Affinage

SLC9A3

Sodium/hydrogen exchanger 3 · UniProt P48764

Length
834 aa
Mass
92.9 kDa
Annotated
2026-04-28
100 papers in source corpus 50 papers cited in narrative 50 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9A3 encodes NHE3, the principal apical Na⁺/H⁺ exchanger of renal proximal tubule and intestinal brush-border epithelia, responsible for the bulk of transepithelial Na⁺, HCO₃⁻, and fluid reabsorption (PMID:9662405, PMID:11960774, PMID:32227118). NHE3 surface expression is dynamically regulated by clathrin-mediated endocytosis and PI3K/Akt2/ezrin-dependent exocytosis, with its cytoplasmic tail anchored to the actin cytoskeleton via direct ezrin FERM-domain binding and scaffolded by PDZ-domain adaptors NHERF1, NHERF2, and PDZK1 that organize inhibitory (cAMP/PKA, cGMP/PKG, PKCα, ERK) and stimulatory (SGK1-Ser663 phosphorylation, angiotensin II, SGLT1-coupled p38/MAPKAPK-2/Akt2 cascade) signaling inputs converging on NHE3 trafficking (PMID:9792717, PMID:15531580, PMID:15888551, PMID:16540524, PMID:21191106, PMID:16793766). Beyond vectorial ion transport, NHE3 maintains endosomal pH to support megalin/cubilin-mediated receptor endocytosis of filtered proteins in the proximal tubule (PMID:12167607, PMID:15113744). Recessive loss-of-function mutations in SLC9A3 cause congenital sodium diarrhea in humans (PMID:26358773).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1995 High

    An early mechanistic question was how NHE3 activity is upregulated by intracellular acidosis; experiments showed that acid-induced NHE3 activation requires src-family tyrosine kinases, establishing that NHE3 is not simply an autonomous acid sensor but is regulated by upstream signaling cascades.

    Evidence Csk overexpression and herbimycin A treatment in OKP cells blocked acid-induced NHE3 activation and c-src activation

    PMID:7541536

    Open questions at the time
    • Direct phosphorylation of NHE3 by src was not demonstrated
    • Whether src pathway is relevant in vivo was untested
  2. 1996 High

    Establishing where NHE3 operates required proof of polarized targeting; multiple methods demonstrated that NHE3 is exclusively apical in epithelial cells, and glucocorticoids stimulate NHE3 through transcriptional activation via a glucocorticoid response element in the NHE3 promoter.

    Evidence Biotinylation, confocal microscopy, and functional assays in polarized OK/MDCK cells confirmed apical restriction; reporter assays identified a GRE driving transcription in renal cells

    PMID:8631855 PMID:8743940 PMID:8769835 PMID:8772498

    Open questions at the time
    • Sorting signals for apical targeting were not identified
    • GRE identity and in vivo occupancy not confirmed by ChIP at the time
  3. 1998 High

    The functional importance of NHE3 was established definitively when NHE3 knockout mice showed severe reductions in proximal tubule HCO₃⁻/fluid reabsorption and intestinal Na⁺ absorption, with compensatory upregulation of distal nephron transporters, proving NHE3 is the dominant apical NHE isoform for bulk electrolyte reabsorption.

    Evidence Constitutive Slc9a3⁻/⁻ knockout mice with microperfusion, blood gas, and transporter expression analysis

    PMID:10444585 PMID:11960774 PMID:9662405

    Open questions at the time
    • Relative contributions of renal vs. intestinal NHE3 loss to the phenotype were unresolved until tissue-specific knockouts
  4. 1998 High

    A key question was how cAMP/PKA inhibits NHE3 with spatial specificity; discovery that PDZ-domain adaptors NHERF/E3KARP scaffold PKA type II near NHE3 via ezrin provided the first molecular mechanism for signal compartmentalization at the apical membrane.

    Evidence Co-immunoprecipitation of NHERF–NHE3–ezrin complex and functional cAMP-dependent inhibition assays in OK cells

    PMID:9792717

    Open questions at the time
    • Which specific PKA phosphorylation sites on NHE3 mediate inhibition was not resolved here
  5. 1999 High

    The endocytic route for NHE3 removal from the surface was identified as clathrin-mediated, using dominant-negative dynamin and multiple endocytosis-blocking strategies, establishing that NHE3 surface density is controlled by regulated endocytosis rather than passive turnover.

    Evidence Dominant-negative dynamin, hypertonic/acid block, K⁺ depletion, and ε-COP mutant cells with NHE3 internalization assays

    PMID:10608808

    Open questions at the time
    • Endocytic adaptor proteins linking NHE3 to clathrin were not identified
    • Role of ubiquitination in NHE3 endocytosis was unknown
  6. 1999 High

    Additional stimulatory and inhibitory signals were mapped: endothelin ETB receptors stimulate NHE3 via serine/threonine phosphorylation, thyroid hormone T3 stimulates NHE3 transcription, and PTH causes natriuresis by redistributing NHE3 from apical membranes to intracellular compartments via cAMP/PKA in vivo.

    Evidence Phosphoamino acid analysis for ETB; transcription run-on for T3; in vivo subcellular fractionation after PTH infusion in rats

    PMID:10199826 PMID:10330053 PMID:9886925

    Open questions at the time
    • Specific ETB-targeted phosphosites on NHE3 were not mapped
    • Mechanism of T3 receptor action on NHE3 promoter not determined
  7. 2000 High

    RhoA/ROCK and Gsα were identified as additional regulators: RhoA/ROCK supports basal NHE3 activity through actin/myosin organization, while Gsα directly co-associates with NHE3 to mediate dopamine D1 receptor inhibition independently of cytoplasmic second messengers.

    Evidence Dominant-negative RhoA and Y-27632 inhibitor for Rho pathway; brush-border membrane vesicle Co-IP for Gsα–NHE3

    PMID:10749796 PMID:10893221

    Open questions at the time
    • Direct Gsα–NHE3 binding domain was not mapped
    • Gβγ stimulatory mechanism was not dissected
  8. 2002 High

    NHE3 was shown to have a non-canonical role beyond vectorial ion transport: it acidifies endosomes to support megalin/cubilin receptor-mediated endocytosis of filtered proteins, and its loss abolishes cAMP sensitivity of endocytosis.

    Evidence NHE3-null and NHE3-reconstituted OK cells assayed for albumin uptake, endosomal pH, and cAMP-regulated endocytosis

    PMID:12167607 PMID:15113744

    Open questions at the time
    • Whether NHE3 directly acidifies sorting endosomes vs. recycling endosomes was unclear
    • Contribution to proteinuria in human NHE3 deficiency was unknown
  9. 2004 High

    A complete signaling cascade linking Na⁺-glucose cotransport (SGLT1) to NHE3 apical insertion was delineated: SGLT1 activity activates p38 MAPK → MAPKAPK-2 → Akt2, which directly phosphorylates ezrin-Thr567 to drive NHE3 exocytosis, revealing how postprandial nutrient absorption couples to salt absorption.

    Evidence In vitro Akt kinase assay on recombinant ezrin, Akt2-specific siRNA, p38 inhibitors, dominant-negative ezrin, and NHE3 translocation assays

    PMID:15197272 PMID:15531580 PMID:16793766

    Open questions at the time
    • How SGLT1 activity triggers p38 MAPK activation was not determined
    • Whether this cascade operates identically in kidney vs. intestine was untested
  10. 2005 High

    SGK1 was identified as the kinase mediating glucocorticoid stimulation of NHE3 by phosphorylating Ser663, resolving the acute nongenomic component of glucocorticoid action on NHE3 that precedes transcriptional effects.

    Evidence In vitro SGK1 kinase assay, S663A mutagenesis blocking dexamethasone-stimulated NHE3 activation

    PMID:15888551 PMID:16971495

    Open questions at the time
    • Whether SGK1-Ser663 phosphorylation is sufficient without other co-regulatory events was not established
  11. 2006 High

    The direct structural basis for NHE3–ezrin interaction was mapped to a juxtamembrane basic residue cluster (K516/R520/R527) binding ezrin's FERM domain III, and lipid raft integrity was shown to be required for NHE3 activity and basal endocytosis, placing NHE3 in cholesterol-enriched microdomains.

    Evidence Site-directed mutagenesis with FRAP, exo/endocytosis assays; methyl-β-cyclodextrin raft disruption with cholesterol rescue

    PMID:16540524 PMID:16648141

    Open questions at the time
    • Structural model of the NHE3–ezrin complex was lacking
    • Whether raft localization is regulated by signaling was not tested
  12. 2006 High

    TNF-induced diarrhea was mechanistically linked to PKCα-dependent NHE3 internalization from the brush border, and aldosterone was shown to inhibit NHE3 in the thick ascending limb nongenomically via rapid ERK activation, expanding the repertoire of inhibitory signals.

    Evidence PKCα knockout and inhibitor mice resisted TNF-induced NHE3 internalization; microperfused MTALs with MEK inhibitors blocked aldosterone's effect

    PMID:16757729 PMID:17016558

    Open questions at the time
    • PKCα substrate site(s) on NHE3 not identified
    • Whether ERK directly phosphorylates NHE3 was not tested
  13. 2007 High

    PKA phosphorylation of NHE3 at Ser552 and Ser605 was confirmed in vivo but shown NOT to directly alter transport activity, dissociating phosphorylation from inhibition and implying that trafficking (not intrinsic activity change) is the primary inhibitory mechanism.

    Evidence Phospho-specific antibodies with in vivo PTH infusion and in vitro forskolin; activity assays showed no correlation with phosphorylation state

    PMID:17409282

    Open questions at the time
    • The actual mechanism linking PKA phosphorylation to endocytic trafficking remains undefined
    • Additional PKA phosphosites may exist
  14. 2007 High

    PDZK1 (NHERF3) was established as a distinct scaffold required for cAMP- and Ca²⁺-mediated NHE3 inhibition in colon without affecting surface targeting, complementing NHERF1/2 roles and demonstrating tissue-specific scaffold utilization.

    Evidence PDZK1 knockout mice with fluorometric NHE3 activity in colonic crypts; direct binding of NHE3 aa 588–667

    PMID:17395628 PMID:19535329

    Open questions at the time
    • How three NHERF family members partition regulatory control in cells co-expressing them was unclear
  15. 2010 High

    Systematic NHERF1/NHERF2 knockdown in intestinal cells revealed non-redundant scaffold functions: NHERF1 is required for EGF stimulation and basal activity, NHERF2 for cGMP/Ca²⁺ inhibition, while either suffices for cAMP inhibition, establishing a scaffold code for signal-specific NHE3 regulation.

    Evidence Stable lentiviral shRNA knockdown of NHERF1/NHERF2 in Caco-2/bbe with second-messenger-specific NHE3 activity assays

    PMID:21191106

    Open questions at the time
    • Whether double NHERF1/2 knockout has additive or synergistic effects was not tested
    • Biochemical basis for signal-specific scaffold selectivity unknown
  16. 2015 High

    Three advances converged: CAII was shown to physically bind and catalytically activate NHE3; IRBIT was identified as a component of NHE3–NHERF1–ezrin macrocomplexes disrupted in diabetes and restored by insulin; and circadian clock protein Per1/CLOCK was found to directly bind and transcriptionally regulate the NHE3 promoter.

    Evidence Proximity ligation and CAII mutant assays; Co-IP of IRBIT–NHERF1–NHE3 in diabetic vs. insulin-treated mice; ChIP of Per1/CLOCK on NHE3 promoter

    PMID:26041446 PMID:26258413 PMID:26377793

    Open questions at the time
    • CAII binding site on NHE3 C-terminus not mapped to specific residues
    • Circadian oscillation of NHE3 protein and activity in vivo not quantified
  17. 2015 High

    Recessive SLC9A3 mutations were identified as a cause of congenital sodium diarrhea in humans, with functional studies confirming that disease-associated missense variants reduce surface expression and/or transport activity.

    Evidence Whole-exome sequencing of affected families plus functional validation of mutations in NHE-null fibroblasts

    PMID:26358773

    Open questions at the time
    • Genotype-phenotype correlations across mutation spectrum not established
    • Whether partial loss-of-function variants cause milder phenotypes is unknown
  18. 2019 High

    Tissue-specific knockouts dissected the individual contributions of renal and intestinal NHE3: renal NHE3 is required for blood pressure maintenance and mediates angiotensin II-induced hypertension downstream of AT1 receptors; intestinal NHE3 is independently essential for systemic acid-base and volume homeostasis.

    Evidence Proximal tubule-specific (SGLT2-Cre) and intestinal epithelial (inducible Villin-Cre) NHE3 knockouts with Ang II infusion, telemetry, and electrolyte analysis

    PMID:28385297 PMID:31352824 PMID:32227118

    Open questions at the time
    • Whether combined renal + intestinal NHE3 loss recapitulates the full constitutive knockout phenotype was not tested
  19. 2020 High

    The SGLT2 inhibitor empagliflozin was shown to inhibit NHE3, and its natriuretic effect was NHE3-dependent, revealing an unexpected pharmacological link between SGLT2 inhibition and NHE3 regulation that is relevant to cardiovascular protection in diabetes.

    Evidence Empagliflozin treatment in NHE3-knockout mice showed no natriuretic effect; enhanced NHE3-S552/S605 phosphorylation in diabetic Akita mice

    PMID:32893663

    Open questions at the time
    • Whether empagliflozin directly binds NHE3 or acts indirectly is unknown
    • Relative contribution of NHE3 inhibition vs. SGLT2 inhibition to empagliflozin's renal and cardiac benefits is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the atomic structure of NHE3 and how its large cytoplasmic domain integrates multiple scaffold and kinase inputs; the precise endocytic adaptor linking phosphorylated NHE3 to the clathrin machinery; and how the three NHERF scaffolds achieve signal-specific partitioning at the molecular level.
  • No high-resolution structure of NHE3
  • Endocytic adaptor for NHE3 clathrin-mediated internalization unidentified
  • Molecular basis for NHERF scaffold selectivity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-382551 Transport of small molecules 4
Partners
AKT2CA2EZRPDZK1SGK1SLC5A1SLC9A3R1SLC9A3R2
Complex memberships
NHE3–NHERF1–ezrin–IRBIT complexNHE3–PDZK1 complex

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NHE3 (encoded by Slc9a3) is the major absorptive Na+/H+ exchanger in kidney proximal tubule and intestinal epithelial apical membranes; deletion of NHE3 in mice causes sharply reduced HCO3- and fluid absorption in proximal convoluted tubules, severe intestinal absorptive defect, mild metabolic acidosis, reduced blood pressure, and compensatory upregulation of aldosterone, renin, AE1, colonic H+,K+-ATPase mRNA, and epithelial Na+ channel activity. Gene knockout mouse (Slc9a3-/-), in vivo microperfusion, blood analysis, Northern blot, immunohistochemistry Nature genetics High 9662405
1996 NHE3 is exclusively restricted to the apical membrane of polarized epithelial cells (and not the basolateral membrane), as demonstrated by functional Na+/H+ exchange measurements, immunofluorescence, confocal microscopy, and cell-surface biotinylation in OK and MDCK cells. Stable transfection, immunofluorescence, confocal microscopy, cell-surface biotinylation, functional NHE activity assays Journal of cell science High 8743940
1996 NHE2 and NHE3 are both present in brush-border but not basolateral membranes of small intestinal and colonic villus epithelial cells in humans and rabbits, as shown by Western analysis and immunohistochemistry. Western blot, immunohistochemistry on human and rabbit intestinal tissue The American journal of physiology High 8772498
1998 cAMP-mediated inhibition of NHE3 requires the PDZ-domain adapter proteins NHERF or E3KARP, which bind both NHE3 and ezrin (shown by co-immunoprecipitation), functioning as adapters that localize PKA type II near NHE3 to allow NHE3 phosphorylation; NHERF is phosphorylated basally but not after cAMP treatment, and E3KARP is not phosphorylated. Co-immunoprecipitation, in vivo phosphorylation studies, cAMP analog profiling, intracellular pH recovery assays in opossum kidney cells The Journal of biological chemistry High 9792717
1999 NHE3 undergoes endocytosis primarily via clathrin-coated pits and vesicles; inhibition of clathrin-mediated endocytosis (by hypertonicity, acid treatment, K+ depletion, or dominant-negative dynamin DynS45N) blocks NHE3 internalization; intracellular trafficking of NHE3 also involves an epsilon-COP-dependent step. Immunofluorescence, radiolabeling, dominant-negative dynamin transfection, ldlF temperature-sensitive epsilon-COP mutant cells, isolation of clathrin-coated vesicles from ileal villus cells The Journal of biological chemistry High 10608808
2000 PTH acutely inhibits NHE3 in a biphasic manner: early inhibition (5 min) is mediated by NHE3 phosphorylation on multiple serines; late inhibition (30 min) involves dynamin-dependent endocytosis of NHE3 from the surface, as blocking endocytic trafficking with dominant-negative dynamin K44A abrogates late but not early inhibition. Dominant-negative dynamin K44A transfection, cell-surface NHE3 antigen detection, NHE3 phosphorylation assays, intracellular pH recovery in opossum kidney cells The Journal of biological chemistry High 10866993
1999 In NHE3 null mice, the remaining proximal tubule HCO3- reabsorption is mediated by bafilomycin-sensitive H+-ATPase; NHE2 and other EIPA-sensitive NHE isoforms do not contribute to HCO3- reabsorption in the absence of NHE3, and H+-K+-ATPase activity is undetectable in proximal tubule. In situ microperfusion of proximal tubules in NHE3-/- vs. wild-type mice, pharmacological inhibitors (EIPA, bafilomycin, Sch-28080) The American journal of physiology High 10444585
2002 NHE3 is the dominant NHE isoform responsible for Na+ absorption in the small intestine; NHE3 knockout mice have markedly reduced net Na+ absorption in jejunum while NHE2 knockout mice do not, demonstrating isoform-specific roles. Radioisotopic Na+ and Cl- flux measurements across isolated jejuna from NHE2-/-, NHE3-/-, and wild-type mice; pharmacological inhibition with EIPA; quantitative RT-PCR American journal of physiology. Gastrointestinal and liver physiology High 11960774
1999 In vivo PTH administration causes natriuresis by redistributing NHE3 (and NaPi2) from apical membranes to intracellular fractions and inhibiting basolateral Na-K-ATPase; cAMP/PKA signaling is required for NHE3 internalization but not for Na-K-ATPase inhibition. In vivo PTH infusion in rats, subcellular membrane fractionation on sorbitol density gradients, immunodetection of NHE3, urinary cAMP measurement The American journal of physiology High 10330053
2000 NHERF (but not NHERF2) colocalizes with NHE3 and ezrin in the apical membrane of renal proximal tubule cells, forming a multiprotein signaling complex required for PKA-mediated inhibition of NHE3; NHERF2 colocalizes with ROMK in collecting duct. Immunocytochemistry with isoform-specific antibodies in rat kidney, colocalization analysis American journal of physiology. Cell physiology Medium 11121391
2003 Angiotensin II stimulates NHE3 activity by PI3-kinase-dependent exocytic insertion of NHE3 protein into the apical membrane (without changing total NHE3), and this requires actin cytoskeleton integrity. Cell surface biotinylation, 22Na uptake assays, AT1 receptor antagonists, wortmannin (PI3K inhibitor), latrunculin B (actin inhibitor) in proximal tubular MKCC cells Kidney international High 12911544
2004 Initiation of Na+-glucose cotransport (SGLT1 activity) triggers NHE3 translocation to the apical membrane via a pathway requiring p38 MAP kinase activation followed by ezrin phosphorylation at Thr567; dominant-negative ezrin blocks NHE3 recruitment and cytoplasmic pH increases. Dominant-negative ezrin construct, p38 MAP kinase inhibitors, live cell pH imaging, confocal microscopy of NHE3 distribution, ezrin phosphorylation assays in intestinal epithelial cells Proceedings of the National Academy of Sciences of the United States of America High 15197272
2004 Akt2 directly phosphorylates ezrin at Thr567 to trigger NHE3 translocation to the apical membrane; purified Akt phosphorylates recombinant ezrin in vitro; siRNA knockdown of Akt2 specifically prevents ezrin phosphorylation, NHE3 translocation, and NHE3 activation after Na+-glucose cotransport. In vitro kinase assay with purified Akt and recombinant ezrin, siRNA knockdown of Akt2, PI3K inhibitors, pharmacological Akt inhibitors, NHE3 translocation assay The Journal of biological chemistry High 15531580
2005 SGK1 phosphorylates NHE3 at Ser663, and this phosphorylation is the key mechanism for glucocorticoid (dexamethasone)-stimulated NHE3 activation; mutation of Ser663 to Ala blocks the dexamethasone effect; phosphorylation precedes increased NHE3 surface expression. In vitro SGK1 kinase assay, site-directed mutagenesis (S663A), cell surface NHE3 measurement, NHE3 activity assays American journal of physiology. Cell physiology High 15888551
2006 The NHE3 juxtamembrane cytoplasmic domain (aa 475-589) directly binds the FERM domain III of ezrin; a positive amino acid cluster (K516, R520, R527) is necessary for this binding; point mutations abolishing ezrin binding decrease NHE3 surface expression (by reducing exocytosis), decrease brush-border mobility, and reduce NHE3 activity. Direct binding assays, site-directed mutagenesis of NHE3 (K516Q, R520F, R527F), cell surface biotinylation, FRAP for mobility measurements, exo/endocytosis rate measurements Molecular biology of the cell High 16540524
2006 NHE3 activity and basal endocytosis require lipid raft integrity; ~50% of surface NHE3 resides in lipid rafts; disruption of lipid rafts with methyl-β-cyclodextrin decreases NHE3 activity (Vmax and K'H+i) and basal endocytosis rate without changing surface NHE3 amount; cholesterol repletion reverses these effects. Density gradient centrifugation, methyl-β-cyclodextrin treatment, cholesterol repletion, 22Na uptake assays, cell surface biotinylation in opossum kidney (OK) cells The Journal of biological chemistry High 16648141
2006 TNF-induced NHE3 internalization from the brush border is mediated by PKCα activation; pharmacological or genetic PKCα inhibition prevents NHE3 internalization, Na+ malabsorption, and diarrhea despite continued barrier dysfunction. In vivo mouse model of T cell-mediated diarrhea, PKCα inhibitors, PKCα genetic knockout, NHE3 localization by immunofluorescence The Journal of clinical investigation High 17016558
2000 RhoA and Rho-associated kinase (ROK/ROCK) are required for optimal NHE3 activity; dominant-negative RhoA or pharmacological ROK inhibition (Y-27632) depresses NHE3 activity; this pathway acts by controlling myosin light chain phosphorylation and actin cytoskeleton organization. Transient transfection of dominant-negative RhoA, Rac1, Cdc42; Y-27632 and dominant-negative ROK; myosin light chain phosphorylation assays; microfluorimetry of NHE3 activity The Journal of biological chemistry High 10893221
1999 ETB receptor activation by endothelin-1 increases NHE3 activity by phosphorylating NHE3 on multiple serine and threonine residues; phosphorylation precedes activity increases and is reversed by alkaline phosphatase; ETB but not ETA receptor mediates this phosphorylation. Immunoprecipitation of NHE3, phosphoamino acid analysis, alkaline phosphatase treatment, SDS-PAGE mobility shift, NHE3 activity (pHi recovery) in OKP cells expressing ETB or ETA receptors The American journal of physiology High 10199826
1995 Acid-induced activation of NHE3 requires src family non-receptor tyrosine kinases; overexpression of Csk (a physiological inhibitor of src kinases) inhibits acid-induced increases in NHE3 activity and NHE3 mRNA abundance; herbimycin A (tyrosine kinase inhibitor) blocks acid-induced NHE3 activation and c-src activation. Overexpression of Csk in OKP cells, herbimycin A treatment, c-src activity assays, pHi recovery assays for NHE3 activity Proceedings of the National Academy of Sciences of the United States of America High 7541536
2002 Acid-induced activation of NHE3 requires both c-Src and MEK/ERK pathways; dominant-negative c-Src (c-SrcK295M) prevents acid-induced NHE3 activation; MEK inhibitor PD98059 also blocks NHE3 activation by acid; the two pathways are activated independently. Dominant-negative c-Src transfection, MEK inhibitor PD98059, immune complex kinase assays for ERK, JNK, c-Src; pHi recovery assay for NHE3 activity Kidney international High 12081562
2002 NHE3 supports receptor-mediated endocytosis (RME) in proximal tubule cells and confers cAMP sensitivity to RME; NHE3 activity maintains endosomal pH homeostasis and is required for megalin/cubilin-mediated albumin uptake; NHE3-deficient cells lack cAMP sensitivity of RME. Cellular NHE3 knockout/retransfection, endosomal pH measurement, megalin-mediated albumin uptake assays, fluid-phase vs. receptor-mediated endocytosis comparison in opossum kidney cells American journal of physiology. Renal physiology High 12167607
2004 NHE3 supports proximal tubular receptor-mediated endocytosis of filtered proteins in vivo; NHE3 inhibition (by EIPA or S-3226) reduces fractional cytochrome c reabsorption ~50% during early proximal microperfusion; NHE3 knockout mice exhibit significantly higher urinary protein excretion. In vivo microinfusion with radiolabeled cytochrome c in rats, NHE3 pharmacological inhibitors, urinary protein analysis in NHE3-/- mice American journal of physiology. Renal physiology High 15113744
2007 PDZK1 (NHERF3) absence abolishes cAMP- and Ca2+-dependent inhibition of NHE3 in native colonic enterocytes without affecting NHE3 abundance or apical membrane targeting, or hyperosmolarity-induced inhibition; PDZK1 directly binds NHE3 C terminus (aa 588-667). PDZK1 knockout mice, fluorometric NHE3 activity assay in isolated colonic crypts, immunohistochemistry, Western blot, co-immunoprecipitation, in vitro binding assays The Journal of physiology High 17395628
2010 NHERF2 is necessary for cGMP- and Ca2+-dependent inhibition of NHE3; NHERF1 is necessary for EGF stimulation of NHE3; both NHERF1 and NHERF2 are required for cAMP-dependent inhibition (either alone is sufficient); NHERF1 knockdown reduces basal NHE3 activity while NHERF2 knockdown stimulates it. Stable lentiviral shRNA knockdown of NHERF1/NHERF2 in Caco-2/bbe cells, adenoviral NHE3 expression, second messenger-specific NHE3 activity assays American journal of physiology. Cell physiology High 21191106
1996 Glucocorticoid regulation of NHE3 is mediated by transcriptional activation; the NHE3 gene (Nhe3) 5'-regulatory region contains a functional glucocorticoid response element that drives reporter gene expression in renal epithelial cells treated with glucocorticoids. Genomic library screening, S1 nuclease protection, luciferase reporter assay in transiently transfected OK and LLC-PK1 cells The Journal of biological chemistry High 8631855
1996 Glucocorticoid-induced NHE3 activation is mediated by transcriptional upregulation of NHE3 gene; dexamethasone increases NHE3 mRNA abundance 2-3 fold via increased transcription rate (not mRNA stability), as shown by in vitro transcription and mRNA half-life experiments in OKP cells. Northern blot, mRNA half-life assay (actinomycin D chase), in vitro transcription run-on assay in OKP cells The American journal of physiology High 8769835
2000 G protein subunit Gsα mediates D1-like receptor-induced inhibition of NHE3 activity in renal brush-border membranes directly (independent of cytoplasmic second messengers); Gsα co-immunoprecipitates with NHE3 and co-precipitation increases with GTPγS and fenoldopam treatment; Gβγ dimers have a stimulatory effect on NHE3 activity. Renal brush-border membrane vesicle NHE3 activity assays, co-immunoprecipitation with anti-Gsα, anti-Giα, anti-Gβ antibodies, GTPγS/GDP loading American journal of physiology. Regulatory, integrative and comparative physiology Medium 10749796
2002 Nitric oxide inhibits NHE3 activity in Caco-2 cells via activation of soluble guanylate cyclase, leading to increased intracellular cGMP and activation of protein kinase G; this pathway is specific to NHE3 (not NHE2) and is independent of PKA and PKC. 22Na uptake assays, NO donors (SNAP, sodium nitroprusside), guanylate cyclase inhibitors (LY-83583, ODQ), 8-bromo-cGMP, PKG inhibitor KT-5823, PKA inhibitor Rp-cAMPS, PKC inhibitors American journal of physiology. Gastrointestinal and liver physiology High 12181191
2005 Flow-dependent modulation of proximal tubule HCO3- reabsorption involves NHE3 activity (in addition to H+-ATPase); flow-induced torque on brush-border microvilli regulates luminal transporter activity through an intact actin cytoskeleton; cytochalasin D (actin disruption) blocks flow-stimulated HCO3- transport. In vitro microperfusion of mouse S2 proximal tubules with EIPA, bafilomycin, cytochalasin D; mathematical modeling of microvillus torque; transepithelial PD measurement American journal of physiology. Renal physiology High 16144961
2009 Angiotensin II infusion causes NHE3 (and NaPi2, myosin VI, NHERF-1, ezrin, megalin) to redistribute into proximal tubule brush-border microvilli within 20 min; captopril (ACE inhibitor) causes the reverse redistribution; this trafficking increases PT salt reabsorption. In vivo ANG II and captopril infusion in rats, confocal microscopy, density gradient membrane fractionation of renal cortex American journal of physiology. Renal physiology High 19864301
2007 NHE3 phosphorylation at Ser552 and Ser605 by PKA is physiologically regulated in vivo and in vitro, but phosphorylation at these sites does not directly alter Na+/H+ exchange activity; phosphorylation clearly precedes transport inhibition, dissociating these events. In vivo PTH infusion in rats, forskolin/IBMX in OKP cells, phosphospecific monoclonal antibodies to pSer552 and pSer605, 22Na uptake and microvillar membrane vesicle NHE3 activity assays American journal of physiology. Renal physiology High 17409282
2006 Acute dexamethasone activation of NHE3 requires SGK1 kinase activity (not new protein synthesis) and a functional glucocorticoid receptor; the acute effect involves nongenomic GR-dependent SGK1 activation preceding NHE3 surface expression increases; chronic regulation (>12h) additionally requires protein synthesis. SGK1 kinase activity assays, cycloheximide/actinomycin D, glucocorticoid receptor blocker RU486, NHE3 protein surface expression and activity assays in Caco-2 and OKP cells American journal of physiology. Cell physiology High 16971495
2006 Aldosterone inhibits NHE3 and HCO3- absorption in the medullary thick ascending limb through a rapid, nongenomic pathway involving ERK activation; aldosterone activates ERK within 5 min in microdissected MTALs; MEK/ERK inhibitors prevent both ERK activation and NHE3 inhibition; this effect is independent of mineralocorticoid receptor transcriptional activity. In vitro microperfusion of rat MTALs, ERK activity assays in microdissected tubules, MEK inhibitors (U-0126, PD-98059), spironolactone, actinomycin D American journal of physiology. Renal physiology High 16757729
2001 Dopamine inhibits NHE3 activity via DA1 receptor activation of PKA (phosphorylating NHE3); DA2 receptors alone are insufficient to inhibit NHE3 but synergize with DA1 and alter NHE3 phosphorylation via distinct kinases/phosphatases; DA2 agonists phosphorylate NHE3 on different sites than DA1/PKA. NHE3 activity (pHi recovery), PKA/PKC inhibitors, DA1/DA2 specific agonists and antagonists, NHE3 immunoprecipitation and phosphorylation analysis in opossum kidney (OK) cells Kidney international High 11135072
2006 MAPKAPK-2 links p38 MAPK to Akt2 activation in the pathway coupling SGLT1 Na+-glucose cotransport to NHE3 translocation; MAPKAPK-2 can directly phosphorylate Akt2 in vitro; siRNA knockdown of MAPKAPK-2 inhibits Akt2 and ezrin phosphorylation and blocks NHE3 translocation. siRNA knockdown, in vitro kinase assay (MAPKAPK-2 phosphorylating Akt2-derived peptide), phosphorylation cascade analysis with inhibitors, NHE3 translocation assay The Journal of biological chemistry High 16793766
2009 NHE3 localizes predominantly to flotillin-enriched lipid raft domains in renal proximal tubule microvilli (84% of NHE3 in lipid rafts); hypertension redistributes NHE3 to the base of microvilli without changing its lipid raft partitioning; NaPi2 localizes to nonraft domains (69%) and traffics to endosomes under hypertension. Cold 1% Triton X-100 extraction, OptiPrep flotation gradients, confocal microscopy, arterial pressure manipulation in anesthetized rats American journal of physiology. Cell physiology Medium 19158399
2015 CAII (carbonic anhydrase II) physically binds the C-terminal domain of NHE3 (shown by proximity ligation assay and solid-phase binding assay) and activates NHE3 function; CAII-V143Y (catalytically inactive) and CAII-HEX (cannot bind transporters) mutants fail to activate NHE3, demonstrating that both CAII binding and catalytic activity are required. Proximity ligation assay, solid-phase binding assay with GST-fusion constructs, intracellular pH recovery assay, acetazolamide inhibition, co-expression of CAII mutants in proximal tubule cells American journal of physiology. Renal physiology High 26041446
2015 NHE3 forms macrocomplexes with NHERF1, IRBIT, and ezrin in the intestinal brush-border membrane; under diabetic conditions these macrocomplexes are disrupted; insulin restores NHE3 activity by reconstituting these macrocomplexes; IRBIT facilitates NHE3-NHERF1 interaction via PKD2-dependent phosphorylation; NHERF1 or IRBIT silencing prevents NHE3 trafficking to the brush-border membrane. Co-immunoprecipitation, siRNA silencing, insulin treatment of STZ-diabetic mice, surface expression assay, NHE3 activity measurement, PKD2 inhibition The Journal of clinical investigation High 26258413
2015 Recessive loss-of-function mutations in SLC9A3 (NHE3) cause congenital sodium diarrhea; missense mutations in the N-terminal transmembrane transport domain reduce basal surface expression and/or basal transport function without affecting acute regulation. Whole-exome sequencing, Sanger sequencing, functional characterization of missense mutations in NHE-null fibroblasts (surface expression and transport activity assays) Human molecular genetics High 26358773
2017 Constitutive tubule-specific NHE3 knockout mice (NHE3loxloxCre) show that renal NHE3 is required for blood pressure maintenance and steady-state plasma sodium when dietary NaCl is modified; loss of renal NHE3 blunts Npt2c expression and alters NCC phosphorylation and ENaC abundance. Tubule-specific Cre-lox knockout, telemetric blood pressure measurement, dietary NaCl challenge, immunoblotting of downstream transporters Kidney international High 28385297
2015 The circadian clock protein Per1 transcriptionally regulates NHE3 and SGLT1 in renal proximal tubule cells; Per1 and CLOCK are detected at the NHE3 promoter by ChIP; blockade of nuclear Per1 entry reduces NHE3 mRNA, protein (membrane and intracellular), and is associated with reduced Na+-K+-ATPase activity. Pharmacological Per1 nuclear entry blockade, Per1 siRNA, quantitative RT-PCR, heterogeneous nuclear RNA analysis, chromatin immunoprecipitation (ChIP), immunoblotting in HK-2 cells and mouse renal cortex American journal of physiology. Renal physiology High 26377793
2017 SLC9A3 (NHE3) loss in the male reproductive tract causes obstructive azoospermia; CFTR protein expression is dramatically decreased in epididymis and vas deferens of Slc9a3 knockout mice, indicating interdependence between NHE3 and CFTR expression in the male excurrent duct epithelium. Slc9a3 knockout mouse model, immunoblotting, immunohistochemistry, electron microscopy of epididymis/vas deferens epithelium PLoS genetics Medium 28384194
2019 Proximal tubule-specific NHE3 deletion (PT-Nhe3-/-) attenuates Ang II-induced hypertension and improves pressure-natriuresis response; Ang II hypertension is completely blocked by AT1 receptor antagonism in both WT and PT-Nhe3-/- mice, placing NHE3 downstream of AT1 receptor signaling in proximal tubule. SGLT2-Cre/Nhe3loxlox proximal tubule-specific knockout, Ang II infusion (high and slow pressor), telemetric blood pressure, pharmacological AT1 blockade with losartan, NHE3 inhibitor AVE0657 Hypertension (Dallas, Tex. : 1979) High 31352824
2020 Intestinal epithelial cell-specific inducible NHE3 knockout (NHE3IEC-KO) mice develop watery alkaline diarrhea, metabolic acidosis, hyponatremia, hyperkalemia, and markedly elevated aldosterone, demonstrating that intestinal NHE3 is essential for acid-base, Na+, and volume homeostasis. Tamoxifen-inducible intestinal epithelial cell-specific Cre-lox knockout, blood gas analysis, electrolyte measurements, aldosterone measurement, intestinal histology Clinical science (London, England : 1979) High 32227118
2009 NHE3 is present on the apical membrane of rat cholangiocytes; NHE3-/- mouse bile duct units fail to absorb secreted fluid after forskolin stimulation, establishing a functional role for NHE3 in cholangiocyte fluid absorption. Immunocytochemistry, Western blot, isolated bile duct unit videomicroscopy in NHE3-/- mice, NHE inhibitor EIPA American journal of physiology. Gastrointestinal and liver physiology High 11208547
2009 NHERF3/PDZK1 directly binds NHE3 C-terminus (aa 588-667) in vitro and co-localizes with NHE3 at brush border in vivo (Co-IP, FRET); elevated [Ca2+]i dissociates NHE3-NHERF3 complexes and inhibits NHE3 Vmax; NHERF3 shRNA knockdown reduces basal NHE3 activity and brush-border NHE3 amount in Caco-2BBe cells. In vitro binding assay with C-terminal NHE3 fragments, co-immunoprecipitation, FRET, confocal microscopy, shRNA knockdown, Ca2+ ionophore treatment, NHE3 surface expression assay The Journal of biological chemistry High 19535329
1999 Thyroid hormone (T3) stimulates NHE3 activity by transcriptional activation of the NHE3 gene, increasing NHE3 mRNA and protein abundance; T3 has no effect on NHE3 mRNA stability or protein stability/translation, and requires de novo transcription and translation. NHE3 activity assays, transcription/translation inhibitors (actinomycin D, cycloheximide), NHE3 mRNA stability assay, run-on transcription, surface and total NHE3 protein measurement, constitutive promoter-driven NHE3 construct as control The American journal of physiology High 9886925
2004 D3 dopamine receptor-mediated inhibition of NHE3 in SHR proximal tubular cells requires Giα3 protein coupling and is transduced via PLC-PKC pathway (not PKA); pertussis toxin, PLC inhibitor U-73122, and PKC downregulation all block the D3-mediated NHE3 inhibition; elevated intracellular Ca2+ modulates this pathway. Isoform-specific G protein antibody pretreatment, pertussis toxin, cholera toxin, PLC inhibitor, PKC inhibitors/downregulation, NHE3 activity assays in SHR proximal tubule cells American journal of physiology. Renal physiology Medium 15265766
2020 Empagliflozin (SGLT2 inhibitor) inhibits proximal tubular NHE3 activity and its natriuretic effect depends on tubular NHE3; empagliflozin had no natriuretic effect in NHE3-ko mice; in diabetic Akita mice, empagliflozin enhanced NHE3 phosphorylation at S552/S605, linked to reduced NHE3 reabsorption. Tubule-specific NHE3 knockdown mice, urinary electrolyte measurement, urine pH, empagliflozin treatment, phospho-NHE3 immunoblotting American journal of physiology. Renal physiology High 32893663

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nature genetics 669 9662405
1996 NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. The American journal of physiology 242 8772498
1998 The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3. The Journal of biological chemistry 178 9792717
2006 Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. The Journal of clinical investigation 168 17016558
2020 A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. American journal of physiology. Renal physiology 162 32893663
1999 Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. The American journal of physiology 139 10444585
2002 Intestinal NaCl transport in NHE2 and NHE3 knockout mice. American journal of physiology. Gastrointestinal and liver physiology 123 11960774
2001 Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. American journal of physiology. Cell physiology 115 11121391
2010 Physiological relevance of cell-specific distribution patterns of CFTR, NKCC1, NBCe1, and NHE3 along the crypt-villus axis in the intestine. American journal of physiology. Gastrointestinal and liver physiology 108 21030607
2015 Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Human molecular genetics 107 26358773
1996 Differential localization of Na+/H+ exchanger isoforms (NHE1 and NHE3) in polarized epithelial cell lines. Journal of cell science 106 8743940
2000 Signal complex regulation of renal transport proteins: NHERF and regulation of NHE3 by PKA. American journal of physiology. Renal physiology 100 10966919
2000 Acute regulation of Na+/H+ exchanger NHE3 by parathyroid hormone via NHE3 phosphorylation and dynamin-dependent endocytosis. The Journal of biological chemistry 99 10866993
1999 The epithelial Na(+)/H(+) exchanger, NHE3, is internalized through a clathrin-mediated pathway. The Journal of biological chemistry 91 10608808
1995 Acid incubation increases NHE-3 mRNA abundance in OKP cells. The American journal of physiology 87 7631739
2014 Human Clostridium difficile infection: inhibition of NHE3 and microbiota profile. American journal of physiology. Gastrointestinal and liver physiology 84 25552580
2006 Expression of SLC26A3, CFTR and NHE3 in the human male reproductive tract: role in male subfertility caused by congenital chloride diarrhoea. Molecular human reproduction 81 16421216
2004 Ezrin regulates NHE3 translocation and activation after Na+-glucose cotransport. Proceedings of the National Academy of Sciences of the United States of America 79 15197272
2004 Akt2 phosphorylates ezrin to trigger NHE3 translocation and activation. The Journal of biological chemistry 78 15531580
1999 ETB receptor activation leads to activation and phosphorylation of NHE3. The American journal of physiology 77 10199826
2008 Intracellular ANG II directly induces in vitro transcription of TGF-beta1, MCP-1, and NHE-3 mRNAs in isolated rat renal cortical nuclei via activation of nuclear AT1a receptors. American journal of physiology. Cell physiology 75 18256274
2006 The NHE3 juxtamembrane cytoplasmic domain directly binds ezrin: dual role in NHE3 trafficking and mobility in the brush border. Molecular biology of the cell 75 16540524
2006 Na+/H+ exchanger NHE3 activity and trafficking are lipid Raft-dependent. The Journal of biological chemistry 75 16648141
2005 NHE3 in an ancestral vertebrate: primary sequence, distribution, localization, and function in gills. American journal of physiology. Regulatory, integrative and comparative physiology 74 15994375
2021 Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure. Journal of the American Society of Nephrology : JASN 73 33846238
2010 Mechanisms of the regulation of the intestinal Na+/H+ exchanger NHE3. Journal of biomedicine & biotechnology 72 20011065
1999 In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition. The American journal of physiology 72 10330053
2003 Angiotensin II stimulates NHE3 activity by exocytic insertion of the transporter: role of PI 3-kinase. Kidney international 67 12911544
2004 The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation. American journal of physiology. Gastrointestinal and liver physiology 66 14962844
1997 Functional and molecular characterization of NHE3 expression during ontogeny in rat jejunal epithelium. The American journal of physiology 66 9435499
1996 Genomic organization and glucocorticoid transcriptional activation of the rat Na+/H+ exchanger Nhe3 gene. The Journal of biological chemistry 66 8631855
2009 Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli. American journal of physiology. Renal physiology 64 19864301
2007 NHE3 phosphorylation at serines 552 and 605 does not directly affect NHE3 activity. American journal of physiology. Renal physiology 64 17409282
2005 Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments. American journal of physiology. Renal physiology 63 16144961
2002 Altered expression of renal NHE3, TSC, BSC-1, and ENaC subunits in potassium-depleted rats. American journal of physiology. Renal physiology 62 12388387
2005 Activation of NHE3 by dexamethasone requires phosphorylation of NHE3 at Ser663 by SGK1. American journal of physiology. Cell physiology 61 15888551
2017 Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis. Kidney international 60 28385297
2006 Acute activation of NHE3 by dexamethasone correlates with activation of SGK1 and requires a functional glucocorticoid receptor. American journal of physiology. Cell physiology 60 16971495
1998 Quantitative contribution of NHE2 and NHE3 to rabbit ileal brush-border Na+/H+ exchange. The American journal of physiology 59 9612213
2000 RhoA and rho kinase regulate the epithelial Na+/H+ exchanger NHE3. Role of myosin light chain phosphorylation. The Journal of biological chemistry 58 10893221
2019 Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice. American journal of physiology. Renal physiology 57 31166707
2003 Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 56 12649600
1996 Role of tyrosine kinase pathways in ETB receptor activation of NHE3. The American journal of physiology 56 8843705
2015 Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells. American journal of physiology. Renal physiology 55 26377793
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
2007 NHE3 inhibition by cAMP and Ca2+ is abolished in PDZ-domain protein PDZK1-deficient murine enterocytes. The Journal of physiology 54 17395628
2002 Role of c-SRC and ERK in acid-induced activation of NHE3. Kidney international 54 12081562
2004 NHE3 Na+/H+ exchanger supports proximal tubular protein reabsorption in vivo. American journal of physiology. Renal physiology 53 15113744
2000 Regulation of NHE3 activity by G protein subunits in renal brush-border membranes. American journal of physiology. Regulatory, integrative and comparative physiology 53 10749796
1997 Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney international 52 9083276
1995 Overexpression of csk inhibits acid-induced activation of NHE-3. Proceedings of the National Academy of Sciences of the United States of America 52 7541536
2004 Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine. American journal of physiology. Regulatory, integrative and comparative physiology 50 15550620
2002 Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. American journal of physiology. Gastrointestinal and liver physiology 49 12181169
2019 Proximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice. Hypertension (Dallas, Tex. : 1979) 48 31352824
2010 NHERF1 and NHERF2 are necessary for multiple but usually separate aspects of basal and acute regulation of NHE3 activity. American journal of physiology. Cell physiology 48 21191106
2002 Transcriptional regulation of the rat NHE3 gene. Functional interactions between GATA-5 and Sp family transcription factors. The Journal of biological chemistry 48 12464626
2006 Aldosterone stimulates activity and surface expression of NHE3 in human primary proximal tubule epithelial cells (RPTEC). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 47 16543718
2002 Regulation of NHE3 by nitric oxide in Caco-2 cells. American journal of physiology. Gastrointestinal and liver physiology 47 12181191
2015 Caffeine-induced diuresis and natriuresis is independent of renal tubular NHE3. American journal of physiology. Renal physiology 46 25925253
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
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
2009 Tethering, recycling and activation of the epithelial sodium-proton exchanger, NHE3. The Journal of experimental biology 44 19448073
2001 Characterization of acute inhibition of Na/H exchanger NHE-3 by dopamine in opossum kidney cells. Kidney international 44 11135072
2001 Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. Current opinion in nephrology and hypertension 44 11496061
2000 Immunolocalization of NBC3 and NHE3 in the rat epididymis: colocalization of NBC3 and the vacuolar H+-ATPase. Journal of andrology 44 10975418
1996 Characterization of the rat NHE3 promoter. The American journal of physiology 44 8853425
2005 Cardiac glycoside downregulates NHE3 activity and expression in LLC-PK1 cells. American journal of physiology. Renal physiology 43 16352745
2001 Regulation of the rat NHE3 gene promoter by sodium butyrate. American journal of physiology. Gastrointestinal and liver physiology 43 11557515
2015 Carbonic anhydrase II binds to and increases the activity of the epithelial sodium-proton exchanger, NHE3. American journal of physiology. Renal physiology 42 26041446
2015 Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss. The Journal of clinical investigation 42 26258413
2014 Local pH domains regulate NHE3-mediated Na⁺ reabsorption in the renal proximal tubule. American journal of physiology. Renal physiology 41 25298526
2012 Berberine increases the expression of NHE3 and AQP4 in sennosideA-induced diarrhoea model. Fitoterapia 41 22668974
2009 Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT1 receptor blockade. American journal of physiology. Renal physiology 41 19776175
2006 Aldosterone inhibits apical NHE3 and HCO3- absorption via a nongenomic ERK-dependent pathway in medullary thick ascending limb. American journal of physiology. Renal physiology 40 16757729
2001 Role of sodium/hydrogen exchanger isoform NHE3 in fluid secretion and absorption in mouse and rat cholangiocytes. American journal of physiology. Gastrointestinal and liver physiology 40 11208547
2009 Renal NHE3 and NaPi2 partition into distinct membrane domains. American journal of physiology. Cell physiology 39 19158399
1999 Thyroid hormone stimulates the renal Na/H exchanger NHE3 by transcriptional activation. The American journal of physiology 39 9886925
2010 Modulatory effect of the SLC9A3 gene on susceptibility to infections and pulmonary function in children with cystic fibrosis. Pediatric pulmonology 38 20967843
2017 Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice. PLoS genetics 37 28384194
2007 The acid-activated signaling pathway: starting with Pyk2 and ending with increased NHE3 activity. Kidney international 37 17882150
2001 D(1) dopamine receptor regulation of NHE3 during development in spontaneously hypertensive rats. American journal of physiology. Regulatory, integrative and comparative physiology 37 11353667
2001 Acute regulation of NHE3 by protein kinase A requires a multiprotein signal complex. Kidney international 36 11473625
2008 The epithelial brush border Na+/H+ exchanger NHE3 associates with the actin cytoskeleton by binding to ezrin directly and via PDZ domain-containing Na+/H+ exchanger regulatory factor (NHERF) proteins. Clinical and experimental pharmacology & physiology 35 18430067
2004 Gialpha3 protein-coupled dopamine D3 receptor-mediated inhibition of renal NHE3 activity in SHR proximal tubular cells is a PLC-PKC-mediated event. American journal of physiology. Renal physiology 35 15265766
2002 NHE3 serves as a molecular tool for cAMP-mediated regulation of receptor-mediated endocytosis. American journal of physiology. Renal physiology 35 12167607
2012 NHE3 regulatory factor 1 (NHERF1) modulates intestinal sodium-dependent phosphate transporter (NaPi-2b) expression in apical microvilli. The Journal of biological chemistry 34 22904329
2012 Novel signaling mechanisms of intracellular angiotensin II-induced NHE3 expression and activation in mouse proximal tubule cells. American journal of physiology. Renal physiology 34 23034941
2020 An inducible intestinal epithelial cell-specific NHE3 knockout mouse model mimicking congenital sodium diarrhea. Clinical science (London, England : 1979) 33 32227118
2017 Association of clinical severity of cystic fibrosis with variants in the SLC gene family (SLC6A14, SLC26A9, SLC11A1 and SLC9A3). Gene 33 28756021
2007 Molecular mechanism of rat NHE3 gene promoter regulation by sodium butyrate. American journal of physiology. Cell physiology 33 17344314
1996 Glucocorticoids regulate NHE-3 transcription in OKP cells. The American journal of physiology 33 8769835
2012 Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice. PloS one 32 22848392
2012 Fructose acutely stimulates NHE3 activity in kidney proximal tubule. Kidney & blood pressure research 32 23235337
2009 NHERF3 (PDZK1) contributes to basal and calcium inhibition of NHE3 activity in Caco-2BBe cells. The Journal of biological chemistry 32 19535329
1999 HCO-3 reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response. The American journal of physiology 32 10362780
2006 MAPKAPK-2 is a critical signaling intermediate in NHE3 activation following Na+-glucose cotransport. The Journal of biological chemistry 31 16793766
2003 Aldosterone stimulates surface expression of NHE3 in renal proximal brush borders. Pflugers Archiv : European journal of physiology 31 12684793
2001 S3226, a novel NHE3 inhibitor, attenuates ischemia-induced acute renal failure in rats. Kidney international 31 11737601
2007 Involvement of Sp1 and Sp3 in differential regulation of human NHE3 promoter activity by sodium butyrate and IFN-gamma/TNF-alpha. American journal of physiology. Gastrointestinal and liver physiology 30 17540780
2000 Chronic effect of parathyroid hormone on NHE3 expression in rat renal proximal tubules. Kidney international 30 11012896