Affinage

SLC9A3

Sodium/hydrogen exchanger 3 · UniProt P48764

Length
834 aa
Mass
92.9 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9A3/NHE3 is the principal apical Na+/H+ exchanger of renal proximal tubule and intestinal brush-border epithelia, where it drives the bulk of transepithelial Na+, HCO3-, and fluid absorption (PMID:1374392, PMID:9662405, PMID:32227118). It operates as an electroneutral, voltage-independent antiporter with low amiloride sensitivity, an extracellular Na+ affinity near 4.7 mM, and cooperative activation by intracellular H+ (PMID:8393860, PMID:7494140). Genetic ablation establishes its physiological centrality: whole-body and tissue-specific knockouts produce defective renal HCO3-/fluid reabsorption, severe intestinal Na+ malabsorption, watery alkaline diarrhea, acidosis, and disturbed volume homeostasis (PMID:9662405, PMID:32227118), and loss-of-function missense mutations in its N-terminal transport domain cause congenital sodium diarrhea by reducing basal surface expression and transport (PMID:26358773). NHE3 activity is governed by dynamic endocytic recycling, with PI3-kinase required for return of intracellular transporter to the surface and dynamin-/clathrin/AP2-dependent internalization removing it (PMID:9694828, PMID:10866993, PMID:11328806). This trafficking is organized by a C-terminal scaffold: NHE3 binds directly to ezrin through a juxtamembrane basic cluster and to the PDZ proteins NHERF1/NHERF2(E3KARP) and PDZK1(NHERF3), assembling macrocomplexes that also recruit IRBIT, alpha-actinin-4, and anchored kinases (PKA, cGKII) to position signaling enzymes near the cytoplasmic tail (PMID:9748260, PMID:11948184, PMID:15722341, PMID:18430067, PMID:26258413, PMID:17395628). Hormonal and metabolic inputs converge on phosphorylation of defined serines that bidirectionally tune surface abundance and intrinsic activity: PKA (Ser552/Ser605), cGKII (multi-site, inhibitory), SGK1 and CK2 (Ser663, Ser719; stimulatory), acting downstream of cAMP, cGMP, glucocorticoids, PTH, dopamine, endothelin, TNF, and Na+-glucose cotransport (PMID:7593604, PMID:9933588, PMID:15888551, PMID:15722341, PMID:18614797, PMID:25480791). Notably, PKA phosphorylation at Ser552/Ser605 can be dissociated from transport changes, and a PKA-independent EPAC arm also mediates cAMP inhibition (PMID:16407144, PMID:17409282).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 High

    Establishing that NHE3 is a distinct Na+/H+ exchanger isoform with tissue-restricted expression defined the molecule whose absorptive function the field would dissect.

    Evidence cDNA cloning, sequencing, and Northern/RNase protection mapping to intestine and kidney

    PMID:1374392

    Open questions at the time
    • Sequence alone did not establish transport kinetics or membrane topology in situ
    • Subcellular localization not yet defined
  2. 1993 High

    Localizing NHE3 to the apical brush-border membrane and characterizing its electroneutral kinetics tied the cloned isoform to vectorial epithelial Na+ absorption.

    Evidence Isoform-specific antibody immunocytochemistry/Western blot, and 22Na+ influx kinetics in NHE-deficient CHO cells

    PMID:8238556 PMID:8393860

    Open questions at the time
    • Did not address acute hormonal regulation
    • Oligomeric/quaternary state not resolved
  3. 1995 High

    Demonstrating PKA-dependent phosphorylation of the NHE3 C-terminal tail with functional inhibition opened the mechanism of acute hormonal control.

    Evidence In vitro PKA phosphorylation of recombinant cytoplasmic domain, truncation mutagenesis in oocytes and fibroblasts

    PMID:7494140 PMID:7593604

    Open questions at the time
    • Specific regulatory serines not yet identified
    • Link between phosphorylation and trafficking unestablished
  4. 1998 High

    Knockout mice and the discovery of PI3-kinase-dependent recycling and NHERF2/ezrin scaffolding showed NHE3 is the dominant absorptive exchanger and is regulated by both trafficking and a C-terminal protein complex.

    Evidence Slc9a3-/- mouse physiology, PI3-K inhibitor surface assays, in vitro NHERF2-NHE3-ezrin binding/co-localization

    PMID:9662405 PMID:9694828 PMID:9748260

    Open questions at the time
    • Compensatory upregulation complicated interpretation of basal role
    • How scaffold links to kinase recruitment not yet mechanistic
  5. 1999 High

    Mapping PKA phosphorylation to Ser552/Ser605 and showing NHERF/E3KARP adapters are required for cAMP-dependent phosphorylation defined the molecular logic of cAMP regulation.

    Evidence Site-directed mutagenesis, phosphopeptide mapping, dominant-negative PKA and NHERF in PS120 fibroblasts

    PMID:10455146 PMID:9933588

    Open questions at the time
    • Additional serines contribute but were not fully resolved
    • Causal link of these specific sites to transport rate left open
  6. 1999 High

    Dissection of PTH action established a biphasic model: rapid phosphorylation-driven inhibition followed by dynamin-dependent endocytic retrieval of NHE3.

    Evidence Dominant-negative dynamin, surface antigen time-course in OKP cells, in vivo PTH infusion with membrane fractionation

    PMID:10330053 PMID:10866993

    Open questions at the time
    • Identity of early intrinsic-inhibition mechanism not defined
    • Endocytic adaptor machinery not yet identified
  7. 2000 Medium

    Direct Gsalpha association with NHE3 in brush-border vesicles indicated regulation that can bypass cytoplasmic second messengers.

    Evidence Co-IP with GTPgammaS and anti-G protein antibodies in membrane vesicles, D1 agonist

    PMID:10749796

    Open questions at the time
    • Single-lab membrane-vesicle co-IP without reciprocal validation
    • Physiological significance of direct G protein binding unclear
  8. 2001 High

    Defining endocytic and lipid-raft pools and the dopamine/AP2/dynamin internalization pathway connected specific PKA sites to clathrin-mediated retrieval.

    Evidence Surface antigen and AP2 binding assays, Ser560/Ser613 mutagenesis, detergent/raft fractionation in renal and intestinal cells

    PMID:11121391 PMID:11328806 PMID:11731584

    Open questions at the time
    • Recognition of NHE3 by endocytic machinery not molecularly defined
    • Raft-dependence mechanism incompletely resolved
  9. 2001 High

    Identifying the SGLT1->p38 MAPK pathway that activates NHE3 linked nutrient cotransport to coordinate downstream absorptive activation.

    Evidence BCECF pH imaging, NHE3-selective inhibitor S-3226, p38 inhibitors and anisomycin in Caco-2 monolayers

    PMID:11600416

    Open questions at the time
    • Effector linking p38 to NHE3 membrane recruitment not yet identified
  10. 2002 High

    Showing Ca2+ inhibition requires an E3KARP-alpha-actinin-4 complex and that acid activation requires c-Src/ERK expanded the scaffold and kinase repertoire controlling NHE3.

    Evidence Co-IP and dominant-negative alpha-actinin-4 in PS120 cells; dominant-negative c-Src and MEK inhibitors with renal kinase assays

    PMID:11948184 PMID:12081562 PMID:12167607

    Open questions at the time
    • How Ca2+ triggers oligomerization mechanistically unresolved
    • Direct substrate of c-Src/ERK on NHE3 pathway not defined
  11. 2004 High

    Identifying ezrin Thr567 phosphorylation by Akt2 downstream of p38 as the step recruiting NHE3 to the apical membrane completed the SGLT1-to-trafficking axis.

    Evidence Dominant-negative ezrin, phospho-Thr567 antibody, in vitro Akt2 kinase assay and Akt2 siRNA in intestinal cells

    PMID:15197272 PMID:15531580

    Open questions at the time
    • How phospho-ezrin physically delivers NHE3 to surface not visualized
    • Generalizability beyond glucose-coupled stimulus untested here
  12. 2005 High

    Resolving distinct stimulatory and inhibitory anchored-kinase modules (SGK1/Ser663 for glucocorticoids; NHERF2-anchored cGKII for cGMP) demonstrated bidirectional, scaffold-localized phosphoregulation.

    Evidence In vitro SGK1 kinase assay with S663A mutant and surface assays; cGKII myristoylation/NHERF2 binding mutants in PS120 cells

    PMID:15722341 PMID:15888551 PMID:15942046

    Open questions at the time
    • cGKII inhibitory phospho-sites not yet all mapped (resolved later)
    • Crosstalk between stimulatory and inhibitory modules unquantified
  13. 2006 High

    Discovery of a PKA-independent EPAC arm and of TNF-PKCalpha-driven brush-border internalization broadened cAMP signaling and connected NHE3 inhibition to inflammatory diarrhea.

    Evidence PKA- vs EPAC-selective cAMP analogs; in vivo T-cell activation model with PKCalpha inhibition; perfused MTAL aldosterone/ERK assays

    PMID:16407144 PMID:16757729 PMID:17016558

    Open questions at the time
    • EPAC downstream effector on NHE3 not identified
    • Molecular target of nongenomic aldosterone/ERK on NHE3 unresolved
  14. 2007 High

    Showing Ser552/Ser605 phosphorylation can be dissociated from activity, identifying synaptotagmin I as an endocytic partner, and PDZK1 as an inhibition-specific scaffold refined the relationship between phosphorylation, trafficking, and function.

    Evidence Phosphospecific antibodies with transport assays in PTH-rats; Syt I/AP2/clathrin siRNA co-IP in Caco-2/jejunum; pdzk1-/- colonic crypt assays; ETB tyrosine-kinase pathway dissection

    PMID:17307723 PMID:17395628 PMID:17409282 PMID:8843705

    Open questions at the time
    • Functional phospho-site(s) directly controlling transport rate still uncertain
    • How distinct NHERF isoforms specify different responses unresolved
  15. 2008 High

    Defining the direct NHE3-ezrin binding cluster, the IRBIT-mediated Ca2+/CaMKII exocytic activation, and CK2 phosphorylation of Ser719 detailed the molecular determinants of basal and stimulated surface delivery.

    Evidence Point-mutant binding assays (K516/R520/R527-FERM); IRBIT co-IP/siRNA with CaM/CaMKII inhibitors; LC-MS/MS, CK2 assay, S719A/D mutagenesis

    PMID:18430067 PMID:18614797 PMID:18829453

    Open questions at the time
    • Structural basis of multivalent scaffold assembly not solved
    • Integration of competing IRBIT-activation vs E3KARP-inhibition unresolved
  16. 2011 High

    Localizing SGK3 to recycling endosomes as a PI3K/PDK1-dependent NHE3 activator added a compartment-specific layer to acute glucocorticoid regulation.

    Evidence SGK isoform transfection, PX-domain R90A mutant, PDK1 translocation imaging, knockout mouse comparison

    PMID:21865597

    Open questions at the time
    • Direct SGK3 substrate site on NHE3 not pinpointed
    • Relative contribution of SGK1 vs SGK3 in vivo unquantified
  17. 2014 High

    Mapping the three obligate cGKII inhibitory sites and confirming Ser663 as the glucocorticoid stimulatory site established multi-site phospho-codes with opposite functional outcomes.

    Evidence iTRAQ/TiO2 LC-MS/MS, phosphospecific antibodies, mutagenesis, surface/activity assays in PS120/NHERF2, Caco-2, mouse ileum

    PMID:25480791

    Open questions at the time
    • How combinatorial phosphorylation is decoded into trafficking remains mechanistic
  18. 2015 High

    Linking SLC9A3 loss-of-function mutations to congenital sodium diarrhea and showing insulin-restored macrocomplexes in diabetes connected the molecular model to human disease and metabolic state.

    Evidence Exome sequencing with mutant reconstitution in NHE-null fibroblasts; diabetic mouse co-IP with NHERF1/IRBIT/PKD2 siRNA

    PMID:26258413 PMID:26358773

    Open questions at the time
    • Genotype-phenotype severity correlation not fully mapped
    • In vivo dynamics of macrocomplex assembly not directly observed
  19. 2020 High

    Conditional tissue-specific knockouts proved renal NHE3 is required for SGLT2-inhibitor natriuresis and that intestinal NHE3 is essential for systemic Na+/acid-base/volume homeostasis.

    Evidence Pax8-Cre and Villin-CreERT2 NHE3 knockouts, empagliflozin challenge, urine/blood chemistry, phosphospecific antibodies

    PMID:32227118 PMID:32893663

    Open questions at the time
    • Mechanism linking SGLT2 inhibition to NHE3 phosphorylation not fully defined
    • Reproductive role mechanism (CFTR dependence) addressed separately
  20. 2017 High

    Discovery that NHE3 loss reduces CFTR in the male reproductive tract revealed a non-absorptive role coupling NHE3 to epithelial secretion and fertility.

    Evidence Slc9a3 knockout mice, CFTR immunoblot/IHC, electron microscopy of vas deferens/epididymis

    PMID:28384194

    Open questions at the time
    • Mechanism by which NHE3 controls CFTR abundance unresolved
    • Direct vs indirect coupling not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How combinatorial multi-site phosphorylation, competing scaffold assemblies, and endosomal recycling are integrated in real time to set NHE3 surface density remains the central unresolved mechanistic question.
  • No structural model of the assembled NHE3-scaffold-kinase macrocomplex
  • Quantitative decoding of opposing phospho-marks into trafficking outcomes not established
  • Direct mechanism of NHE3-dependent control of CFTR abundance unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 2
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-382551 Transport of small molecules 3
Partners
ACTN4EZRIRBITNHERF1NHERF2PDZK1PRKACASYT1
Complex memberships
NHE3-E3KARP(NHERF2)-alpha-actinin-4 complexNHE3-NHERF1-IRBIT-ezrin brush-border macrocomplex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 NHE3 (NHE-3) encodes a Na+/H+ exchanger isoform with 832 amino acids, 10–12 membrane-spanning domains, and a long cytoplasmic tail with putative protein kinase phosphorylation motifs; it is expressed specifically in intestine and kidney. cDNA cloning, sequencing, Northern blot, ribonuclease protection assay The Journal of biological chemistry High 1374392
1993 NHE3 protein localizes to the brush-border (apical) membrane of renal proximal tubule cells, identified as an ~80 kDa polypeptide by isoform-specific antibody on Western blot and immunocytochemistry. Isoform-specific antibody (Western blot, immunocytochemistry), NHE3-transfected cell controls The American journal of physiology High 8238556
1993 NHE3 functions as an electroneutral Na+/H+ exchanger with low amiloride sensitivity, apparent KNa of ~4.7 mM for extracellular Na+, and positive cooperative activation by intracellular H+ (half-maximal pK ~6.45); K+o does not inhibit NHE3 (unlike NHE1). Stable transfection in NHE-deficient CHO (AP-1) cells, amiloride-inhibitable 22Na+ influx assay, kinetic analysis The Journal of biological chemistry High 8393860
1995 NHE3 is localized to the apical membrane of S1 and S2 proximal convoluted tubules and medullary/cortical thick ascending limbs in rat kidney; cross-linking studies indicate oligomeric forms of the transporter exist. Polyclonal antisera against cytoplasmic epitopes, Western blot of fractionated membranes, immunohistochemistry, chemical cross-linking Kidney international High 8569082
1995 PKA activation acutely inhibits NHE3 activity (~39% inhibition); this requires the cytoplasmic C-terminal domain of NHE3, and the purified recombinant cytoplasmic domain is phosphorylated by PKA catalytic subunit in vitro on serine residues; cAMP increases NHE3 phosphocontent ~3-fold in cells. Stable expression in AP-1 fibroblasts, Xenopus oocyte expression with truncation mutants, in vitro PKA phosphorylation of recombinant domain, immunoprecipitation of phospho-NHE3 The Journal of clinical investigation High 7593604
1995 NHE-1, NHE-2, and NHE-3 are electroneutral and voltage-independent Na+/H+ exchangers; currents observed in some cell types during exchange are due to a pre-existing H+ conductance, not the exchanger itself. Whole-cell patch clamp combined with microfluorimetric pH measurement, CHO cells transfected with NHE isoforms, Zn2+ dissociation experiment The Journal of general physiology High 7494140
1998 NHE3 knockout mice (Slc9a3-/-) exhibit reduced HCO3- and fluid absorption in proximal convoluted tubules, a severe intestinal absorptive defect, mild acidosis, reduced blood pressure, and compensatory upregulation of AE1, renin, colonic H+,K+-ATPase, and ENaC; NHE3 is the major absorptive Na+/H+ exchanger in kidney and intestine. Gene targeting/knockout mouse model, blood chemistry, renal tubule perfusion, intestinal flux measurements Nature genetics High 9662405
1998 E3KARP (NHERF2) directly binds NHE3 at an internal region in its C-terminal cytoplasmic tail via E3KARP's second PDZ domain plus C-terminal domain; E3KARP also binds the cytoskeletal protein ezrin, suggesting a scaffold linking NHE3 to ezrin and thereby to PKA (type II). In vitro binding assays (pulldown), co-localization in PS120 fibroblasts, deletion/domain mapping The Journal of biological chemistry High 9748260
1998 PI3-kinase activity is required for recycling of intracellular NHE3 to the cell surface; PI3-K inhibitors (wortmannin, LY294002) reduce NHE3 plasma membrane expression by decreasing the rate of recycling of endosomal NHE3, thereby inhibiting NHE3-mediated H+ extrusion. PI3-K inhibitors, epitope-tagged NHE3 in AP-1 cells, immunofluorescence microscopy, ELISA-based surface quantification, temperature-block experiments The Journal of biological chemistry High 9694828
1999 cAMP inhibition of NHE3 requires PKA (dominant-negative PKA-regulatory subunit abolishes the effect) and involves in vivo phosphorylation of NHE3 at Ser-552 and Ser-605; single or multiple mutations at these serines reduce PKA regulation, though complex mechanisms involving additional serines also contribute. Dominant-negative PKA expression, site-directed mutagenesis (8 serines mutated), in vitro PKA phosphorylation, tryptic phosphopeptide mapping of in vivo phosphorylated NHE3 The Journal of biological chemistry High 9933588
1999 NHERF and E3KARP are necessary for cAMP-dependent phosphorylation of NHE3 in vivo; they act as adapters facilitating PKA-mediated phosphorylation of NHE3, but phosphorylation of NHERF itself is not required for this effect. Co-immunoprecipitation, in vivo phosphorylation assay, dominant-negative NHERF mutant (triple Ser→Ala), 8-Br-cAMP treatment in PS120 fibroblasts The Journal of biological chemistry High 10455146
1999 PTH acutely inhibits NHE3 in a biphasic manner: early inhibition (5 min) via NHE3 phosphorylation on multiple serines, followed by dynamin-dependent endocytosis that decreases surface NHE3 antigen (detectable at 30 min); blocking endocytic trafficking with dominant-negative dynamin (K44A) abolishes the late but not early inhibition. Dominant-negative dynamin mutant, surface NHE3 quantification, phosphorylation assay, OKP cell model The Journal of biological chemistry High 10866993
1999 In vivo PTH infusion provokes redistribution of ~25% of NHE3 from apical membranes to intracellular membrane fractions in renal proximal tubule, associated with natriuresis/diuresis; cAMP-PKA signaling is necessary for NHE3 and NaPi2 internalization. Intravenous PTH infusion in rats, sorbitol density gradient fractionation of renal cortex membranes, immunoblotting The American journal of physiology High 10330053
1999 ETB receptor activation increases NHE3 phosphorylation on multiple threonine and serine residues in OKP cells, with ETB but not ETA receptor specificity; phosphorylation correlates temporally with activation of NHE3 activity. Stable transfection of ETB vs ETA receptor cDNA in OKP cells, immunoprecipitation, phosphoamino acid analysis, SDS-PAGE mobility shift, alkaline phosphatase treatment The American journal of physiology High 10199826
2000 G protein subunit Gsα directly associates with and regulates NHE3 in renal brush-border membrane vesicles independently of cytoplasmic second messengers; D1-like receptor-mediated inhibition of NHE3 is partially reversed by anti-Gsα antibodies, and GTPγS increases Gsα co-immunoprecipitation with NHE3; Gβγ dimers appear to have a stimulatory effect on NHE3. Brush-border membrane vesicles devoid of cytoplasmic components, anti-G protein antibodies, co-immunoprecipitation, D1 agonist fenoldopam American journal of physiology. Regulatory, integrative and comparative physiology Medium 10749796
2001 NHERF co-localizes with NHE3 and ezrin specifically in the apical membrane of proximal tubule cells in rat kidney; NHERF2 is absent from proximal tubule but present in collecting duct where it co-localizes with ROMK, indicating isoform-specific compartmentalization. Isoform-specific antibodies, immunocytochemical analysis of rat kidney sections American journal of physiology. Cell physiology Medium 11121391
2001 Dopamine (DA) acutely decreases surface NHE3 via stimulation of NHE3 endocytosis through clathrin-coated vesicles; this requires GTPase dynamin, involves increased NHE3 binding to adaptor protein AP2, and is dependent on PKA-mediated phosphorylation of NHE3 at Ser-560 and Ser-613. Surface NHE3 antigen quantification, dominant-negative dynamin, AP2 binding assay, PKA inhibition (pharmacological and genetic), Ser→Ala mutations, renal cell line The Journal of biological chemistry High 11328806
2001 Ileal brush-border NHE3 exists in three pools: ~50% Triton X-100 soluble, ~50% detergent-insoluble, of which ~33% resides in cholesterol-enriched lipid rafts. EGF and clonidine increase the raft pool of NHE3 in the brush border, associated with increased NHE3 activity; lipid rafts and actin cytoskeleton regulate NHE3 basal endocytosis. Detergent extraction, density gradient fractionation (OptiPrep), EEA1-immunoisolated early endosomes, cholesterol depletion with MβCD, cytochalasin D The Journal of physiology High 11731584
2001 NHE3 is activated downstream of SGLT1-mediated Na+-glucose cotransport in intestinal epithelial cells, causing NHE3-dependent cytoplasmic alkalinization that requires p38 MAP kinase activity; p38 MAP kinase activation also occurs with Na+-glucose cotransport and is sufficient to trigger NHE3-dependent alkalinization when activated alone. pH-sensitive dye (BCECF), NHE3-preferential inhibitor S-3226, p38 MAP kinase inhibitors (PD-169316, SB-202190), anisomycin activation, Caco-2 cell monolayers American journal of physiology. Cell physiology High 11600416
2002 Ca2+-dependent inhibition of NHE3 requires E3KARP (not NHERF), and depends on Ca2+-dependent association of α-actinin-4 with E3KARP (via α-actinin-4's actin-binding plus spectrin repeat domain), forming an NHE3–E3KARP–α-actinin-4 complex; elevated Ca2+ causes NHE3 oligomerization and endocytosis, inhibiting activity. PS120 fibroblasts stably expressing E3KARP or NHERF, co-immunoprecipitation, dominant-negative α-actinin-4 fragment, ionomycin treatment, NHE3 activity assay The Journal of biological chemistry High 11948184
2002 NHE3 supports receptor-mediated, clathrin-dependent endocytosis (RME) in proximal tubule cells by maintaining endosomal pH homeostasis and endocytic fusion; NHE3 confers cAMP sensitivity to RME, and NHE3 deficiency abolishes cAMP effects on endosomal pH and RME. Cellular knockout/retransfection in OKP cells, albumin uptake assay, endosomal pH measurement, cAMP treatment American journal of physiology. Renal physiology High 12167607
2004 Ezrin phosphorylation at Thr567 is required for NHE3 recruitment to the apical membrane after Na+-glucose cotransport; this occurs downstream of p38 MAP kinase, and a dominant-negative N-terminal ezrin construct blocks NHE3 membrane recruitment and cytoplasmic alkalinization without affecting p38 activation. Dominant-negative ezrin construct, phospho-specific antibody for Thr567, p38 MAP kinase inhibitors, cell surface NHE3 quantification, intestinal epithelial cells Proceedings of the National Academy of Sciences of the United States of America High 15197272
2004 Akt2 phosphorylates ezrin at Thr567 in vitro and in cells downstream of PI3-kinase and p38 MAP kinase; Akt2-specific siRNA knockdown prevents ezrin phosphorylation, NHE3 translocation, and NHE3 activation after Na+-glucose cotransport. In vitro Akt kinase assay with recombinant ezrin, Akt2-specific siRNA, PI3-K inhibitors, Akt inhibitors, NHE3 surface translocation assay The Journal of biological chemistry High 15531580
2004 Carbachol inhibits ileal NHE3 activity by stimulating NHE3 endocytosis from the brush border (detergent-soluble fraction) into early endosomes; carbachol increases the size of NHE3-containing complexes (specifically in detergent-resistant fraction), enhancing co-immunoprecipitation of NHERF2, α-actinin-4, and PKC with NHE3; this inhibition is fully abolished by Src family kinase inhibitor PP2. OptiPrep gradient centrifugation, sucrose gradient centrifugation for complex size, co-immunoprecipitation, surface biotinylation, PP2 Src inhibitor, ileal preparations The Journal of physiology High 14978207
2005 Glucocorticoid (dexamethasone) activation of NHE3 requires SGK1-mediated phosphorylation of NHE3 at Ser663; in vitro SGK1 kinase assay confirms phosphorylation at Ser663; S663A mutation blocks dexamethasone effect; phosphorylation precedes increased NHE3 activity and is associated with increased surface NHE3 expression. In vitro SGK1 kinase assay, site-directed mutagenesis (S663A), surface biotinylation, pH-sensitive dye NHE3 activity assay American journal of physiology. Cell physiology High 15888551
2005 NHERF2 (but not NHERF1) acts as a cGMP-dependent protein kinase G (cGKII) anchoring protein; cGKII must be membrane-anchored via its myristoyl group and bound to NHERF2 to inhibit NHE3; NHERF2 PDZ2 C-terminus binds both NHE3 and cGKII, enabling cGMP inhibition of NHE3. PS120 cell co-expression system, in vitro NHERF-cGKII binding assay, non-myristoylated cGKII mutant, NHE3 activity assay, cAMP/cGMP analog pharmacology The Journal of biological chemistry High 15722341
2005 Glucocorticoids acutely increase surface NHE3 via stimulation of NHE3 exocytosis (insertion), without changes in total NHE3 protein or NHE3 endocytosis; this effect does not require new protein synthesis. Surface biotinylation, biotinylatable NHE3 insertion assay (sulfo-NHS-acetate blockade), MesNa cleavage endocytosis assay, cycloheximide treatment in OKP cells American journal of physiology. Renal physiology High 15942046
2006 EPAC (exchange protein directly activated by cAMP) provides a second, PKA-independent pathway for cAMP inhibition of NHE3 activity; EPAC activation inhibits NHE3 without inducing phosphorylation of NHE3 at serines 552/605 and without redistribution of NHE3 from brush-border membrane. cAMP analogs selective for PKA vs. EPAC, PKA activity assay, H89 inhibitor, NHE3 phosphorylation assay, surface NHE3 quantification in OK cells and murine kidney slices Proceedings of the National Academy of Sciences of the United States of America High 16407144
2006 TNF causes NHE3 internalization from the intestinal brush border via PKCα activation, leading to Na+ malabsorption; PKCα inhibition (pharmacological or genetic) prevents NHE3 internalization and diarrhea despite continued barrier dysfunction, demonstrating that coordinated NHE3 inhibition and barrier dysfunction are both required for TNF-mediated diarrhea. In vivo T cell activation mouse model, surface NHE3 quantification, pharmacological and genetic PKCα inhibition, Na+ absorption measurement The Journal of clinical investigation High 17016558
2006 Aldosterone inhibits apical NHE3 and HCO3- absorption in the medullary thick ascending limb (MTAL) through a rapid, nongenomic ERK-dependent pathway; aldosterone activates ERK within 5 min, and MEK/ERK inhibitors (U-0126, PD-98059) prevent both ERK activation and NHE3 inhibition; spironolactone and actinomycin D do not block this effect. In vitro perfused rat MTALs, HCO3- flux measurement, ERK immune-complex kinase assay, MEK/ERK inhibitors, spironolactone, actinomycin D American journal of physiology. Renal physiology High 16757729
2007 NHE3 phosphorylation at Ser552 and Ser605 by PKA is dissociated from changes in NHE3 transport activity; dramatic phosphorylation at these sites occurs without altered NHE3 activity in vivo (PTH-infused rats) and precedes transport inhibition in vitro, indicating these phosphorylations do not directly inhibit NHE3. PTH infusion in Sprague-Dawley rats, phosphospecific monoclonal antibodies to pSer552 and pSer605, microvillar membrane vesicle NHE3 activity assay, 22Na uptake in OKP cells American journal of physiology. Renal physiology High 17409282
2007 Synaptotagmin I (Syt I) binds NHE3, co-immunoprecipitates with NHE3 preferentially after cAMP or Ca2+ elevation, and is required for cAMP- and Ca2+-induced NHE3 endocytosis; Syt I siRNA blocks NHE3 endocytosis without preventing NHE3 activity inhibition; Syt I interaction with NHE3 precedes and is required for recruitment of AP2 and clathrin. Co-immunoprecipitation, siRNA of Syt I/AP2/clathrin, 22Na influx, apical membrane biotin labeling, confocal microscopy in Caco-2BBe cells and mouse jejunum American journal of physiology. Gastrointestinal and liver physiology High 17307723
2008 NHE3's C-terminal domain directly binds ezrin via a positively charged juxtamembrane cluster (K516, R520, R527) interacting with the FERM domain III of ezrin; this direct NHE3–ezrin binding is necessary for basal exocytosis, delivery from synthetic pathway, and brush border movement of NHE3. In vitro binding assays with domain deletions and point mutants, biochemical fractionation, surface NHE3 quantification Clinical and experimental pharmacology & physiology Medium 18430067
2008 IRBIT (IP3 receptor-binding protein released with IP3) binds the C-terminal domain of NHE3 and mediates Ca2+-dependent activation of NHE3 via exocytic trafficking to the plasma membrane; this activation requires calmodulin and CaM-dependent kinase II, and IRBIT can reverse NHERF2-dependent Ca2+-inhibition of NHE3. Co-immunoprecipitation, siRNA knockdown of IRBIT, exocytosis assay, calmodulin inhibitor, CaM kinase II inhibitor, NHE3 activity assay The Journal of biological chemistry High 18829453
2008 Casein kinase 2 (CK2) binds to the NHE3 C-terminal domain (aa 590–667) and phosphorylates a separate site, Ser719, to stimulate basal NHE3 activity; S719A mutation reduces NHE3 surface expression by decreasing exocytosis and plasma membrane delivery; CK2 inhibitor DMAT inhibits NHE3 carrying S719 but not S719A mutant. LC-MS/MS identification of phosphorylation site, in vitro CK2 kinase assay, S719A/S719D mutagenesis, surface biotinylation, exocytosis assay, CK2 inhibitor DMAT, co-immunoprecipitation Molecular biology of the cell High 18614797
2011 SGK3, localized to recycling endosomes (via its Arg90-dependent PX domain), acutely activates NHE3 within 15 min of glucocorticoid treatment in a PI3K- and PDK1-dependent manner; PDK1 translocates to endosomes upon dexamethasone treatment; mutation of SGK3 Arg90 disrupts endosomal localization and delays NHE3 activation. Transfection of SGK isoforms in PS120 and Caco-2bbe cells, immunofluorescence colocalization, R90A point mutation, PI3K and PDK1 inhibitors, NHE3 activity assay, SGK1/NHERF2 knockout mouse comparison Molecular biology of the cell High 21865597
2014 cGKII inhibits NHE3 by phosphorylating it at three required sites (rabbit Ser554, Ser607, Ser663; mouse Ser552, Ser605, Ser659); all three phosphorylations must be present simultaneously for cGMP inhibition; cGMP/cGKII reduces surface NHE3. Additionally, Ser663 phosphorylation by dexamethasone is required for glucocorticoid stimulation of NHE3 activity and surface expression. iTRAQ/LC-MS/MS with TiO2 enrichment, phosphospecific antibodies, site-directed mutagenesis, surface biotinylation, NHE3 activity assay in PS120/NHERF2, Caco-2bbe, and mouse ileum The Journal of biological chemistry High 25480791
2015 Loss-of-function SLC9A3 missense mutations (in the N-terminal transport domain and membrane-spanning regions) cause congenital sodium diarrhea; functionally, these mutations reduce NHE3 activity by decreasing basal surface expression and/or abolishing basal transport function of NHE3 in plasma membrane NHE null fibroblasts, while acute regulation remains normal. Whole-exome sequencing, Sanger sequencing, functional expression of mutants in NHE null fibroblasts, Na+/H+ exchange activity assay, surface expression assay Human molecular genetics High 26358773
2015 NHE3 and scaffold proteins NHERF1, IRBIT, and ezrin form macrocomplexes in the intestinal brush border; in streptozotocin-diabetic mice these macrocomplexes are disrupted, reducing NHE3 activity; insulin restores the macrocomplexes and NHE3 surface expression. IRBIT facilitates NHE3–NHERF1 interaction via protein kinase D2-dependent phosphorylation, and insulin-stimulated ezrin phosphorylation enhances ezrin–NHERF1–IRBIT–NHE3 interactions. Co-immunoprecipitation, diabetic mouse model, insulin treatment, NHERF1/IRBIT siRNA knockdown, NHE3 trafficking assay, PKD2 knockdown The Journal of clinical investigation High 26258413
2020 Tubule-specific NHE3 knockout mice do not respond to empagliflozin (SGLT2 inhibitor) with increased urinary Na+ and bicarbonate excretion or urine pH change, demonstrating that renal NHE3 is required for the natriuretic effect of empagliflozin; empagliflozin in diabetic mice increases NHE3 phosphorylation at S552/S605 (linked to reduced NHE3-mediated reabsorption). Tubule-specific NHE3 knockout mouse (Pax8-Cre), acute empagliflozin dosing, urine electrolyte/pH measurement, phosphospecific NHE3 antibodies American journal of physiology. Renal physiology High 32893663
2020 Inducible intestinal epithelial cell-specific NHE3 knockout mice develop watery alkaline diarrhea, metabolic acidosis, hyponatremia, hyperkalemia, and elevated aldosterone, demonstrating that intestinal NHE3 is essential for Na+, acid-base, and volume homeostasis. Tamoxifen-inducible intestinal epithelial NHE3 knockout (Villin-CreERT2), blood chemistry, urinary and fecal measurements Clinical science (London, England : 1979) High 32227118
1996 ETB receptor (but not ETA) activation increases Na+/H+ antiporter (NHE3) activity in OKP cells via Ca2+/calmodulin kinase pathway (~50%) and tyrosine kinase pathway (~50%); Ca2+ elevation alone (through ETA) is not sufficient for activation. Stable ETB and ETA receptor transfection in OKP cells, BAPTA Ca2+ clamping, KN62 (CaM kinase inhibitor), pertussis toxin, PKC/PLA2/COX inhibitors The Journal of clinical investigation High 8617878
1996 ETB receptor-induced NHE3 activation is 50% mediated by tyrosine kinase pathways, involving p210 (integral membrane protein); ET-1 causes tyrosine phosphorylation of focal adhesion proteins (paxillin, p125FAK) via ETB, but these are not required for Na+/H+ antiporter activation. Cytochalasin D disruption of focal adhesions, immunoprecipitation identifying paxillin and p125FAK, tyrosine phosphorylation assay The American journal of physiology Medium 8843705
2002 c-Src and ERK are both required for acid-induced activation of NHE3 in renal proximal tubule cells; dominant-negative c-Src (K295M) prevents NHE3 activation and acidosis activates both c-Src and ERK/MEK (but not JNK) independently; MEK inhibition (PD98059) also blocks NHE3 activation by acid. Dominant-negative c-Src transfection, immune complex kinase assays (enolase, MBP, GST-c-Jun substrates), MEK inhibitor PD98059, in vivo renal cortical kinase activation Kidney international High 12081562
2007 PDZK1 (NHERF3) is required for cAMP- and Ca2+-mediated inhibition of NHE3 in native colonic enterocytes but not for NHE3 abundance, apical targeting, or hyperosmolarity-induced inhibition; pdzk1-/- mice show drastically reduced acid-activated NHE3 activity and abolished responses to forskolin and ionomycin. pdzk1 knockout mice, fluorometric NHE3 activity assay in isolated colonic crypts, Western blot, immunohistochemistry, selective NHE3 inhibitor S1611 The Journal of physiology High 17395628
2017 Loss of SLC9A3 in mice dramatically decreases CFTR protein expression in the epididymis and vas deferens, leading to obstructive azoospermia with abnormal secretions, calcification, and disorganized stereocilia in the male reproductive tract. Slc9a3 knockout mice, immunoblotting of CFTR, immunohistochemistry, ultrastructural analysis (electron microscopy) PLoS genetics High 28384194

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 671 9662405
1993 NHE3: a Na+/H+ exchanger isoform of renal brush border. The American journal of physiology 353 8238556
1992 Cloning and sequencing of a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). The Journal of biological chemistry 338 1374392
1995 Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney international 322 8569082
1998 NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ezrin. The Journal of biological chemistry 244 9748260
1996 NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. The American journal of physiology 243 8772498
1993 Heterologous expression and functional properties of amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the rat Na/H exchanger. The Journal of biological chemistry 224 8393860
1994 Na+/H+ exchangers, NHE-1 and NHE-3, of rat intestine. Expression and localization. The Journal of clinical investigation 209 8282777
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 166 32893663
1998 Endosomal recycling of the Na+/H+ exchanger NHE3 isoform is regulated by the phosphatidylinositol 3-kinase pathway. The Journal of biological chemistry 143 9694828
2002 Intestinal NaCl transport in NHE2 and NHE3 knockout mice. American journal of physiology. Gastrointestinal and liver physiology 123 11960774
2001 Dopamine acutely stimulates Na+/H+ exchanger (NHE3) endocytosis via clathrin-coated vesicles: dependence on protein kinase A-mediated NHE3 phosphorylation. The Journal of biological chemistry 123 11328806
1999 Acute inhibition of Na/H exchanger NHE-3 by cAMP. Role of protein kinase a and NHE-3 phosphoserines 552 and 605. The Journal of biological chemistry 122 9933588
2001 Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. American journal of physiology. Cell physiology 115 11121391
2001 Na+-H+ exchanger 3 (NHE3) is present in lipid rafts in the rabbit ileal brush border: a role for rafts in trafficking and rapid stimulation of NHE3. The Journal of physiology 112 11731584
2015 Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Human molecular genetics 107 26358773
2002 Ca(2+)-dependent inhibition of Na+/H+ exchanger 3 (NHE3) requires an NHE3-E3KARP-alpha-actinin-4 complex for oligomerization and endocytosis. The Journal of biological chemistry 106 11948184
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
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 cAMP-induced phosphorylation and inhibition of Na(+)/H(+) exchanger 3 (NHE3) are dependent on the presence but not the phosphorylation of NHE regulatory factor. The Journal of biological chemistry 99 10455146
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
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 86 25552580
2006 Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC). Proceedings of the National Academy of Sciences of the United States of America 84 16407144
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
2005 cGMP inhibition of Na+/H+ antiporter 3 (NHE3) requires PDZ domain adapter NHERF2, a broad specificity protein kinase G-anchoring protein. The Journal of biological chemistry 80 15722341
1997 Chronic metabolic acidosis enhances NHE-3 protein abundance and transport activity in the rat thick ascending limb by increasing NHE-3 mRNA. The Journal of clinical investigation 80 9011571
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 79 15531580
1995 Activation of protein kinase A acutely inhibits and phosphorylates Na/H exchanger NHE-3. The Journal of clinical investigation 78 7593604
1999 ETB receptor activation leads to activation and phosphorylation of NHE3. The American journal of physiology 77 10199826
2006 Na+/H+ exchanger NHE3 activity and trafficking are lipid Raft-dependent. The Journal of biological chemistry 75 16648141
2010 Mechanisms of the regulation of the intestinal Na+/H+ exchanger NHE3. Journal of biomedicine & biotechnology 74 20011065
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
1999 In vivo PTH provokes apical NHE3 and NaPi2 redistribution and Na-K-ATPase inhibition. The American journal of physiology 72 10330053
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
2005 Glucocorticoids acutely increase cell surface Na+/H+ exchanger-3 (NHE3) by activation of NHE3 exocytosis. American journal of physiology. Renal physiology 65 15942046
2007 NHE3 phosphorylation at serines 552 and 605 does not directly affect NHE3 activity. American journal of physiology. Renal physiology 64 17409282
1999 Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys. The American journal of physiology 64 10444581
2008 IRBIT, inositol 1,4,5-triphosphate (IP3) receptor-binding protein released with IP3, binds Na+/H+ exchanger NHE3 and activates NHE3 activity in response to calcium. The Journal of biological chemistry 63 18829453
1996 Endothelin(B) receptor activates NHE-3 by a Ca2+-dependent pathway in OKP cells. The Journal of clinical investigation 63 8617878
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
1998 Quantitative contribution of NHE2 and NHE3 to rabbit ileal brush-border Na+/H+ exchange. The American journal of physiology 59 9612213
2019 Effect of renal tubule-specific knockdown of the Na+/H+ exchanger NHE3 in Akita diabetic mice. American journal of physiology. Renal physiology 58 31166707
2001 NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia. American journal of physiology. Cell physiology 58 11600416
2001 Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading. Kidney international 57 11703600
2004 Carbachol regulation of rabbit ileal brush border Na+-H+ exchanger 3 (NHE3) occurs through changes in NHE3 trafficking and complex formation and is Src dependent. The Journal of physiology 56 14978207
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
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
2007 NHE3 inhibition by cAMP and Ca2+ is abolished in PDZ-domain protein PDZK1-deficient murine enterocytes. The Journal of physiology 55 17395628
2002 Na+/H+ exchange activity and NHE-3 expression in renal tubules from the spontaneously hypertensive rat. Kidney international 55 12081574
2004 NHE3 Na+/H+ exchanger supports proximal tubular protein reabsorption in vivo. American journal of physiology. Renal physiology 54 15113744
2002 Role of c-SRC and ERK in acid-induced activation of NHE3. Kidney international 54 12081562
1996 Role of tyrosine kinase pathways in ETB receptor activation of NHE3. The American journal of physiology 54 8843705
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
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 Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. Kidney international 52 9083276
2002 Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis. American journal of physiology. Gastrointestinal and liver physiology 49 12181169
2014 Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site. The Journal of biological chemistry 48 25480791
2009 AT1 receptor-mediated uptake of angiotensin II and NHE-3 expression in proximal tubule cells through a microtubule-dependent endocytic pathway. American journal of physiology. Renal physiology 48 19726542
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
2011 Serum- and glucocorticoid-induced kinase 3 in recycling endosomes mediates acute activation of Na+/H+ exchanger NHE3 by glucocorticoids. Molecular biology of the cell 47 21865597
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
2009 Tethering, recycling and activation of the epithelial sodium-proton exchanger, NHE3. The Journal of experimental biology 44 19448073
2001 Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. Current opinion in nephrology and hypertension 44 11496061
2008 Casein kinase 2 binds to the C terminus of Na+/H+ exchanger 3 (NHE3) and stimulates NHE3 basal activity by phosphorylating a separate site in NHE3. Molecular biology of the cell 43 18614797
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 Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss. The Journal of clinical investigation 42 26258413
2012 Berberine increases the expression of NHE3 and AQP4 in sennosideA-induced diarrhoea model. Fitoterapia 41 22668974
2000 Short-term regulation of NHE3 by EGF and protein kinase C but not protein kinase A involves vesicle trafficking in epithelial cells and fibroblasts. Annals of the New York Academy of Sciences 41 11193592
2016 Lactobacillus acidophilus counteracts inhibition of NHE3 and DRA expression and alleviates diarrheal phenotype in mice infected with Citrobacter rodentium. American journal of physiology. Gastrointestinal and liver physiology 40 27634011
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
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
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 36 15265766
2002 NHE3 serves as a molecular tool for cAMP-mediated regulation of receptor-mediated endocytosis. American journal of physiology. Renal physiology 36 12167607
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
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
2012 Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice. PloS one 32 22848392
2007 Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2. Clinical and experimental pharmacology & physiology 32 18177483
1999 HCO-3 reabsorption in renal collecting duct of NHE-3-deficient mouse: a compensatory response. The American journal of physiology 32 10362780
2003 Aldosterone stimulates surface expression of NHE3 in renal proximal brush borders. Pflugers Archiv : European journal of physiology 31 12684793
2007 Synaptotagmin I binds intestinal epithelial NHE3 and mediates cAMP- and Ca2+-induced endocytosis by recruitment of AP2 and clathrin. American journal of physiology. Gastrointestinal and liver physiology 30 17307723
2002 Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function. American journal of physiology. Gastrointestinal and liver physiology 29 12065291

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