Open questions at the time
    • Only NKCC2A isoform characterized; B and F isoform kinetics not yet compared
    • Structural basis for affinity differences unknown
  3. 2003 High

    Demonstration that vasopressin promotes both NKCC2 phosphorylation at N-terminal threonines and its translocation to the apical membrane in vivo revealed that hormonal regulation operates through dual mechanisms — covalent modification and membrane trafficking.

    Evidence Phosphospecific antibody immunofluorescence and EM morphometry in mouse kidney after dDAVP administration

    PMID:12732642

    Open questions at the time
    • Kinase responsible for vasopressin-induced phosphorylation not identified
    • Trafficking machinery not defined
  4. 2005 High

    Identification of the WNK3–NKCC2 regulatory axis and the requirement for three N-terminal regulatory threonines for full activation resolved how upstream kinase signaling controls NKCC2 phosphorylation and surface expression, while exon 4 residues in TM2/ICL1 were shown to determine ion affinity differences among splice variants.

    Evidence Coexpression studies in Xenopus oocytes with kinase-active/dead WNK3 mutants; systematic mutagenesis of regulatory threonines and exon 4 residues with ion uptake assays

    PMID:16077079 PMID:16275913 PMID:17186942

    Open questions at the time
    • Intermediate kinase between WNK3 and NKCC2 not yet identified
    • In vivo validation of WNK3 regulation of NKCC2 lacking
  5. 2005 High

    Demonstration that cAMP stimulates NKCC2 surface expression via VAMP-dependent exocytosis in native TAL cells identified the vesicular fusion machinery responsible for regulated NKCC2 insertion, linking hormonal signaling to membrane trafficking.

    Evidence Surface biotinylation, confocal microscopy, and tetanus toxin inhibition of VAMP in isolated perfused rat TALs with Cl⁻ absorption assays

    PMID:16144963

    Open questions at the time
    • Specific VAMP isoform not yet determined
    • Role of PKA vs. other cAMP effectors not dissected
  6. 2007 High

    AMPK was identified as a direct kinase for NKCC2 at Ser126, physically associating with the N-terminal domain and required for isotonic NKCC2 activity, establishing a metabolic sensing input distinct from the WNK–SPAK pathway.

    Evidence In vitro kinase assay, co-immunoprecipitation, AMPK activator in MMDD1 cells, S126A mutagenesis with functional assay in oocytes

    PMID:17341212

    Open questions at the time
    • Physiological stimuli activating AMPK-NKCC2 axis in TAL not defined
    • Crosstalk between AMPK and WNK pathways unknown
  7. 2007 High

    Discovery that aldolase B binds the NKCC2 C-terminus and reduces surface expression — reversibly by its substrate fructose-1,6-bisphosphate — revealed a metabolic coupling mechanism linking glycolytic flux to NKCC2 trafficking.

    Evidence Yeast two-hybrid, co-IP, surface biotinylation, transport assays, substrate competition in renal cells

    PMID:17848580

    Open questions at the time
    • In vivo relevance in TAL not demonstrated
    • Whether aldolase enzymatic activity is required not resolved
  8. 2008 High

    The complete WNK3–SPAK–NKCC2 signaling cascade was reconstituted, showing that intracellular chloride depletion activates NKCC2 through WNK3 acting as a chloride sensor upstream of SPAK, which phosphorylates the three conserved N-terminal threonines, thereby defining the chloride-sensing mechanism for NKCC2 regulation.

    Evidence Coexpression in Xenopus oocytes with low-Cl⁻ stress, WNK3 SPAK-binding motif mutagenesis, kinase-dead WNK3, threonine mutagenesis

    PMID:18550832

    Open questions at the time
    • Role of OSR1 relative to SPAK not resolved
    • In vivo chloride sensing mechanism in TAL not validated
  9. 2009 High

    PKA (not Epac) was identified as the cAMP effector driving NKCC2 exocytic insertion, and conserved C-terminal di-leucine motifs (LLV) were found essential for ER exit, separating regulated trafficking from biosynthetic quality control.

    Evidence Selective PKA/Epac agonists with surface biotinylation in perfused TALs; systematic C-terminal truncation and site-directed mutagenesis with pulse-chase and confocal ER co-localization

    PMID:19535327 PMID:19592485

    Open questions at the time
    • PKA substrate on NKCC2 or trafficking machinery not identified
    • Whether ER exit motifs are recognized by coat proteins not determined
  10. 2010 High

    Quantitative measurement of constitutive NKCC2 endocytosis and recycling in native TAL, combined with genetic evidence from KS-WNK1 gain- and loss-of-function mouse models, established that steady-state apical NKCC2 density is set by the balance of exocytosis, endocytosis, and recycling under tonic WNK signaling.

    Evidence Surface biotinylation with cholesterol depletion in perfused TALs; KS-WNK1 transgenic overexpression and exon 4A knockout mice with NKCC2 phosphorylation and localization analysis

    PMID:20719977 PMID:21131289

    Open questions at the time
    • Molecular machinery of recycling endosome to apical membrane pathway not identified
    • Mechanism by which KS-WNK1 opposes full-length WNK1 unclear
  11. 2011 High

    Multiple modulatory partners — Tamm-Horsfall protein, SCAMP2, MAL/VIP17 — were shown to regulate NKCC2 surface abundance through distinct trafficking steps (phosphorylation/apical retention, exocytic delivery, endocytic attenuation), and SPAK/OSR1 were confirmed as direct kinases for T95/T100/T105 with T105 and S130 being the functionally dominant sites.

    Evidence THP-knockout mice and oocyte co-expression; Y2H/Co-IP/surface biotinylation for SCAMP2 and MAL/VIP17; direct kinase assays and mutagenesis in oocytes for SPAK/OSR1 phosphorylation site mapping

    PMID:20861303 PMID:21205824 PMID:21321328 PMID:21737451

    Open questions at the time
    • Hierarchy and interdependence of multiple trafficking regulators not established
    • Whether THP modulation is direct or through chloride sensing not resolved
  12. 2011 High

    Functional characterization of Bartter syndrome mutations and population-derived rare variants revealed that many disease-causing alleles produce properly routed but functionally impaired transporters, while others cause processing defects, indicating distinct pathogenic mechanisms (transport vs. trafficking).

    Evidence Expression of patient-derived and population-derived NKCC2 mutants in oocytes and HEK-293 cells with ion uptake, immunoblotting, and localization analysis

    PMID:12761241 PMID:21209010

    Open questions at the time
    • Genotype–phenotype correlation for intermediate-severity variants not established
    • Contribution of individual variant alleles to population blood pressure not quantified
  13. 2012 High

    VAMP2 was specifically identified as the v-SNARE mediating cAMP/PKA-stimulated NKCC2 exocytosis (not VAMP3), additional C-terminal ER exit motifs (LL, LI) were mapped, and NKCC2 was shown to be an ion-only transporter (unlike water-cotransporting NKCC1), establishing unique biophysical features for renal concentration.

    Evidence Isoform-selective in vivo VAMP siRNA with Co-IP in TALs; systematic di-leucine mutagenesis; comparative volume measurements in oocytes expressing NKCC1 vs NKCC2

    PMID:22250214 PMID:23105100 PMID:25008321

    Open questions at the time
    • SNARE complex partners of VAMP2 in TAL apical trafficking unknown
    • Structural basis for water exclusion by NKCC2 not determined
  14. 2012 High

    AC6 was identified as the adenylyl cyclase isoform linking vasopressin/V2 receptor signaling to NKCC2 Ser126 phosphorylation in vivo, as AC6-knockout mice phenocopy mild Bartter syndrome, placing AC6 as a critical node in the hormonal control of NKCC2.

    Evidence AC6 knockout mice with dDAVP stimulation, phosphospecific immunoblotting, renal phenotype analysis

    PMID:23123217

    Open questions at the time
    • Whether AC6 acts exclusively through PKA-Ser126 or also through SPAK pathway not resolved
    • Redundancy with other AC isoforms not fully assessed
  15. 2013 High

    Dietary salt intake was found to modulate alternative splicing of NKCC2 pre-mRNA between low-affinity (A) and high-affinity (B) variants, partly through angiotensin II/AT1 signaling, revealing a transcriptional/splicing layer of NKCC2 regulation superimposed on post-translational control.

    Evidence Mouse dietary salt manipulation with isoform-specific RT-PCR; furosemide, angiotensin II, and AT1 antagonist treatments in vivo and ex vivo

    PMID:23946287

    Open questions at the time
    • Splicing factor(s) mediating the switch not identified
    • Functional consequence of isoform shift on overall NaCl reabsorption not directly measured
  16. 2014 Medium

    Nedd4-2-mediated ubiquitination was identified as a mechanism for NKCC2 proteasomal degradation in the context of high salt and 20-HETE signaling, adding a ubiquitin–proteasome degradation pathway to the post-translational regulatory repertoire.

    Evidence Co-IP of ubiquitin and Nedd4-2 with NKCC2 in CYP4F2 transgenic mice on high-salt diet; proteasome and 20-HETE synthesis inhibitor treatments

    PMID:23104236

    Open questions at the time
    • Specific ubiquitination sites on NKCC2 not mapped
    • Direct Nedd4-2–NKCC2 interaction not validated by reciprocal or domain-mapping approaches
    • Pathway not reconstituted in a minimal system
  17. 2015 High

    OS9 was identified as an ERAD lectin that selectively binds immature (ER-resident) NKCC2 and targets it for N-glycan-dependent proteasomal degradation, defining the ER quality control mechanism for NKCC2 biogenesis.

    Evidence Y2H, Co-IP selective for immature NKCC2, OS9 overexpression/knockdown with pulse-chase, proteasome inhibitor, N-glycosylation and MRH domain mutagenesis

    PMID:26721884

    Open questions at the time
    • Other ERAD components (e.g. Hrd1, SEL1L) in the NKCC2 degradation pathway not identified
    • Whether disease-causing NKCC2 mutants are preferentially targeted by OS9 not tested
  18. 2015 High

    NKCC2 expression was discovered in the hypothalamo-neurohypophyseal system, where it regulates chloride homeostasis in AVP neurons and contributes to systemic fluid balance, extending NKCC2 function beyond the kidney.

    Evidence Immunohistochemistry, in vivo HNS-specific NKCC2 knockdown, bumetanide treatment, electrophysiology of AVP neurons

    PMID:25834041

    Open questions at the time
    • Which NKCC2 splice variant(s) are expressed in HNS not determined
    • Whether WNK-SPAK regulation operates in neurons not tested
  19. 2016 High

    The NO–cGMP pathway was shown to inhibit NKCC2 activity in TAL, and this natriuretic brake is impaired in angiotensin II hypertension due to PDE5-mediated cGMP degradation, establishing a mechanism by which hypertension sustains excessive NKCC2-dependent sodium reabsorption.

    Evidence Pharmacological dissection (NO donors, cGMP analogues, PDE5 inhibitor vardenafil) in perfused TALs from normotensive and ANG II-infused rats

    PMID:26887831

    Open questions at the time
    • Direct molecular target of cGMP/PKG on NKCC2 or its regulators not identified
    • Whether PDE5 inhibition corrects blood pressure via NKCC2 in vivo not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of NKCC2 is lacking, leaving the structural basis for ion selectivity, splice-variant affinity differences, water exclusion, and the mechanism of furosemide inhibition unresolved; additionally, the integration and hierarchy among the multiple trafficking regulators (VAMP2, SCAMP2, MAL/VIP17, aldolase B, THP, Nedd4-2, OS9) in native TAL cells has not been systematically dissected.
  • No cryo-EM or crystal structure of NKCC2
  • No systems-level model integrating phosphorylation, trafficking, and degradation pathways
  • Splicing factor(s) mediating salt-dependent isoform switching remain unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-382551 Transport of small molecules 4 R-HSA-9609507 Protein localization 4 R-HSA-392499 Metabolism of proteins 2
Partners
ALDOBMALOS9OSR1SCAMP2SPAKVAMP2WNK3

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Loss-of-function mutations in NKCC2 (SLC12A1) cause Bartter's syndrome type I, establishing NKCC2 as the renal Na-K-2Cl cotransporter responsible for NaCl reabsorption in the thick ascending limb. Genetic linkage analysis and identification of frameshift/missense mutations co-segregating with disease in affected families Nature genetics High 8640224
1996 NKCC2 protein is localized exclusively to the apical membrane of medullary and cortical thick ascending limb (TAL) cells in rat kidney, and its abundance is upregulated by chronic oral saline loading; chronic furosemide infusion causes an upward shift in apparent molecular mass. Peptide-derived polyclonal antibody immunoblotting and immunoperoxidase immunohistochemistry of rat kidney fractions; in vivo manipulation experiments The American journal of physiology High 8853424
2003 Short-term vasopressin administration causes a 2-fold increase in NKCC2 phosphorylation at regulatory threonines in the amino terminus AND promotes trafficking (translocation) of NKCC2 to the apical membrane (55% increase in apical NKCC2), with phosphorylated cotransporter restricted to the cell membrane compartment. Phosphospecific antibody immunofluorescence and electron microscope morphometric analysis of NKCC2 distribution in mouse kidney after vasopressin analogue (dDAVP) administration The Journal of biological chemistry High 12732642
2005 WNK3 kinase is a positive regulator of NKCC2 activity; kinase-active WNK3 activates NKCC2 while kinase-inactive WNK3 inhibits it. WNK3 regulates NKCC2 by altering its plasma membrane expression and increasing phosphorylation at Thr-184 and Thr-189, sites required for vasopressin-mediated activation. Coexpression studies in Xenopus oocytes, ion transport assays, plasma membrane expression analysis, phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 16275913
2005 NKCC2 transport activity is stimulated by hypertonicity and regulated by a threonine regulatory domain (T99, T104, T117) in the N-terminus; all three threonines together are required for the full hypertonic response, and the transmembrane domain 2 (TM2) and intracellular loop 1 (ICL1) contribute to ion affinity differences among splice variants. Site-directed mutagenesis of regulatory threonines and splice-variant residues, functional expression in Xenopus oocytes with ion uptake assays American journal of physiology. Renal physiology High 16077079
2008 Intracellular chloride depletion activates NKCC2 by promoting phosphorylation of three conserved threonines (T96, T101, T111) in the amino terminus, in a mechanism requiring WNK3 (the chloride-sensitive kinase, upstream) and SPAK (downstream); elimination of threonines renders NKCC2 unresponsive to [Cl-]i reductions, and elimination of WNK3's SPAK-binding motif prevents NKCC2 activation. Coexpression in Xenopus oocytes; KCC2 co-expression or hypotonic low-Cl stress to deplete intracellular Cl-; mutagenesis of threonines and WNK3 motifs; kinase-dead WNK3 mutant; ion transport assays Proceedings of the National Academy of Sciences of the United States of America High 18550832
2005 cAMP increases surface expression of NKCC2 in thick ascending limb (TAL) cells by stimulating translocation (trafficking) of NKCC2 to the apical membrane via a mechanism requiring VAMP (vesicle-associated membrane protein); tetanus toxin (which inactivates VAMP-2 and VAMP-3) completely blocks cAMP-stimulated NKCC2 surface expression and Cl- absorption. Surface biotinylation of rat medullary TALs; confocal microscopy; tetanus toxin inhibition of VAMP; isolated perfused TAL Cl- absorption assays American journal of physiology. Renal physiology High 16144963
2006 The six residues in TM2 and ICL1 encoded by alternatively spliced exon 4 determine the ion affinity differences among NKCC2 splice variants (B, A, F); three TM2 residues and three ICL1 residues each contribute half the effect, and the ICL1 region may be a membrane-embedded domain contributing to Cl- binding/translocation. Site-directed mutagenesis converting NKCC2B residues to A or F variant residues; functional expression in Xenopus oocytes; ion affinity measurements The Journal of biological chemistry High 17186942
2007 AMPK (AMP-activated protein kinase) directly phosphorylates NKCC2 at Ser126 in vitro; AMPK physically associates with the N-terminal cytoplasmic domain of NKCC2 (co-precipitation); activation of AMPK in MMDD1 cells increases Ser126 phosphorylation; mutation of Ser126 to Ala markedly reduces NKCC2 activity under isotonic but not hypertonic conditions. In vitro kinase assay; co-immunoprecipitation; AMPK activator treatment of MMDD1 cells; site-directed mutagenesis (S126A) with functional assay in Xenopus oocytes The Biochemical journal High 17341212
2007 Aldolase B interacts with the C-terminal tail of NKCC2 and reduces NKCC2 surface expression, thereby decreasing cotransporter transport activity; addition of aldolase substrate (fructose 1,6-bisphosphate) disrupts the interaction and abolishes the effect on surface NKCC2. Yeast two-hybrid screen with NKCC2 C-terminal tail as bait; co-immunoprecipitation; co-immunolocalization in renal cells; surface biotinylation; transport activity assays; substrate competition experiment The Journal of biological chemistry High 17848580
2009 cAMP stimulates NKCC2 exocytic insertion into the apical membrane of TAL cells via protein kinase A (PKA) but not Epac; PKA inhibition blocks cAMP-stimulated exocytic insertion without affecting constitutive exocytosis. Surface biotinylation; confocal imaging of apical surface NKCC2 in isolated perfused TALs; FM1-43 apical exocytosis assay; selective PKA agonist (N6-benzoyl-cAMP) vs. Epac agonist; H-89 PKA inhibitor The Journal of biological chemistry High 19592485
2009 A trihydrophobic motif LLV (residues 1081-1083) in the distal C-terminus of NKCC2 is required for ER exit and cell surface expression; naturally occurring truncation mutations interfering with this motif result in ER retention of NKCC2, absence of complex-glycosylated (mature) protein, and loss of surface expression. This motif is conserved across all SLC12A family members. Confocal microscopy; surface biotinylation; pulse-chase analysis; co-immunolocalization with ER marker (PDI); serial C-terminal truncations and site-directed mutagenesis; proteasome/lysosome inhibitor treatment The Journal of biological chemistry High 19535327
2010 NKCC2 undergoes constitutive endocytosis (21.5% of surface pool per 30 min) in TAL cells; blockade of endocytosis with methyl-β-cyclodextrin (chelating membrane cholesterol) increases steady-state surface NKCC2 by 60% and enhances NaCl entry by 57%; a fraction of retrieved NKCC2 (36%) recycles back to the plasma membrane. Surface biotinylation; Western blot; confocal microscopy; cholesterol chelation (MβCD); isolated perfused rat TALs; functional NaCl entry assay American journal of physiology. Renal physiology High 20719977
2010 Kidney-specific WNK1 (KS-WNK1) is a negative regulator of NKCC2 in vivo; KS-WNK1 overexpression reduces surface expression of total and phosphorylated NKCC2 in the thick ascending limb, while deletion of KS-WNK1 (exon 4A knockout) increases surface expression and phosphorylation of NKCC2 with consequent Na+ retention. Transgenic mouse overexpression of KS-WNK1; targeted KS-WNK1 exon 4A knockout mice; immunofluorescent staining of NKCC2 surface expression in nephron segments; physiological measurements Human molecular genetics High 21131289
2011 SPAK and OSR1 kinases interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 (and possibly Ser91) under hypotonic low-chloride conditions. A SPAK/OSR1-independent kinase (possibly AMPK) phosphorylates Ser130. Phosphorylation of Thr105 and Ser130 plays the most important role in stimulating NKCC2 activity. Unlike NCC, NKCC2 is constitutively at the membrane and SPAK/OSR1-phosphorylation does not trigger translocation. Mutational analysis of phosphorylation sites; direct kinase assays; functional expression in Xenopus oocytes; hypotonic low-Cl stress; phosphospecific antibody analysis Journal of cell science High 21321328
2011 Tamm-Horsfall protein (THP) co-localizes and interacts with NKCC2 in TAL cells, modulating NKCC2 activity in a chloride-sensitive manner: THP-deficient mice show increased intracellular NKCC2 in subapical vesicles, decreased baseline phosphorylation, and blunted vasopressin-stimulated NKCC2 phosphorylation. THP-knockout mice (THP-/-); cultured TAL cells with THP transfection; NKCC2-expressing Xenopus oocytes co-injected with THP cRNA; phosphorylation assays; intracellular Cl- measurement; dDAVP stimulation The Journal of biological chemistry High 21737451
2011 Mutations in hNKCC2 identified in Bartter syndrome type I patients result in low expression of normally routed but functionally impaired transporters when expressed in Xenopus oocytes; mutant proteins show reduced bumetanide-sensitive Na+ uptake despite plasma membrane localization confirmed by immunocytochemistry. Functional expression of FLAG-tagged wild-type and mutant hNKCC2 in Xenopus oocytes; 22Na+ uptake assay; immunoblotting; immunocytochemistry Journal of the American Society of Nephrology : JASN High 12761241
2011 TNF-α is an endogenous inhibitor of NKCC2A isoform expression and function in the thick ascending limb; TNF gene deletion causes a 2-fold increase in total NKCC2 protein and 4-fold increase in NKCC2A mRNA with enhanced bumetanide-sensitive O2 consumption, all reversed by exogenous TNF administration. TNF-/- knockout mice; recombinant TNF administration; RT-PCR for isoform-specific mRNA; Western blot; bumetanide-sensitive O2 consumption assay in isolated mTAL tubules American journal of physiology. Renal physiology High 21511694
2011 Rare missense mutations in SLC12A1 found in Framingham Heart Study subjects with lower blood pressure reduce basal NKCC2 cotransporter activity in Xenopus oocytes; the most impaired mutants (R302W, L505V) show processing defects with reduced complex-glycosylated protein and absent plasma membrane localization; P569H shows 50% reduction in sodium affinity. Heterologous expression in Xenopus oocytes and HEK-293 cells; ion transport assays; immunoblotting; plasma membrane localization by immunostaining; ion affinity kinetics American journal of physiology. Renal physiology High 21209010
2011 Dynamin-2 and clathrin mediate NKCC2 endocytosis at the apical surface of TAL cells, with lipid rafts (caveolin-1-dependent) providing an additional endocytic pathway; simultaneous inhibition of both clathrin- and lipid raft-mediated pathways completely blocks NKCC2 internalization. Dynasore treatment and dominant-negative Dyn2K44A expression; chlorpromazine (clathrin inhibitor); synaptojanin-clathrin disruption; lipid raft disruption; caveolin-1 siRNA; surface biotinylation; NKCC2 endocytosis rate measurements in native rat TALs The Journal of biological chemistry High 22977238
2011 MAL/VIP17 tetraspan protein co-localizes and co-immunoprecipitates with NKCC2 in LLC-PK1 cells and rat kidney medulla; a 150-aa stretch of NKCC2 C-terminal tail is required for interaction with MAL/VIP17; MAL/VIP17 increases cell surface retention of NKCC2 by attenuating its internalization and increases cotransporter phosphorylation. Co-immunoprecipitation; co-immunolocalization; deletion mapping of interaction domain; surface NKCC2 measurement; phosphorylation assays; transgenic mice overexpressing MAL/VIP17 Molecular biology of the cell High 20861303
2011 SCAMP2 (secretory carrier membrane protein 2) interacts with the NKCC2 C-terminus (identified by yeast two-hybrid, confirmed by co-IP and co-immunolocalization in renal cells), reduces NKCC2 surface expression and transport activity by interfering with exocytotic trafficking (not endocytosis), with retained NKCC2 localizing to recycling endosomes; a single mutation in SCAMP2 E peptide (C201A) abolishes this effect. Yeast two-hybrid screen; co-immunoprecipitation; confocal co-immunolocalization; surface biotinylation; MESNA cleavage assay for endocytosis rate; transport activity assays; SCAMP2 C201A mutagenesis The Journal of biological chemistry High 21205824
2012 VAMP2 (but not VAMP3) mediates cAMP-stimulated exocytic delivery of NKCC2 to the apical membrane in TAL cells; NKCC2 co-immunoprecipitates with VAMP2 in rat TALs; cAMP stimulation enhances VAMP2-NKCC2 co-immunoprecipitation and VAMP2 exocytosis; in vivo silencing of VAMP2 blocks cAMP-stimulated NKCC2 exocytic delivery without affecting constitutive trafficking. Co-immunoprecipitation; in vivo siRNA silencing of VAMP2 and VAMP3 in TALs; surface biotinylation; exocytosis assays; co-localization by confocal microscopy The Journal of biological chemistry High 25008321
2012 NKCC2 expressed in Xenopus oocytes does not cotransport water (unlike NKCC1 which cotransports ~460-600 water molecules per turnover), indicating NKCC2 functions as an ion-only transporter in the kidney. Heterologous expression of NKCC1 and NKCC2 in Xenopus oocytes; volume change measurements; 86Rb+ uptake; bumetanide blockade; temperature dependence analysis The Journal of physiology High 22250214
2012 Two additional di-leucine-like motifs in the NKCC2 C-terminus, LL(1038-1039) and LI(1048-1049), are required for ER exit and surface expression of NKCC2; double alanine mutations of these motifs disrupt glycosylation and surface expression by causing ER retention. All three motifs (including LLV 1081-1083) are evolutionarily conserved across SLC12A family members. Site-directed mutagenesis; pulse-chase analysis; co-immunolocalization with ER marker calnexin; surface biotinylation; multiple expression systems The Journal of biological chemistry High 23105100
2012 Adenylyl cyclase isoform 6 (AC6) mediates vasopressin-induced phosphorylation of NKCC2 at Ser126 and determines total NKCC2 protein abundance in the thick ascending limb; AC6 knockout mice lack dDAVP-induced NKCC2 phosphorylation and have lower NKCC2 expression with a mild Bartter syndrome-like phenotype. AC6 knockout mice; V2 receptor agonist (dDAVP) stimulation; phosphospecific immunoblotting; renal phenotype analysis The American journal of pathology High 23123217
2013 Dietary salt intake modulates differential splicing of NKCC2 pre-mRNA: low-salt diet shifts expression from low-affinity NKCC2A to high-affinity NKCC2B in renal cortex/outer stripe; this shift is mimicked by furosemide and is partly mediated by angiotensin II acting on AT1 receptors. Mouse dietary manipulation (low/standard/high salt); RT-PCR for isoform-specific mRNA; furosemide treatment in vivo and in cultured kidney slices; angiotensin II infusion; AT1 receptor antagonism American journal of physiology. Renal physiology High 23946287
2015 OS9 protein interacts with the immature (ER-localized) form of NKCC2, targets it for ER-associated degradation (ERAD) in a proteasome-dependent and N-glycan-dependent manner; OS9 knockdown increases NKCC2 stability and expression, while OS9 overexpression decreases NKCC2 protein through increased degradation of its immature form. Yeast two-hybrid screen; co-immunoprecipitation (selective for immature NKCC2); co-immunolocalization with ER marker; overexpression and siRNA knockdown with pulse-chase/cycloheximide-chase; proteasome inhibitor (MG132); N-glycosylation site mutagenesis; MRH domain mutation in OS9 The Journal of biological chemistry High 26721884
2015 NKCC2 is expressed in the hypothalamo-neurohypophyseal system (HNS) of the brain; HNS NKCC2 expression is upregulated by osmotic stress, and knockdown of HNS NKCC2 causes increased urine output and impaired fluid balance after high-salt ingestion. GABA-mediated excitation of arginine vasopressin neurons following dehydration is reversed by bumetanide (NKCC2 inhibitor), linking HNS NKCC2 to chloride homeostasis and AVP neuron excitability. Immunohistochemistry; in vivo NKCC2 knockdown in HNS; physiological measurements (urine output, plasma osmolality); bumetanide treatment in vivo and in hypothalamic explants; electrophysiology of AVP neurons The Journal of neuroscience : the official journal of the Society for Neuroscience High 25834041
2015 IL-1 receptor activation potentiates sodium reabsorption via NKCC2 in angiotensin II-induced hypertension by preventing intra-renal myeloid cells from maturing into Ly6C+Ly6G- macrophages that produce nitric oxide (a natriuretic suppressor of NKCC2); IL-1R1 deficiency limits blood pressure elevation by reducing NKCC2-mediated sodium reabsorption. IL-1R1 knockout mice; angiotensin II infusion model; flow cytometry of renal immune cells; physiological measurements; IL-1R1 blockade Cell metabolism Medium 26712462
1998 NKCC2A (kidney-specific isoform) has distinct kinetic properties from NKCC1: 4-fold lower Rb+ (K+) affinity and 3-fold higher affinity for bumetanide; activity is increased in low-[Cl-] media but resting activity is higher than NKCC1; volume response is direct rather than mediated by [Cl-]i changes. Stable heterologous expression of NKCC2A in HEK-293 cells using NKCC1/NKCC2 chimera; ion affinity measurements; bumetanide inhibition assays; volume response assays; RT-PCR confirmation The Journal of biological chemistry High 9556622
2010 NKCC2 mutation (I299F) in mice causes severe polyuria, metabolic alkalosis, and other features of type I Bartter syndrome; the mutant NKCC2 shows decreased activity, establishing the amino acid I299 in the transmembrane domain as functionally critical. ENU-induced mutagenesis; homozygous Slc12a1(I299F) mouse phenotyping; metabolic measurements; urine analysis American journal of physiology. Renal physiology Medium 20219826
2014 NKCC2 is ubiquitinated and targeted for proteasomal degradation via Nedd4-2 E3 ubiquitin ligase in the context of high salt and elevated 20-HETE; inhibition of 20-HETE synthesis or proteasome activity reverses NKCC2 reduction. Co-immunoprecipitation of ubiquitin and Nedd4-2 with NKCC2; CYP4F2 transgenic mice on high-salt diet; proteasome inhibitor treatment; 20-HETE synthesis inhibitor Human genetics Medium 23104236
2016 Nitric oxide (NO)-induced inhibition of NKCC2 activity in thick ascending limbs operates via cGMP, and this pathway is impaired in angiotensin II-induced hypertension due to enhanced PDE5 (phosphodiesterase 5)-mediated cGMP degradation; PDE5 inhibition with vardenafil restores NO's ability to inhibit NKCC2 and elevate cGMP. Isolated perfused rat TALs; NO donor application; ET-1 stimulation; dibutyryl-cGMP; vardenafil (PDE5 inhibitor); cGMP measurements; NKCC2 activity (Cl- absorption) assays in vehicle vs. ANG II-infused rats American journal of physiology. Renal physiology High 26887831

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1984 Growth inhibitor from BSC-1 cells closely related to platelet type beta transforming growth factor. Science (New York, N.Y.) 778 6093254
1996 Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature genetics 711 8640224
2008 Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. Proceedings of the National Academy of Sciences of the United States of America 194 18550832
1996 Localization and regulation of the rat renal Na(+)-K(+)-2Cl- cotransporter, BSC-1. The American journal of physiology 183 8853424
2006 The Atx1-Ccc2 complex is a metal-mediated protein-protein interaction. Nature chemical biology 181 16732294
2000 Energetics of copper trafficking between the Atx1 metallochaperone and the intracellular copper transporter, Ccc2. The Journal of biological chemistry 173 10764731
1991 Microsurgical removal of centrosomes blocks cell reproduction and centriole generation in BSC-1 cells. Cell 173 1934057
2003 Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein. The Journal of biological chemistry 172 12732642
2011 Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways. Journal of cell science 161 21321328
1977 Density-dependent regulation of growth of BSC-1 cells in cell culture: control of growth by serum factors. Proceedings of the National Academy of Sciences of the United States of America 153 303774
2005 WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proceedings of the National Academy of Sciences of the United States of America 152 16275913
2002 Upregulation of renal BSC1 and TSC in prenatally programmed hypertension. American journal of physiology. Renal physiology 148 12060603
2011 Molecular regulation of NKCC2 in the thick ascending limb. American journal of physiology. Renal physiology 143 21900458
2011 Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner. The Journal of biological chemistry 142 21737451
1988 Amino acid sequence of the BSC-1 cell growth inhibitor (polyergin) deduced from the nucleotide sequence of the cDNA. Proceedings of the National Academy of Sciences of the United States of America 142 3277172
1995 Sequence, mapping and disruption of CCC2, a gene that cross-complements the Ca(2+)-sensitive phenotype of csg1 mutants and encodes a P-type ATPase belonging to the Cu(2+)-ATPase subfamily. Yeast (Chichester, England) 136 7785328
2015 Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron. Cell metabolism 123 26712462
1999 Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy. Lung cancer (Amsterdam, Netherlands) 114 10403690
1978 Density-dependent regulation of growth of BSC-1 cells in cell culture: growth inhibitors formed by the cells. Proceedings of the National Academy of Sciences of the United States of America 111 273914
1998 Comparison of Na-K-Cl cotransporters. NKCC1, NKCC2, and the HEK cell Na-L-Cl cotransporter. The Journal of biological chemistry 110 9556622
2005 Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2). American journal of physiology. Renal physiology 103 16077079
2013 Physiology and pathophysiology of SLC12A1/2 transporters. Pflugers Archiv : European journal of physiology 100 24097229
2002 Time course of renal Na-K-ATPase, NHE3, NKCC2, NCC, and ENaC abundance changes with dietary NaCl restriction. American journal of physiology. Renal physiology 100 12217855
2005 cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP. American journal of physiology. Renal physiology 96 16144963
2008 Thick ascending limb: the Na(+):K (+):2Cl (-) co-transporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Archiv : European journal of physiology 94 18982348
2010 Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models. Human molecular genetics 84 21131289
2012 Cotransport of water by Na⁺-K⁺-2Cl⁻ cotransporters expressed in Xenopus oocytes: NKCC1 versus NKCC2. The Journal of physiology 77 22250214
2007 Regulation of the renal-specific Na+-K+-2Cl- co-transporter NKCC2 by AMP-activated protein kinase (AMPK). The Biochemical journal 77 17341212
2009 cAMP stimulates apical exocytosis of the renal Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in the thick ascending limb: role of protein kinase A. The Journal of biological chemistry 73 19592485
1992 Mechanism of centrosome positioning during the wound response in BSC-1 cells. The Journal of cell biology 71 1740470
2008 Isoforms of renal Na-K-2Cl cotransporter NKCC2: expression and functional significance. American journal of physiology. Renal physiology 70 18495801
2012 Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC. The American journal of pathology 64 23123217
1985 Kidney epithelial cells of monkey origin (BSC-1) express a sodium bicarbonate cotransport. Characterization by 22Na+ flux measurements. The Journal of biological chemistry 64 2999122
1982 Serum and epidermal growth factor transiently depolarize quiescent BSC-1 epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 63 6984193
2002 Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats. American journal of physiology. Renal physiology 62 12388387
1992 Mutations within the 5' nontranslated region of hepatitis A virus RNA which enhance replication in BS-C-1 cells. Journal of virology 59 1404601
1987 Diphtheria toxin receptor. Identification of specific diphtheria toxin-binding proteins on the surface of Vero and BS-C-1 cells. The Journal of biological chemistry 52 3654609
2004 Elevated BSC-1 and ROMK expression in Dahl salt-sensitive rat kidneys. Hypertension (Dallas, Tex. : 1979) 50 14967839
2015 NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension. Genes & diseases 48 26114157
2011 Rare mutations in SLC12A1 and SLC12A3 protect against hypertension by reducing the activity of renal salt cotransporters. Journal of hypertension 48 21157372
2002 Renal Na-K-Cl cotransporter NKCC2 in Dahl salt-sensitive rats. Journal of hypertension 48 11910309
2011 High salt differentially regulates surface NKCC2 expression in thick ascending limbs of Dahl salt-sensitive and salt-resistant rats. American journal of physiology. Renal physiology 47 21307126
2003 Mutations in the human Na-K-2Cl cotransporter (NKCC2) identified in Bartter syndrome type I consistently result in nonfunctional transporters. Journal of the American Society of Nephrology : JASN 47 12761241
2011 A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo. Biology open 45 23213404
2003 Regulation of NHE3, NKCC2, and NCC abundance in kidney during aldosterone escape phenomenon: role of NO. American journal of physiology. Renal physiology 45 12837683
2012 Dynamin2, clathrin, and lipid rafts mediate endocytosis of the apical Na/K/2Cl cotransporter NKCC2 in thick ascending limbs. The Journal of biological chemistry 44 22977238
2009 A highly conserved motif at the COOH terminus dictates endoplasmic reticulum exit and cell surface expression of NKCC2. The Journal of biological chemistry 44 19535327
2001 Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. Current opinion in nephrology and hypertension 44 11496061
2012 Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Clinical and experimental nephrology 43 22294159
1997 Caenorhabditis elegans cDNA for a Menkes/Wilson disease gene homologue and its function in a yeast CCC2 gene deletion mutant. Journal of biochemistry 43 9354393
2011 Rare mutations in the human Na-K-Cl cotransporter (NKCC2) associated with lower blood pressure exhibit impaired processing and transport function. American journal of physiology. Renal physiology 42 21209010
1973 Synthesis of infective poliovirus in BSC-1 monkey cells enucleated with cytochalasin B. Science (New York, N.Y.) 42 4347169
2018 Pre-eclampsia is associated with altered expression of the renal sodium transporters NKCC2, NCC and ENaC in urinary extracellular vesicles. PloS one 40 30248150
2011 Tumor necrosis factor-alpha is an endogenous inhibitor of Na+-K+-2Cl- cotransporter (NKCC2) isoform A in the thick ascending limb. American journal of physiology. Renal physiology 40 21511694
1997 A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect. Journal of the American Society of Nephrology : JASN 40 9355073
2008 Treating lithium-induced nephrogenic diabetes insipidus with a COX-2 inhibitor improves polyuria via upregulation of AQP2 and NKCC2. American journal of physiology. Renal physiology 39 18216147
2006 Acute growth hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2. American journal of physiology. Renal physiology 39 17062845
2004 Increased expression of the sodium transporter BSC-1 in spontaneously hypertensive rats. The Journal of pharmacology and experimental therapeutics 39 15340004
2007 Ciclosporin-induced hypertension is associated with increased sodium transporter of the loop of Henle (NKCC2). Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 38 17595192
2006 The residues determining differences in ion affinities among the alternative splice variants F, A, and B of the mammalian renal Na-K-Cl cotransporter (NKCC2). The Journal of biological chemistry 38 17186942
2013 Dietary salt intake modulates differential splicing of the Na-K-2Cl cotransporter NKCC2. American journal of physiology. Renal physiology 37 23946287
2004 Reduced renal Na+-K+-Cl- co-transporter activity and inhibited NKCC2 mRNA expression by Leptospira shermani: from bed-side to bench. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 37 15388818
2009 In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation. Human genetics 36 19513753
2008 Expression of aquaporin1, 3, and 4, NKCC1, and NKCC2 in the human endolymphatic sac. Auris, nasus, larynx 36 18606512
1983 Rapid selective effects by a growth inhibitor and epidermal growth factor on the incorporation of [35S]methionine into proteins secreted by African green monkey (BSC-1) cells. Proceedings of the National Academy of Sciences of the United States of America 36 6604275
2007 NKCC2 surface expression in mammalian cells: down-regulation by novel interaction with aldolase B. The Journal of biological chemistry 35 17848580
2015 Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2. The Journal of neuroscience : the official journal of the Society for Neuroscience 34 25834041
2010 Localization and functional characterization of the human NKCC2 isoforms. Acta physiologica (Oxford, England) 34 20146722
2010 Mutation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia. American journal of physiology. Renal physiology 34 20219826
2003 Differential expression pattern of chloride transporters NCC, NKCC2, KCC1, KCC3, KCC4, and AE3 in the developing rat auditory brainstem. Cell and tissue research 34 12712325
1993 Synthesis and assembly of hepatitis A virus-specific proteins in BS-C-1 cells. Journal of virology 34 8388489
1978 Density-dependent regulation of growth of BSC-1 cells in cell culture: control of growth by low molecular weight nutrients. Proceedings of the National Academy of Sciences of the United States of America 34 272650
2010 Constitutive endocytosis and recycling of NKCC2 in rat thick ascending limbs. American journal of physiology. Renal physiology 32 20719977
2007 Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2. Clinical and experimental pharmacology & physiology 32 18177483
2006 Rosiglitazone regulates ENaC and Na-K-2Cl cotransporter (NKCC2) abundance in the obese Zucker rat. American journal of nephrology 31 16757903
2014 Vesicle-associated membrane protein 2 (VAMP2) but Not VAMP3 mediates cAMP-stimulated trafficking of the renal Na+-K+-2Cl- co-transporter NKCC2 in thick ascending limbs. The Journal of biological chemistry 30 25008321
2008 Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat. American journal of physiology. Renal physiology 30 18305093
2001 Essential role for NHERF in cAMP-mediated inhibition of the Na+-HCO3- co-transporter in BSC-1 cells. The Journal of biological chemistry 30 11535598
2016 Spilanthol from Acmella Oleracea Lowers the Intracellular Levels of cAMP Impairing NKCC2 Phosphorylation and Water Channel AQP2 Membrane Expression in Mouse Kidney. PloS one 29 27213818
2015 OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway. The Journal of biological chemistry 29 26721884
2014 Effects of NKCC2 isoform regulation on NaCl transport in thick ascending limb and macula densa: a modeling study. American journal of physiology. Renal physiology 29 24848496
2011 Secretory carrier membrane protein 2 regulates exocytic insertion of NKCC2 into the cell membrane. The Journal of biological chemistry 29 21205824
2010 MAL/VIP17, a new player in the regulation of NKCC2 in the kidney. Molecular biology of the cell 29 20861303
2014 Novel mechanisms of Na+ retention in obesity: phosphorylation of NKCC2 and regulation of SPAK/OSR1 by AMPK. American journal of physiology. Renal physiology 27 24808538
2012 Multiple evolutionarily conserved Di-leucine like motifs in the carboxyl terminus control the anterograde trafficking of NKCC2. The Journal of biological chemistry 26 23105100
2006 Sequential expression of NKCC2, TonEBP, aldose reductase, and urea transporter-A in developing mouse kidney. American journal of physiology. Renal physiology 26 16926446
1985 The KpnI family of long interspersed nucleotide sequences is present on discrete sizes of circular DNA in monkey (BSC-1) cells. Journal of molecular biology 26 2984431
2012 Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin-proteasome pathway. Human genetics 25 23104236
2009 Expression of NKCC2 in the rat gastrointestinal tract. Neurogastroenterology and motility 25 19460103
2016 Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. American journal of physiology. Renal physiology 24 26887831
2012 Expression of the Slc12a1 gene in pancreatic β-cells: molecular characterization and in silico analysis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 22759959
2011 Differential regulation of NFAT5 by NKCC2 isoforms in medullary thick ascending limb (mTAL) cells. American journal of physiology. Renal physiology 24 21228109
2007 Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Endocrine journal 24 17998760
2001 Alternative splicing of the BSC1 gene generates tissue-specific isoforms in the German cockroach. Insect biochemistry and molecular biology 24 11267908
2010 Differential regulation of the bumetanide-sensitive cotransporter (NKCC2) by ovarian hormones. Steroids 23 20580730
1996 Inhibition of initiation of simian virus 40 DNA replication in infected BSC-1 cells by the DNA alkylating drug adozelesin. The Journal of biological chemistry 23 8702695
2010 Integrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1-SLC12A1 fusion gene. Genes, chromosomes & cancer 22 20196086
2016 Association of Mutations in SLC12A1 Encoding the NKCC2 Cotransporter With Neonatal Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism 21 26963954
1994 The cloned human 5-HT1E receptor couples to inhibition and activation of adenylyl cyclase via two distinct pathways in transfected BS-C-1 cells. Neuropharmacology 21 7984278
2019 Molecular regulation of NKCC2 in blood pressure control and hypertension. Current opinion in nephrology and hypertension 20 31313674