Affinage

SLC9A2

Sodium/hydrogen exchanger 2 · UniProt Q9UBY0

Length
812 aa
Mass
91.5 kDa
Annotated
2026-04-28
69 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9A2 (NHE2) encodes an electroneutral, voltage-independent Na+/H+ exchanger that localizes predominantly to the apical membrane of intestinal, renal tubular, and gastric epithelial cells, where it mediates amiloride-sensitive sodium absorption coupled to proton extrusion (PMID:7685025, PMID:7494140, PMID:8772498). The transporter exhibits Michaelis-Menten kinetics for extracellular Na+ and cooperative activation by intracellular H+, with Leu-143 in the fourth transmembrane domain determining amiloride sensitivity and the first extracellular loop suppressing osmolarity-induced activation (PMID:8244989, PMID:8512555, PMID:12549930). NHE2 activity is inhibited by cAMP and Ca2+, transcriptionally regulated through Sp1, Egr-1, and NF-κB pathways, and the protein undergoes rapid lysosomal degradation (half-life ~3 h); its COOH-terminal cytoplasmic domain binds calmodulin and contains separable regulatory subdomains for growth factor and kinase signaling (PMID:10485997, PMID:10199818, PMID:11698263, PMID:20722069). In the kidney macula densa, NHE2 participates in tubuloglomerular feedback by regulating cell volume, with its loss activating an ERK1/2–COX-2–PGE2 axis that increases renin secretion (PMID:18287398).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1993 High

    Establishing that SLC9A2 encodes a functional Na+/H+ exchanger resolved the identity of a second epithelial NHE isoform distinct from NHE1, with apical targeting in polarized cells and a unique pharmacological profile including high resistance to ethylisopropylamiloride.

    Evidence Stable expression in NHE-deficient PS120 fibroblasts and AP-1 CHO cells with spectrofluorometric pH measurement, 22Na+ influx, and pharmacological profiling

    PMID:7683411 PMID:7685025 PMID:8244989 PMID:8394136

    Open questions at the time
    • Stoichiometry of Na+:H+ exchange not directly measured
    • No crystal structure to define ion translocation pathway
  2. 1993 High

    Identification of Leu-143 in the fourth transmembrane domain as the amiloride sensitivity determinant separated the drug-binding site from the Na+ transport site, establishing the first structure-function map for NHE2.

    Evidence Site-directed mutagenesis (L143F) in PS120-expressed NHE2 with pharmacological inhibition assays

    PMID:8512555

    Open questions at the time
    • No structural model to explain how L143 mediates amiloride binding
    • Other residues contributing to inhibitor sensitivity not mapped
  3. 1995 High

    Demonstrating that NHE2 transport is electroneutral and voltage-independent established the biophysical framework distinguishing mammalian NHEs from electrogenic bacterial homologs.

    Evidence Whole-cell patch clamp combined with microfluorimetric pH measurement in transfected CHO cells

    PMID:7494140

    Open questions at the time
    • Mechanism maintaining electroneutrality at the molecular level not defined
  4. 1996 High

    Localization of NHE2 to the apical brush border of intestinal villus cells and identification of hyperosmolarity-mediated inhibition distinguished its physiological context and regulation from NHE1.

    Evidence Western blot of fractionated membranes, immunohistochemistry in human/rabbit intestine; kinetic analysis under hyperosmolar conditions in PS120 cells with truncation mutants

    PMID:8638709 PMID:8772498

    Open questions at the time
    • Signaling intermediates linking hyperosmolarity to Vmax reduction unknown
    • Whether NHE2 localization is strictly apical or cell-type dependent was not settled
  5. 1997 High

    Mapping NHE2 expression to specific nephron segments (cortical and medullary thick ascending limbs, distal convoluted tubule, connecting tubule) defined renal epithelial contexts where NHE2 contributes to acid-base and Na+ homeostasis.

    Evidence Immunolabeling on rat kidney sections, RT-PCR on microdissected tubules, Western blot of membrane fractions

    PMID:9351894 PMID:9729510

    Open questions at the time
    • Relative contribution of NHE2 vs. other NHE isoforms to renal Na+ transport not quantified in vivo
  6. 1999 High

    Mapping the COOH-terminal regulatory architecture revealed separable subdomains for PMA, okadaic acid, and FGF stimulation, plus direct Ca2+-dependent calmodulin binding that tonically inhibits NHE2, establishing the cytoplasmic tail as an integrative regulatory platform.

    Evidence Systematic COOH-terminal truncation mutants in PS120 cells with second messenger stimulation; dansylated calmodulin binding to GST-fusion proteins

    PMID:10199818

    Open questions at the time
    • Phosphorylation sites mediating PMA and okadaic acid stimulation not identified
    • Structural basis for calmodulin-mediated inhibition unknown
  7. 1999 Medium

    Identification of a 45-residue apical targeting domain (731–777) that binds α-spectrin SH3 domain explained how NHE2 is retained at the apical surface rather than recycling through endosomes like NHE3.

    Evidence Deletion mutagenesis with polar expression assays in renal epithelial cells, in vitro SH3 binding

    PMID:10579058

    Open questions at the time
    • α-Spectrin interaction not confirmed in intact epithelium
    • Other apical retention factors not excluded
  8. 1999 High

    Demonstration that cAMP and Ca2+ inhibit NHE2 in intestinal C2/bbe cells, while phorbol ester does not, defined isoform-specific second messenger regulation relevant to secretory diarrhea pathophysiology.

    Evidence Unidirectional 22Na+ apical influx in stably transfected C2/bbe cells with kinetic analysis

    PMID:10485997

    Open questions at the time
    • Direct phosphorylation events mediating cAMP inhibition not identified
    • Whether regulation differs in native vs. transfected epithelia unclear
  9. 2001 High

    Discovery that NHE2 has a remarkably short plasma membrane half-life (~3 h) and is degraded via the lysosomal pathway established its rapid turnover as a distinctive regulatory property.

    Evidence Cell surface biotinylation pulse-chase in PS120 and Caco-2 cells with lysosome/proteasome inhibitors

    PMID:11698263

    Open questions at the time
    • Ubiquitination or sorting signals directing lysosomal degradation not identified
    • Whether half-life changes under physiological stimulation unknown
  10. 2001 High

    Identification of Sp1-dependent basal transcription from the NHE2 promoter, with Sp3 acting as a competitive repressor, established the transcriptional framework controlling constitutive NHE2 expression.

    Evidence Luciferase reporters, EMSA, and co-transfection in Sp1-null Drosophila SL2 cells

    PMID:11287330

    Open questions at the time
    • Chromatin context and epigenetic regulation of the NHE2 promoter not addressed
  11. 2002 High

    NHE2 knockout mice revealed that NHE3, not NHE2, is the dominant Na+ absorptive exchanger in small intestine, fundamentally redefining NHE2's physiological contribution as dispensable for net intestinal Na+/Cl− absorption under basal conditions.

    Evidence NHE2 and NHE3 single and double knockout mice with radioisotopic Na+/Cl− flux and acid-base measurements

    PMID:11705743 PMID:11960774

    Open questions at the time
    • NHE2's non-redundant role under stress or disease conditions not tested in this study
    • Compensatory upregulation of other transporters not fully assessed
  12. 2003 High

    Demonstrating that the first extracellular loop suppresses osmolarity-induced NHE2 activation (opposite to NHE1) resolved the structural basis for the paradoxical volume-sensitivity difference between apical and basolateral NHE isoforms.

    Evidence Chimeric NHE1/NHE2 exchangers and point mutations in PS120 cells with volume and pH measurements

    PMID:12549930

    Open questions at the time
    • Molecular sensor linking cell shrinkage to the extracellular loop not identified
    • Conformational mechanism not resolved
  13. 2008 High

    Discovery that NHE2 loss in macula densa cells activates ERK1/2–COX-2–PGE2 signaling and increases renin secretion established a non-absorptive role for NHE2 in tubuloglomerular feedback and blood pressure regulation.

    Evidence NHE2 knockout mice with renin immunohistochemistry, ERK1/2 phosphorylation, COX-2/mPGES expression, and MMDD1 cell NHE inhibition

    PMID:18287398

    Open questions at the time
    • Whether NHE2 loss in macula densa affects blood pressure long-term not measured
    • Direct measurement of PGE2 secretion from macula densa not performed
  14. 2008 High

    Functional coupling of NHE2 with the DRA Cl−/base exchanger via synaptotagmin I-dependent clathrin-mediated endocytosis revealed a coordinated apical ion transport module regulated by second messengers.

    Evidence 22Na+ and 36Cl− uptake in Caco2BBE cells with inducible DRA, pharmacological endocytosis pathway analysis

    PMID:19056765

    Open questions at the time
    • Direct physical interaction between NHE2 and DRA not demonstrated
    • Stoichiometry of the coupled transport not measured
  15. 2010 High

    Identification of NF-κB-mediated transcriptional repression of NHE2 by TNF-α provided a molecular mechanism for reduced Na+ absorption during intestinal inflammation.

    Evidence Reporter assays, EMSA, ChIP for p50/p65 at the NHE2 promoter, NF-κB inhibitors in C2BBe1 cells

    PMID:20722069

    Open questions at the time
    • In vivo validation of NF-κB repression of NHE2 during colitis not performed in this study
  16. 2011 High

    Delineation of the PKCδ→ERK1/2→Egr-1 transcriptional cascade for NHE2, combined with acid-induced Egr-1 binding to a GC-rich promoter element, integrated multiple stimulatory signals into a unified transcriptional regulatory model.

    Evidence siRNA knockdown, ChIP, reporter assays, pharmacological inhibitors in C2BBe1 and SK-CO15 cells

    PMID:22052014 PMID:24376510

    Open questions at the time
    • Whether Egr-1 regulation is specific to NHE2 or shared with other NHE isoforms not tested
  17. 2015 High

    Demonstrating that NHE2 mediates butyrate-dependent Na+ absorption specifically during colonic inflammation resolved a context-dependent, non-redundant absorptive role distinct from NHE3.

    Evidence Voltage-clamp Na+ flux in isolated rat colon with isoform-selective pharmacology (HOE694 vs. S3226) in DSS colitis model

    PMID:26350456

    Open questions at the time
    • Mechanism by which inflammation activates NHE2 not defined
    • Whether this role is relevant in human inflammatory bowel disease not established
  18. 2017 Medium

    NHE2 was shown to promote cell cycle progression in AQP2-expressing renal collecting duct cells through regulatory volume increase, linking NHE2 transport activity to proliferative control beyond its classical absorptive role.

    Evidence AQP2-transfected RCCD1 and mpkCCDc14 cells, NHE2 inhibition with cell cycle analysis

    PMID:27191152

    Open questions at the time
    • Molecular link between volume increase and cell cycle machinery not identified
    • In vivo relevance in collecting duct not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for NHE2 ion selectivity, the identity of phosphorylation sites governing second messenger regulation, and the in vivo significance of NHE2 in human renal and inflammatory bowel disease remain undefined.
  • No high-resolution structure of NHE2
  • Phosphorylation sites mediating cAMP, Ca2+, and PKC regulation not mapped
  • Human genetic loss-of-function data absent
  • In vivo role during inflammation not confirmed in human tissue

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6
Localization
GO:0005886 plasma membrane 6 GO:0005764 lysosome 1
Pathway
R-HSA-382551 Transport of small molecules 7 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3
Partners
CALM1SLC26A3SPTAN1SYT1ZDHHC3

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NHE2 (SLC9A2) encodes a functional Na+/H+ exchanger with 809 amino acids; stable expression in PS120 NHE-deficient fibroblasts confirmed amiloride-sensitive Na+-dependent intracellular alkalinization; NHE2 is 25-fold more resistant to ethylisopropylamiloride than NHE1; expression in Caco-2 cells results in apical membrane localization; serum activates NHE2. Stable transfection in PS120 fibroblasts, spectrofluorometric pH measurement, pharmacological profiling, expression in polarized Caco-2 cells The Journal of biological chemistry High 7685025
1993 NHE2 cloned from rat intestinal cDNA library encodes a transporter with 10 transmembrane domains; transfection into PS120 NHE-deficient fibroblasts reconstitutes functional Na+/H+ exchange activity. cDNA cloning, transfection into NHE-deficient PS120 cells, functional Na+/H+ exchange assay Proceedings of the National Academy of Sciences of the United States of America High 7683411
1993 Rat NHE2 stably expressed in NHE-deficient CHO (AP-1) cells shows Michaelis-Menten kinetics for extracellular Na+ (KNa ~50 mM), positive cooperative activation by intracellular H+ (pK ~6.90), and distinct pharmacological profile (EIPA K0.5=79 nM, amiloride K0.5=1.4 µM); Li+ and extracellular H+ act as competitive inhibitors of Na+ transport; K+ has no effect. Stable transfection in AP-1 CHO cells, 22Na+ influx assay, pharmacological and kinetic characterization The Journal of biological chemistry High 8244989
1993 Kinetic analysis of NHE2 expressed in PS120 cells shows Vmax of 24.7 nmol/µl ICW/min and Km of 33.1 mM for Na+; KI for amiloride is 0.15 µM and for EIPA is 0.66 µM; EGF stimulates NHE2 activity; the first two transmembrane domains of NHEs are not essential for amiloride-sensitive Na+ transport. Stable transfection in PS120 cells, 22Na+ influx assay, kinetic analysis Biochimica et biophysica acta High 8394136
1993 Leucine-143 in the fourth putative transmembrane domain of NHE2 is critical for amiloride and EIPA sensitivity; L143F substitution (mimicking NHE3) increases IC50 for amiloride 5-fold and EIPA 20-fold; these mutations do not alter Na+ affinity, indicating amiloride binding and Na+ transport sites are distinct. Site-directed mutagenesis of NHE2, stable expression in PS120 fibroblasts, pharmacological inhibition assays Biochemical and biophysical research communications High 8512555
1995 NHE1, NHE2, and NHE3 are electroneutral and voltage-independent transporters; patch-clamp combined with microfluorimetry in CHO cells transfected with each isoform showed no transmembrane currents during Na+/H+ exchange and pHi changes were independent of holding voltage. Whole-cell patch clamp combined with microfluorimetric pH measurement in transfected CHO cells The Journal of general physiology High 7494140
1996 NHE2 and NHE3 are localized to the brush-border (apical) but not basolateral membranes of villus epithelial cells in human and rabbit small intestine and colon, as determined by Western analysis of fractionated membranes and immunohistochemistry. Western blot of brush-border vs. basolateral membrane fractions, immunohistochemistry The American journal of physiology High 8772498
1996 Hyperosmolarity (450 mosmol/kg) reversibly inhibits NHE2 and NHE3 by reducing maximal velocity without altering Km for intracellular H+ or extracellular Na+; this effect is opposite to the stimulatory effect of hyperosmolarity on NHE1; the COOH-terminus of NHE2 (truncation mutant E2/499) is not required for hyperosmolar inhibition. Spectrofluorometric pH measurement in PS120 fibroblasts stably transfected with NHE2 or NHE3 and COOH-terminal truncation mutants The American journal of physiology High 8638709
1997 NHE2 protein (85 kDa) is localized to the apical membrane of cortical thick ascending limbs, distal convoluted tubules, and connecting tubules in rat kidney; absent in proximal tubule and collecting duct segments. Western blot of apical vs. basolateral membrane fractions, indirect immunolabeling on rat kidney sections The American journal of physiology High 9729510
1997 NHE2 mRNA and protein are expressed in the apical membrane of medullary thick ascending limb (MTAL) in mouse and rat kidney, demonstrated by RT-PCR on microdissected tubules and immunofluorescence. RT-PCR of microdissected MTAL, immunofluorescence, Western blot of renal outer medulla membranes The Journal of membrane biology High 9351894
1998 Under basal conditions, both NHE2 and NHE3 each contribute approximately 50% to ileal brush-border Na+/H+ exchange; glucocorticoids (methylprednisolone) selectively increase NHE3 activity (4.1-fold) and protein abundance without affecting NHE2 activity or protein levels. Radioisotopic 22Na+ flux in isolated rabbit ileal brush-border membranes, HOE-694 pharmacological separation of NHE2/NHE3 contributions, quantitative Western blot The American journal of physiology High 9612213
1998 NHE2 expressed in inner medullary collecting duct (mIMCD-3) cells is localized to the basolateral membrane; high osmolality (510 mosmol/L) stimulates Na+/H+ exchange activity and increases NHE2 mRNA; acidic media (pH 7.1) decreases NHE2 mRNA. 22Na+ uptake from apical vs. basolateral surface, Northern hybridization, osmolality manipulation The Journal of biological chemistry High 7961730
1999 The COOH terminus of NHE2 contains separate stimulatory regulatory subdomains: PMA stimulation requires residues 573–660; okadaic acid stimulation requires residues 540–573; FGF stimulation requires residues 499–540; FBS stimulates even the most truncated mutant (E2/499). Calmodulin binds directly to the last 87 amino acids of NHE2 in a Ca2+-dependent manner (Kd=300 nM, stoichiometry 1:1) and inhibits basal NHE2 activity. COOH-terminal truncation mutants stably expressed in PS120 fibroblasts, second messenger stimulation assays, dansylated calmodulin fluorescence binding assay with GST-fusion protein The American journal of physiology High 10199818
1999 A 45-residue region (residues 731–777) in the cytosolic domain of NHE2 is critical for apical targeting in renal epithelial cells; deletion of this region mistargeted NHE2 to the basolateral surface. This region binds the SH3 domain of α-spectrin in vitro. NHE2 is primarily at the plasma membrane (not recycling endosomes), unlike NHE3. Deletion mutagenesis, polar expression assays in renal epithelial cell line, in vitro SH3 binding assay Clinical and investigative medicine Medium 10579058
1999 NHE2 expressed in intestinal C2/bbe cells localizes to the apical membrane and is inhibited by cAMP and Ca2+ (via changes in both KNa and Vmax) but is unaffected by phorbol ester/PKC; in contrast, NHE3 is inhibited by all three pathways, with cAMP and Ca2+ acting only on Vmax and PKC affecting both Vmax and KNa. Stable transfection in C2/bbe intestinal epithelial cells, unidirectional 22Na+ apical influx assay under non-acid-loaded conditions The Journal of membrane biology High 10485997
1999 Human NHE2 (812 amino acids) expressed in NHE-deficient LAP1 cells catalyzes Na+-dependent pH recovery after acid load, inhibited by amiloride, confirming Na+/H+ exchange activity. Stable transfection in LAP1 NHE-deficient cells, pH recovery assay The American journal of physiology High 10444453
2000 Macula densa cells express NHE2 at the apical membrane (sensitive to EIPA IC50=0.86 µM, Hoechst 694 IC50=7.6 µM) and NHE4 at the basolateral membrane (EIPA IC50=9.0 µM, insensitive to osmolality activation); NHE2 and NHE4 participate in Na+ transport, pHi, and cell volume regulation in macula densa. Isolated perfused thick ascending limb with attached glomerulus, intracellular pH fluorescence microscopy, pharmacological profiling with EIPA and Hoechst 694, immunohistochemistry American journal of physiology. Renal physiology High 10710550
2001 Plasma membrane NHE2 has a short half-life of ~3 h compared to NHE1 (~24 h) and NHE3 (~14 h); NHE2 is degraded by lysosomes but not proteasomes; NHE2 activity is not affected by PI3-kinase inhibition and is not localized in the juxtanuclear recycling endosome, unlike NHE3. Cell surface biotinylation and pulse-chase in PS120 fibroblasts and Caco-2 cells, lysosome/proteasome inhibitors, PI3-kinase inhibitor treatment American journal of physiology. Cell physiology High 11698263
2001 NHE2 and NHE3 are localized to the brush border of human duodenal villus cells; luminal amiloride at concentrations inhibiting NHE2 (10^-5–10^-4 M) or NHE3 (10^-3 M) caused step-wise increases in net duodenal HCO3- output in vivo, indicating that NHE2 and NHE3 participate in duodenal bicarbonate transport. Immunolocalization with polyclonal antibodies, in vivo luminal perfusion with graded amiloride doses in humans American journal of physiology. Gastrointestinal and liver physiology Medium 11408268
2002 NHE3 is the dominant apical Na+/H+ exchanger for small intestinal Na+ absorption; NHE2 knockout mice show no reduction in net Na+ or Cl- absorption compared to wild-type; loss of NHE2 in NHE3-deficient mice causes no further impairment of acid-base status or worsening of diarrhea. NHE2 and NHE3 single and double knockout mice, radioisotopic Na+ and Cl- flux across isolated jejunum, systemic acid-base measurements American journal of physiology. Gastrointestinal and liver physiology High 11705743 11960774
2003 The putative first extracellular loop (residues 41–53) of NHE2 exerts an inhibitory influence on hyperosmolarity-induced activation; point mutations or replacement of this region with the corresponding NHE1 sequence rendered NHE2 responsive to cell shrinkage-induced activation (regulatory volume increase), demonstrating the membrane domain controls differential volume sensitivity between NHE1 and NHE2. Chimeric exchangers and point mutations expressed in PS120 cells, confocal microscopy of cell volume, spectrofluorometric pHi measurement Biochemistry High 12549930
2003 NHE2 is selectively expressed in the apical membrane of an immortalized TAL cell line (MKTAL); chronic (but not acute) nitric oxide donor exposure inhibits NHE2 activity and downregulates NHE2 mRNA. Immortalized TAL cell line, apical vs. basolateral pHi recovery assays, Western blot, mRNA analysis, NO donor treatment Pflugers Archiv : European journal of physiology Medium 12836026
2007 NHE2-CFP translocates to the plasma membrane in response to intracellular acidification, whereas NHE3-CFP translocates in response to extracellular Na+ removal; chimeric NHE2/NHE3 proteins showed the Na+-removal response resides in the NHE3 cytoplasmic tail, and the acidification response sequence is distinct and located in NHE2. NHE2-CFP and NHE3-CFP fusion proteins transiently expressed in PS120 cells, confocal morphometry with FM4-64 plasma membrane labeling, chimeric protein analysis Biochimica et biophysica acta High 17303069
2008 NHE2 activity mediates functional coupling with the DRA Cl-/base exchanger; transfection of NHE2 into Caco2BBE cells increased apical 36Cl- uptake; coupled NHE2/DRA activity was inhibited by elevated cAMP and calcium and was associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. 22Na+ and 36Cl- uptake assays in Caco2BBE cells, tet-off inducible DRA transgene, pharmacological inhibition, endocytosis pathway analysis American journal of physiology. Gastrointestinal and liver physiology High 19056765
2008 NHE2 at the macula densa apical membrane plays a role in tubuloglomerular feedback control of renin secretion; NHE2 knockout mice show ~2.5-fold increase in renin-expressing cells, elevated renal renin content and activity, and chronic activation of ERK1/2 in macula densa cells, with upregulation of COX-2 and mPGES, indicating MD cell shrinkage-ERK1/2-COX2-PGE2-renin signaling pathway. NHE2 knockout mice, renin immunohistochemistry, Western blot, ERK1/2 phosphorylation assay, COX-2/mPGES expression, NHE inhibitor treatment of MMDD1 cells American journal of physiology. Renal physiology High 18287398
2009 NHE2 alpha2-adrenergic receptor stimulation (via clonidine) promotes exocytosis of NHE2 to the apical surface and inhibits cAMP- and Ca2+-induced NHE2 endocytosis; the signaling pathway involves phospholipase C, arachidonic acid epoxygenase, EGF receptor transactivation, and PI3-kinase/Akt. Caco2-3B cells expressing human alpha2A-adrenergic receptor, 22Na+ uptake, apical surface NHE abundance by Western blot, pharmacological pathway dissection The Journal of pharmacology and experimental therapeutics Medium 19556451
2011 PMA activates NHE2 transcription via a PKCδ → MEK-ERK1/2 → Egr-1 signaling axis; PKCδ knockdown by siRNA or rottlerin blocked PMA-induced NHE2 promoter activity; ERK1/2 inhibition by U0126 abrogated Egr-1 expression and its nuclear translocation and interaction with the NHE2 promoter. siRNA knockdown, pharmacological inhibitors, reporter gene assay, immunofluorescence, chromatin immunoprecipitation in C2BBe1 cells American journal of physiology. Gastrointestinal and liver physiology High 22052014
2011 Uroguanylin reduces NHE2 activity at the apical membrane via a GC-C/cGMP-mediated pathway (enhanced by PDE5 inhibitor sildenafil), resulting in reduced Na+ absorption and increased net secretory fluid flow in T84 cells. Transepithelial fluid flow measurement by optic techniques, intracellular pH fluorescence, pharmacological inhibitors in T84 cells Cellular physiology and biochemistry Medium 22178885
2013 Extracellular acidosis induces NHE2 transcriptional upregulation through Egr-1; acid treatment increases Egr-1 mRNA and protein, promotes its nuclear accumulation, and potentiates Egr-1 binding to a GC-rich element (bp -337 to -323) in the NHE2 promoter; siRNA knockdown of Egr-1 abrogates acid-induced NHE2 transcriptional activity. RT-PCR, Western blot, reporter gene assay with deletion/mutation analysis, immunofluorescence, in vitro and in vivo protein-DNA interaction assays, Egr-1 siRNA in C2BBe1 and SK-CO15 cells PloS one High 24376510
2015 In DSS-induced colonic inflammation, NHE2 (not NHE3) mediates butyrate-dependent Na+ absorption; in normal colon NHE3 mediates both HCO3--dependent and butyrate-dependent Na+ absorption; inflammation activates NHE2 which mediates butyrate-dependent Na+ absorption, inhibited by HOE694 but not S3226. In vitro voltage-clamp Na+ flux in isolated rat colon, pharmacological inhibitors (HOE694 for NHE2, S3226 for NHE3), Western blot, DSS colitis model The Journal of biological chemistry High 26350456
2017 NHE2 expressed in gastric surface cells (RGM1) via lentiviral gene transfer increases steady-state pHi and reduces epithelial restitution velocity after low pH preincubation; pharmacological NHE2 inhibition reverses this effect, indicating NHE2 activity inhibits cell migration while NHE1 promotes it. Lentiviral NHE2 overexpression in RGM1 cells, DiR-based wound healing assay, pharmacological NHE inhibition, pH measurements Journal of cellular physiology Medium 28019659
2001 NHE2 transcription in renal mIMCD-3 cells is driven by two Sp1 binding sites in a minimal promoter (-36 to +116); Sp1 activates transcription >100-fold in Drosophila SL2 cells lacking endogenous Sp1, while Sp3 and Sp4 do not activate but repress Sp1-mediated transcription by competing for binding. Luciferase reporter assays, electrophoretic mobility shift assay (EMSA), mutagenesis, co-transfection in Drosophila SL2 cells, antisera supershift in mIMCD-3 cells American journal of physiology. Cell physiology High 11287330
2010 TNF-α represses NHE2 expression and activity via NF-κB activation; NF-κB subunits p50 and p65 bind a κB motif within bp -621 to -471 of the NHE2 promoter; mutation of this motif abolishes NF-κB-DNA interaction and abrogates TNF-α-induced repression; two NF-κB inhibitors block the inhibitory effect of TNF-α. Reporter gene assays, EMSA, ChIP, ectopic NF-κB overexpression, NF-κB inhibitors, 22Na uptake in C2BBe1 cells Inflammatory bowel diseases High 20722069
2024 zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma; zDHHC3 suppression decreases SLC9A2 expression and S-palmitoylation, which inhibits Caki-2 cell apoptosis. Bioinformatics, pan-cancer analysis, cell experiments with zDHHC3 suppression, detection of S-palmitoylation and SLC9A2 expression Journal of cancer research and clinical oncology Low 38619631
2017 NHE2 mediates a regulatory volume increase (RVI) mechanism that promotes cell cycle progression (S and G2/M phases) in AQP2-expressing renal collecting duct cells; NHE2 protein activity and expression are increased in AQP2-expressing cells, and NHE2 inhibition specifically reduces proliferation and delays cell cycle only when AQP2 is expressed. AQP2-transfected RCCD1 and mpkCCDc14 cell lines, NHE2 activity assay, cell cycle analysis, pharmacological NHE2 inhibition Journal of cellular biochemistry Medium 27191152

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. The American journal of physiology 242 8772498
1993 Cloning and expression of a rabbit cDNA encoding a serum-activated ethylisopropylamiloride-resistant epithelial Na+/H+ exchanger isoform (NHE-2). The Journal of biological chemistry 213 7685025
1993 Molecular cloning, sequencing, tissue distribution, and functional expression of a Na+/H+ exchanger (NHE-2). Proceedings of the National Academy of Sciences of the United States of America 128 7683411
2002 Intestinal NaCl transport in NHE2 and NHE3 knockout mice. American journal of physiology. Gastrointestinal and liver physiology 123 11960774
1993 Functional properties of the rat Na/H exchanger NHE-2 isoform expressed in Na/H exchanger-deficient Chinese hamster ovary cells. The Journal of biological chemistry 114 8244989
2001 IFN-gamma downregulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells. American journal of physiology. Cell physiology 103 11287336
2008 Branchial expression and localization of SLC9A2 and SLC9A3 sodium/hydrogen exchangers and their possible role in acid-base regulation in freshwater rainbow trout (Oncorhynchus mykiss). The Journal of experimental biology 95 18626081
1994 Na+/H+ exchanger isoforms NHE-2 and NHE-1 in inner medullary collecting duct cells. Expression, functional localization, and differential regulation. The Journal of biological chemistry 91 7961730
2005 Regulation of branchial V-H(+)-ATPase, Na(+)/K(+)-ATPase and NHE2 in response to acid and base infusions in the Pacific spiny dogfish (Squalus acanthias). The Journal of experimental biology 85 15634853
1998 Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. The American journal of physiology 73 9729510
2000 Macula densa Na(+)/H(+) exchange activities mediated by apical NHE2 and basolateral NHE4 isoforms. American journal of physiology. Renal physiology 72 10710550
2001 Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. American journal of physiology. Gastrointestinal and liver physiology 70 11705743
1997 Tissue distribution of Na+/H+ exchanger isoforms NHE2 and NHE4 in rat intestine and kidney. The American journal of physiology 68 9374634
2009 Cerebral microvascular endothelial cell Na/H exchange: evidence for the presence of NHE1 and NHE2 isoforms and regulation by arginine vasopressin. American journal of physiology. Cell physiology 66 19458287
1996 Hyperosmolarity inhibits the Na+/H+ exchanger isoforms NHE2 and NHE3: an effect opposite to that on NHE1. The American journal of physiology 63 8638709
1998 Quantitative contribution of NHE2 and NHE3 to rabbit ileal brush-border Na+/H+ exchange. The American journal of physiology 59 9612213
2008 Functional coupling of the downregulated in adenoma Cl-/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3. American journal of physiology. Gastrointestinal and liver physiology 54 19056765
1995 The mammalian Na+/H+ antiporters NHE-1, NHE-2, and NHE-3 are electroneutral and voltage independent, but can couple to an H+ conductance. The Journal of general physiology 53 7494140
1997 Na+/H+ exchanger isoform 2 (NHE2) is expressed in the apical membrane of the medullary thick ascending limb. The Journal of membrane biology 49 9351894
2001 Half-lives of plasma membrane Na(+)/H(+) exchangers NHE1-3: plasma membrane NHE2 has a rapid rate of degradation. American journal of physiology. Cell physiology 48 11698263
1999 Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2. The American journal of physiology 48 10444453
2000 NHE1, NHE2, and NHE3 contribute to regulation of intracellular pH in murine duodenal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 47 10666043
1998 Regulation of apical membrane Na+/H+ exchangers NHE2 and NHE3 in intestinal epithelial cell line C2/bbe. The American journal of physiology 45 9730953
2004 Effect of angiotensin-II on renal Na+/H+ exchanger-NHE3 and NHE2. Biochimica et biophysica acta 44 15238256
1993 Leu143 in the putative fourth membrane spanning domain is critical for amiloride inhibition of an epithelial Na+/H+ exchanger isoform (NHE-2). Biochemical and biophysical research communications 40 8512555
2007 NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells. Pflugers Archiv : European journal of physiology 39 17943310
2001 Human duodenal mucosal brush border Na(+)/H(+) exchangers NHE2 and NHE3 alter net bicarbonate movement. American journal of physiology. Gastrointestinal and liver physiology 39 11408268
2006 V-H(+)-ATPase, Na(+)/K(+)-ATPase and NHE2 immunoreactivity in the gill epithelium of the Pacific hagfish (Epatretus stoutii). Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 36 16945564
2002 Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function. American journal of physiology. Gastrointestinal and liver physiology 29 12065291
1999 Regulation and intracellular localization of the epithelial isoforms of the Na+/H+ exchangers NHE2 and NHE3. Clinical and investigative medicine. Medecine clinique et experimentale 28 10579058
1998 Increased NHE2 expression in rat intestinal epithelium during ontogeny is transcriptionally mediated. The American journal of physiology 28 9755068
2003 Evidence for involvement of the putative first extracellular loop in differential volume sensitivity of the Na+/H+ exchangers NHE1 and NHE2. Biochemistry 23 12549930
2000 Variant form of diffuse corporal gastritis in NHE2 knockout mice. Comparative medicine 23 11099134
2008 Increased renal renin content in mice lacking the Na+/H+ exchanger NHE2. American journal of physiology. Renal physiology 22 18287398
2001 The human Na(+)/H(+) exchanger NHE2 gene: genomic organization and promoter characterization. American journal of physiology. Gastrointestinal and liver physiology 22 11254504
1998 Molecular cloning and characterization of the rat NHE-2 gene promoter. Biochimica et biophysica acta 22 9804979
2013 Acidic conditions in the NHE2(-/-) mouse intestine result in an altered mucosa-associated bacterial population with changes in mucus oligosaccharides. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 21 24429819
2001 Transcriptional regulation of rat Na(+)/H(+) exchanger isoform-2 (NHE-2) gene by Sp1 transcription factor. American journal of physiology. Cell physiology 21 11287330
2010 Tumor necrosis factor-α represses the expression of NHE2 through NF-κB activation in intestinal epithelial cell model, C2BBe1. Inflammatory bowel diseases 20 20722069
2003 Differentiated thick ascending limb (TAL) cultured cells derived from SV40 transgenic mice express functional apical NHE2 isoform: effect of nitric oxide. Pflugers Archiv : European journal of physiology 20 12836026
2011 Uroguanylin regulates net fluid secretion via the NHE2 isoform of the Na/H+ exchanger in an intestinal cellular model. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 19 22178885
1999 Regulation of intestinal epithelial brush border Na(+)/H(+) exchanger isoforms, NHE2 and NHE3, in C2bbe cells. The Journal of membrane biology 19 10485997
1995 Molecular cloning, sequencing, chromosomal localization, and tissue distribution of the human Na+/H+ exchanger (SLC9A2). Genomics 19 8595899
1999 NHE2 contains subdomains in the COOH terminus for growth factor and protein kinase regulation. The American journal of physiology 18 10199818
1993 Kinetic characterization of a stably expressed novel Na+/H+ exchanger (NHE-2). Biochimica et biophysica acta 18 8394136
2017 Na+ /H+ exchanger NHE1 and NHE2 have opposite effects on migration velocity in rat gastric surface cells. Journal of cellular physiology 17 28019659
2002 Differential role of Na+/H+ exchange isoforms NHE-1 and NHE-2 in a rat cortical collecting duct cell line. The Journal of membrane biology 17 12474076
1999 Characterization of cis-elements required for osmotic response of rat Na(+)/H(+) exchanger-2 (NHE-2) gene. The American journal of physiology 17 10516252
2015 Na-H Exchanger Isoform-2 (NHE2) Mediates Butyrate-dependent Na+ Absorption in Dextran Sulfate Sodium (DSS)-induced Colitis. The Journal of biological chemistry 13 26350456
2011 PKCδ-dependent activation of ERK1/2 leads to upregulation of the human NHE2 transcriptional activity in intestinal epithelial cell line C2BBe1. American journal of physiology. Gastrointestinal and liver physiology 13 22052014
1996 Transient expression of Na+/H+ exchanger isoform NHE-2 in LLC-PK1 cells: inhibition of endogenous NHE-3 and regulation by hypertonicity. The Journal of membrane biology 13 8661513
2007 Sp1 and Sp3 mediate NHE2 gene transcription in the intestinal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 10 17379926
2007 Different ionic conditions prompt NHE2 and NHE3 translocation to the plasma membrane. Biochimica et biophysica acta 9 17303069
2005 Mammalian NHE2 Na(+)/H+ exchanger mediates efflux of potassium upon heterologous expression in yeast. FEBS letters 9 16098519
2010 Molecular identification of Na(+)-H(+) exchanger isoforms (NHE2) in the gills of the euryhaline teleost Fundulus heteroclitus. Journal of fish biology 8 20738718
2009 Alpha2-adrenergic receptors attenuate secretagogue-induced endocytosis and promote exocytosis of intestinal NHE2 and NHE3. The Journal of pharmacology and experimental therapeutics 8 19556451
2007 Sp1 and Sp3 control constitutive expression of the human NHE2 promoter by interactions with the proximal promoter and the transcription initiation site. The Biochemical journal 8 17561809
2024 zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma. Journal of cancer research and clinical oncology 7 38619631
2023 SLC9A2, suppressing by the transcription suppressor ETS1, restrains growth and invasion of osteosarcoma via inhibition of aerobic glycolysis. Environmental toxicology 7 37688782
2015 Cloning and characterization of Na(+)/H(+) Exchanger isoforms NHE2 and NHE3 from the gill of Pacific dogfish Squalus suckleyi. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 7 26112825
2013 Extracellular acidosis stimulates NHE2 expression through activation of transcription factor Egr-1 in the intestinal epithelial cells. PloS one 7 24376510
1995 The effect of lethal acid stress on Na+/H+ exchanger isoforms in cultured inner medullary collecting duct cells: deletion of NHE-2 and over expression of NHE-1. Biochimica et biophysica acta 7 7548147
2011 Loss of the NHE2 Na+/H+ exchanger in mice results in dilation of folliculo-stellate cell canaliculi. Journal of biomedicine & biotechnology 6 21274460
2000 Expression of rat, renal NHE2 and NHE3 during postnatal development. Biochimica et biophysica acta 6 10704915
2022 Role of the Basolateral Na+/H+ Exchanger-2 (NHE2) in Ionocytes of Seawater- Acclimated Medaka (Oryzias latipes). Frontiers in physiology 5 35399277
2017 AQP2-Induced Acceleration of Renal Cell Proliferation Involves the Activation of a Regulatory Volume Increase Mechanism Dependent on NHE2. Journal of cellular biochemistry 4 27191152
2025 Tumor suppressor SLC9A2 inhibits colorectal cancer metastasis and reverses immunotherapy resistance by suppressing angiogenesis. Journal of experimental & clinical cancer research : CR 2 40474298
2024 Drosophila Nhe2 overexpression induces autophagic cell death. Molecular biology of the cell 1 38696256
2009 Molecular cloning, tissue distribution and ontogenetic expression of sodium proton exchanger isoform 2 ( NHE-2) mRNA in the small intestine of pigs. Animal : an international journal of animal bioscience 1 22444311