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Showing SLC9A1 — NHE1 is a alias.

SLC9A1

Sodium/hydrogen exchanger 1 · UniProt P19634

Length
815 aa
Mass
90.8 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 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

SLC9A1 (NHE1) is an electroneutral, voltage-independent plasma-membrane Na+/H+ antiporter that controls intracellular pH and couples pH homeostasis to cytoskeletal organization, cell migration, and cell-fate decisions (PMID:8393860, PMID:7494140, PMID:12486114). The transporter assembles as a symmetrical homodimer in which each subunit undergoes an elevator-like conformational change during cation exchange; the accessory subunit CHP1 binds differentially to the two conformational states to confer pH-sensitivity, and inhibitors such as cariporide block transport at a defined site (PMID:34108458). Beyond catalysis, NHE1 carries a C-terminal regulatory domain that integrates multiple inputs: p38 MAPK phosphorylates Thr717/Ser722/Ser725/Ser728 to activate the exchanger and drive the alkalinization required for apoptosis after trophic-factor withdrawal (PMID:11604491), PKBα/Akt phosphorylates Ser648 to abolish calmodulin binding and inhibit activity (PMID:18757828), and hypoxia-activated p90RSK phosphorylates NHE1 to promote invadopodium formation (PMID:22216126). CHP1 is additionally required for full biosynthetic glycosylation and membrane targeting of NHE1, with loss of either CHP1 or NHE1 causing Purkinje cell axon degeneration (PMID:23904602). Independently of ion transport, NHE1 anchors actin filaments through direct binding to ERM proteins—a function genetically separable from transport that governs cell polarity, focal adhesion remodeling, and directed migration (PMID:12486114); in invading cancer cells a talin–moesin bridge recruits NHE1 to invadopodia to drive local acidification, cofilin-dependent actin polymerization, matrix degradation, and metastasis (PMID:24891603). NHE1 also localizes to mitochondria, where it modulates Ca2+-induced permeability transition pore opening (PMID:21297023). The loss-of-function p.Gly305Arg mutation, which de-glycosylates and mis-targets NHE1, causes Lichtenstein-Knorr syndrome (ataxia with sensorineural hearing loss) (PMID:25205112).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1993 High

    Establishing the defining biophysical identity of NHE1 required distinguishing it from related isoforms; heterologous expression in exchanger-null cells fixed its kinetic and pharmacological fingerprint.

    Evidence Stable transfection of NHE1/NHE3 in NHE-deficient CHO cells with amiloride-inhibitable 22Na+ influx and kinetic characterization

    PMID:8393860

    Open questions at the time
    • Did not resolve the structural basis of substrate affinity or amiloride binding
    • No information on regulatory domain inputs
  2. 1995 High

    Whether NHE1 carries net charge was unresolved; patch-clamp with pH microfluorimetry showed the exchanger is electroneutral and that apparent currents arise from a separate H+ conductance.

    Evidence Whole-cell patch clamp plus microfluorimetry in CHO cells expressing NHE1/2/3

    PMID:7494140

    Open questions at the time
    • Did not address stoichiometry at the structural level
    • No coupling to downstream signaling
  3. 1996 Medium

    How NHE1 reaches its functional membrane domain was unknown; biosynthesis studies revealed glycosylation-dependent post-biosynthetic sorting to the basolateral membrane.

    Evidence Pulse-chase with endoglycosidase H sensitivity and domain-specific surface biotinylation in A6 epithelial cells

    PMID:8944647

    Open questions at the time
    • Sorting machinery not identified
    • Did not link glycosylation maturation to a specific chaperone
  4. 1996 Medium

    Transcriptional control of NHE1 was undefined; an AP-2 cis-element in the promoter was shown to be critical for expression in cardiomyocytes.

    Evidence Promoter deletion/mutation reporter assays and gel-shift in neonatal cardiomyocytes

    PMID:8769760

    Open questions at the time
    • AP-2 protein identity not definitively confirmed
    • Did not connect to physiological signals
  5. 2001 High

    The kinase inputs to NHE1 activity were unclear; p38 MAPK was shown to directly phosphorylate four C-terminal sites to activate the exchanger and drive apoptotic alkalinization.

    Evidence In vitro kinase assay, mass spectrometry site mapping, and p38 inhibition/dominant-negative in NHE1-deficient cells

    PMID:11604491

    Open questions at the time
    • Conformational consequence of phosphorylation not structurally defined
    • Crosstalk with other kinases not addressed
  6. 2002 High

    The non-transport function of NHE1 was unknown; separation-of-function mutants established that ERM-mediated cytoskeletal anchoring is distinct from ion transport in driving cell polarity and migration.

    Evidence Site-directed mutagenesis of ERM-binding and transport domains with wounding, polarity, PI-signaling, and focal-adhesion readouts in fibroblasts

    PMID:12486114

    Open questions at the time
    • Did not map the ERM contact at atomic resolution
    • Mechanism linking anchoring to PI signaling not fully defined
  7. 2002 Medium

    Hormonal control of NHE1 abundance was unresolved; thyroid hormone receptor TRα1 was shown to bind the promoter and increase NHE1 expression.

    Evidence EMSA, promoter-reporter transfection with TRα1, and Western blot in hypothyroid rats

    PMID:12039959

    Open questions at the time
    • Physiological relevance to cardiac pH regulation not directly tested
    • Single regulatory element examined
  8. 2005 Medium

    How migration signals reach NHE1 spatially was unclear; a compartmentalized RhoA/ROCK/p38 module gated by PKA was shown to activate NHE1 in leading-edge pseudopodia.

    Evidence FRET imaging of RhoA, kinase assays, and pathway manipulation in metastatic breast cancer cells

    PMID:15843433

    Open questions at the time
    • Single lab
    • Direct NHE1 phosphorylation by this module not separately mapped
  9. 2006 Medium

    The transcriptional driver of NHE1 under hypoxia was unknown; HIF-1 was shown necessary and sufficient for hypoxic NHE1 upregulation and alkalinization.

    Evidence HIF-1α heterozygous knockout mice plus HIF-1 overexpression with NHE1 mRNA/protein and pHi measurements in PASMCs

    PMID:16766575

    Open questions at the time
    • Direct HIF-1 promoter occupancy at NHE1 not shown
    • Single lab
  10. 2007 Medium

    How NHE1 contributes to apoptosis at the molecular level was unclear; DNA-damage-induced NHE1 alkalinization was shown necessary and sufficient for Bcl-xL deamidation that disarms its anti-apoptotic function.

    Evidence NHE1 expression/inhibition, NHE1-deficient cells, enforced alkalinization, and Bcl-xL deamidation/BH3 co-IP assays

    PMID:17177603

    Open questions at the time
    • pH-sensing step linking NHE1 to deamidation chemistry not resolved
    • Single lab
  11. 2008 High

    A negative kinase input on NHE1 was undefined; PKBα/Akt was shown to phosphorylate Ser648, abolishing calmodulin binding and inhibiting activity after acidosis.

    Evidence In vitro kinase assay with GST-NHE1, MS site mapping, Ser→Ala mutagenesis, Far-Western CaM binding, and cardiomyocyte expression

    PMID:18757828

    Open questions at the time
    • Structural basis of CaM displacement not resolved
    • Integration with activating phosphorylations not modeled
  12. 2008 Medium

    The causal role of NHE1 in pulmonary vascular disease was unknown; NHE1-null mice were protected from hypoxic pulmonary hypertension, placing NHE1 upstream of ROCK signaling.

    Evidence NHE1-/- mice under hypoxia with RV pressure, morphometry, and ROCK1/ROCK2/p27 immunoblots

    PMID:18310478

    Open questions at the time
    • Mechanism coupling NHE1 activity to ROCK expression not defined
    • Single lab
  13. 2010 Medium

    Whether NHE1 acts within membrane signaling complexes was tested; NaV1.5, Na-K-ATPase α1, and NHE1 were each shown to functionally couple to NHE1-dependent H+ handling and downstream activity.

    Evidence Co-localization/co-IP and pharmacological epistasis with invasion, 86Rb uptake, and rescue assays across cancer and renal cells

    PMID:20427472 PMID:21170089

    Open questions at the time
    • Direct molecular interfaces not mapped
    • Stoichiometry and stability of complexes unknown
  14. 2010 Medium

    The conserved requirement for NHE1 in actin-based motility was tested in a model organism; loss of the Dictyostelium ortholog impaired F-actin assembly and chemotaxis via cofilin/Aip1-dependent dynamics.

    Evidence Ddnhe1- null mutant with Aip1 fragment rescue, F-actin assembly, and chemotaxis assays

    PMID:20668166

    Open questions at the time
    • Ortholog-based; human pathway not directly tested here
    • Single lab
  15. 2010 Medium

    A role for NHE1 in CNS pericyte Ca2+ signaling was unknown; NHE1 was shown to control ER Ca2+ release-dependent oscillation and proliferation.

    Evidence siRNA and pharmacological inhibition with fura-2 Ca2+ imaging and proliferation assays

    PMID:18263712

    Open questions at the time
    • Mechanism linking pH to ER Ca2+ release undefined
    • Single lab
  16. 2011 Medium

    The hypoxic kinase activating NHE1 in invasion was unknown; p90RSK was shown to phosphorylate NHE1 to drive alkalinization and invadopodium formation.

    Evidence shRNA depletion of NHE1/p90RSK, live pHi imaging, and invadopodium/invasion assays

    PMID:22216126

    Open questions at the time
    • Specific p90RSK phosphosite(s) not mapped
    • Single lab
  17. 2011 Medium

    Whether NHE1 mediates the cardiac slow force response was unresolved; knockdown abolished the SFR and acted downstream of ERK1/2 in stretch signaling.

    Evidence Lentiviral shRNA in rat myocardium with pHi, contractility, and ERK1/2 phospho-immunoblot

    PMID:21659487

    Open questions at the time
    • Connection between ERK1/2 and NHE1 phosphosites not directly shown
    • Single lab
  18. 2011 Medium

    An extra-plasmalemmal pool of NHE1 was unrecognized; mitochondrial NHE1 was shown to promote Ca2+-induced permeability transition pore opening.

    Evidence Lentiviral shRNA, mitochondrial Western blot/EM/immunostaining, and Ca2+-induced swelling with pharmacological controls

    PMID:21297023

    Open questions at the time
    • Submitochondrial localization and import route undefined
    • Single lab
  19. 2013 High

    How NHE1 is recruited to invadopodia was unknown; a direct talin C-terminus–moesin FERM bridge was shown to deliver a moesin-NHE1 complex driving local acidification and metastasis.

    Evidence Direct binding assay, siRNA, intracellular pH measurement, invadopodium and in vivo metastasis assays

    PMID:24891603

    Open questions at the time
    • Whether moesin contacts NHE1 directly or via additional factors not fully resolved
    • Single lab in vivo model
  20. 2013 High

    The chaperone requirement for NHE1 maturation was unclear; CHP1 was shown to be required for full glycosylation and membrane targeting, with loss phenocopying Nhe1 ablation in Purkinje neurons.

    Evidence Positional cloning of vacillator Chp1 mutant, glycosylation/fractionation, immunostaining, and Nhe1-KO genetic epistasis

    PMID:23904602

    Open questions at the time
    • Step in the secretory pathway at which CHP1 acts not defined
    • Relationship to transport-coupled CHP1 binding clarified only later structurally
  21. 2013 Medium

    Additional regulatory protein partners were sought; the stress chaperone STCH was shown to bind NHE1 and support pHi recovery via a defined 45-residue region.

    Evidence Co-immunoprecipitation, region mapping, and siRNA with pHi recovery assay in HSG cells

    PMID:23303189

    Open questions at the time
    • Mechanism by which STCH supports NHE1 function unknown
    • Single lab, no reciprocal structural validation
  22. 2014 High

    The genetic and structural basis of an inherited NHE1 disorder was unknown; the TM8 p.Gly305Arg mutation was shown to de-glycosylate, mis-target, and inactivate NHE1, causing Lichtenstein-Knorr syndrome.

    Evidence Exome sequencing with functional expression (glycosylation, targeting, proton transport) of the mutant

    PMID:25205112

    Open questions at the time
    • Cellular consequence in affected neurons not directly examined
    • Genotype-phenotype range not defined
  23. 2014 Medium

    Lipid regulation of NHE1 was incompletely defined; long-chain acyl-CoAs were shown to directly bind the cytosolic domain and competitively displace PI(4,5)P2 to inactivate NHE1 and trigger lipoapoptosis.

    Evidence Direct pulldown of NHE1 cytosolic domain with LC-CoA vs PI(4,5)P2, competition, activity/caspase assays, and albuminuric kidney mouse models

    PMID:24531551

    Open questions at the time
    • Lipid-binding site on NHE1 not structurally mapped
    • Single lab
  24. 2021 High

    The high-resolution architecture and conformational mechanism were unresolved; cryo-EM of the NHE1-CHP1 complex revealed a symmetrical homodimer with elevator-like exchange and conformation-selective CHP1 binding and a defined cariporide site.

    Evidence Cryo-EM in inward-facing and cariporide-bound outward-facing states with functional inhibitor analysis

    PMID:34108458

    Open questions at the time
    • Phosphorylation-dependent regulatory domain conformations not captured
    • Mitochondrial form not addressed
  25. 2022 Medium

    Spatial coordination of NHE1 in confined migration was unclear; NHE1 was shown to polarize at the leading edge and cooperate with SWELL1 in osmotic-engine-driven migration and metastasis under Cdc42 control.

    Evidence shRNA, optogenetic RhoA/Cdc42 activation, confined-migration and spheroid imaging, and in vivo extravasation/metastasis

    PMID:36253369

    Open questions at the time
    • Direct NHE1-SWELL1 physical interaction not shown
    • Cdc42-to-NHE1 effector link undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple kinase phosphorylation events, CHP1 binding, lipid regulation, and ERM/talin-moesin anchoring are integrated on the C-terminal regulatory domain to set NHE1 conformation and activity in real time remains unresolved.
  • No structure of the phosphorylated regulatory domain bound to partners
  • Quantitative model of competing inputs lacking
  • Mitochondrial NHE1 import and topology unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-382551 Transport of small molecules 2 R-HSA-1643685 Disease 1
Partners
ATP1A1 (NA-K-ATPASE Α1)CALM (CALMODULIN)CHP1EZRIN/RADIXIN/MOESIN (ERM)MOESINSCN5A (NAV1.5)STCHTALIN
Complex memberships
NHE1-CHP1 complextalin-moesin-NHE1 invadopodial complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cryo-EM structures of human NHE1-CHP1 complex in inward-facing and inhibitor (cariporide)-bound outward-facing conformations revealed that NHE1 assembles as a symmetrical homodimer, each subunit undergoing an elevator-like conformational change during cation exchange. The cariporide binding site was resolved, illustrating how inhibitors block transport. CHP1 differentially associates with the two conformational states of each NHE1 monomer, underlying CHP1 regulation of NHE1 pH-sensitivity. Cryo-EM structure determination with functional inhibitor binding analysis Nature communications High 34108458
2002 NHE1 functions as a plasma membrane anchor for actin filaments through direct binding of ERM (ezrin/radixin/moesin) family proteins. Mutations independently disrupting ERM binding/cytoskeletal anchoring or ion transport each impaired cell polarity, Golgi orientation, PI signaling, and focal adhesion remodeling in migrating fibroblasts. Loss of ion transport specifically inhibited de-adhesion at trailing edges. Site-directed mutagenesis of ERM-binding domain and ion transport, wounding assay, localization imaging, PI signaling assay The Journal of cell biology High 12486114
2008 Protein kinase B (PKBα/Akt) directly phosphorylates the NHE1 C-terminal regulatory domain principally at Ser648. PKBα-mediated Ser648 phosphorylation abrogates calmodulin (CaM) binding to the NHE1 regulatory domain (shown by Far-Western assay), and expression of myristoylated PKBα in adult rat ventricular myocytes increased NHE1 phosphorylation and reduced NHE1 activity following intracellular acidosis. In vitro kinase assay with GST-NHE1 fusion proteins, mass spectrometry identification of phosphorylation sites, Ser→Ala mutagenesis, Far-Western CaM binding assay, adenovirus-mediated expression in cardiomyocytes Circulation research High 18757828
2001 p38 MAPK directly phosphorylates the C-terminus of NHE1 within a 40-amino-acid region. Mass spectrometry identified four phosphorylation sites: Thr717, Ser722, Ser725, and Ser728. This phosphorylation activates NHE1, causing intracellular alkalinization, which is required for the apoptotic pathway following trophic factor (IL-7/IL-3) withdrawal. In vitro kinase assay, mass spectrometry, pharmacological p38 inhibition, dominant-negative p38 expression, NHE1-deficient cell line Molecular and cellular biology High 11604491
2013 Talin C-terminus directly binds the moesin FERM domain to recruit a moesin-NHE1 complex to invadopodia. Talin silencing decreased cytosolic pH at invadopodia, blocked cofilin-dependent actin polymerization, impaired invadopodium stability and matrix degradation, and reduced mammary tumor cell intravasation and lung metastasis in vivo. Direct binding assay (talin C-terminus to moesin FERM domain), siRNA knockdown, intracellular pH measurement, invadopodium assay, in vivo metastasis model The Journal of cell biology High 24891603
1993 Heterologous expression of NHE1 and NHE3 in Na/H exchanger-deficient CHO (AP-1) cells established their distinct functional properties: NHE1 has higher amiloride sensitivity, ~2-fold lower affinity for extracellular Na+ (KNa ~10 mM vs. ~4.7 mM for NHE3), and ~2-fold higher apparent affinity for intracellular H+ (pK 6.75 vs. 6.45). Both activate H+ transport by positive cooperativity. K+o inhibits NHE1 but not NHE3. Stable transfection in NHE-deficient CHO cells, amiloride-inhibitable 22Na+ influx assay, pharmacological characterization The Journal of biological chemistry High 8393860
1995 Patch-clamp combined with pHi microfluorimetry in CHO cells transfected with NHE1, NHE2, or NHE3 demonstrated that all three mammalian isoforms are electroneutral and voltage-independent. Apparent currents during Na+/H+ exchange in macrophages were attributed to a pH-sensitive H+ conductance, not to electrogenic transport by the exchangers themselves. Whole-cell patch clamp, microfluorimetry, transfection in CHO cells lacking H+ conductance The Journal of general physiology High 7494140
2014 The SLC9A1 p.Gly305Arg missense mutation (in transmembrane segment 8) causes near complete de-glycosylation, mis-targeting, and loss of proton pumping activity of NHE1, establishing complete or near-complete loss of NHE1 function as the cause of Lichtenstein-Knorr syndrome (ataxia and sensorineural hearing loss). Exome sequencing, functional expression of mutant NHE1 (glycosylation analysis, subcellular targeting, proton transport assay) Human molecular genetics High 25205112
2013 CHP1 assists in the full glycosylation of NHE1 required for membrane localization of this transporter. Truncated CHP1 isoforms (from the vacillator mouse mutation in Chp1) were defective in stimulating NHE1 biosynthetic maturation. Loss of CHP1 function reduced NHE1 membrane localization at axon terminals and, like genetic ablation of Nhe1, caused Purkinje cell axon degeneration. Positional cloning, glycosylation assay, membrane fractionation, NHE1 localization by immunostaining, genetic epistasis (Nhe1 knockout recapitulates Chp1 mutant phenotype) The Journal of neuroscience High 23904602
2010 NaV1.5 and NHE1 are colocalized in caveolin-1-containing membrane rafts in breast cancer cells. NaV1.5 increases NHE1-dependent H+ efflux; inhibition of either channel/exchanger alone produced similar reductions in invasiveness and extracellular matrix degradation with no additive effect when both were inhibited simultaneously, indicating functional coupling. Co-localization (immunofluorescence), pharmacological inhibition, invasion assay, ECM degradation assay Oncogene Medium 21170089
2005 In metastatic breast cancer cells, serum deprivation activates NHE1 and invasion through a sequential RhoA/p160ROCK/p38MAPK signaling module that is compartmentalized in leading-edge pseudopodia. Protein kinase A directly phosphorylates and inhibits RhoA, gating this pathway. FRET imaging showed dynamic RhoA activity redistribution during pseudopodium formation. Pharmacological and genetic manipulation of pathway components, FRET imaging of RhoA activity, kinase activity assays, transport assays, immunofluorescence of phospho-RhoA and NHE1 Molecular biology of the cell Medium 15843433
2011 Hypoxia activates p90 ribosomal S6 kinase (p90RSK), which phosphorylates NHE1 at specific site(s), activating Na+/H+ exchange and increasing intracellular pH. This NHE1 activation drives invadopodium formation and cancer cell invasion. shRNA depletion of NHE1 or p90RSK blocked hypoxia-induced invadopodium formation. shRNA knockdown, live-cell intracellular pH imaging, kinase activity assays, invadopodium and invasion assays PloS one Medium 22216126
2007 DNA damage in thymocytes increases NHE1 expression, causing intracellular alkalinization. This alkalinization is necessary and sufficient for Bcl-xL deamidation at Asn52/Asn66 to generate an iso-Asp species unable to sequester pro-apoptotic BH3-only proteins (Bim, Puma), thereby inducing apoptosis. Enforced intracellular alkalinization mimics DNA damage effects in tumor cells and human CLL cells. NHE1 expression analysis, pharmacological inhibition, NHE1-deficient cell line, enforced alkalinization, Bcl-xL deamidation assay, BH3-only protein co-immunoprecipitation PLoS biology Medium 17177603
2011 NHE1 is expressed in rat heart mitochondria. shRNA-mediated knockdown of NHE1 reduced mitochondrial NHE1 by ~60% and significantly reduced Ca2+-induced mitochondrial permeability transition pore (MPTP) opening (swelling). The NHE1 inhibitor HOE-642 had no additional effect on mitochondria from NHE1-knockdown animals, confirming that the mitochondrial effects of HOE-642 are NHE1-dependent. Lentiviral shRNA knockdown, Western blot of mitochondrial lysates, electron microscopy, immunostaining co-localization, Ca2+-induced swelling assay American journal of physiology. Heart and circulatory physiology Medium 21297023
2014 Long-chain acyl-CoA (LC-CoA) metabolites directly interact with the cytosolic domain of NHE1 (by pulldown), with affinity comparable to that of PI(4,5)P2-NHE1 binding. Competing LC-CoAs disrupt PI(4,5)P2-NHE1 binding, reducing NHE1 activity and triggering caspase-2-dependent proximal tubule lipoapoptosis. Inhibition of LC-CoA generation preserved NHE1 activity and protected against apoptosis. Direct protein-lipid interaction assay (pulldown of NHE1 cytosolic domain with LC-CoA vs PI(4,5)P2), pharmacological inhibition of LC-CoA catabolism/generation, NHE1 activity measurements, caspase activity assay, mouse models of albuminuric kidney disease The Journal of clinical investigation Medium 24531551
2011 NHE1 activation is a key determinant of the slow force response (SFR) to myocardial stretch. lentiviral shRNA-mediated NHE1 knockdown (~55% reduction) abolished the SFR and depressed pHi recovery after acidosis, while ERK1/2 phosphorylation (an NHE1 activator) remained intact, placing NHE1 downstream of ERK1/2 in the stretch-response pathway. Lentiviral shRNA knockdown in rat myocardium, intracellular pH measurement, contractility measurement, immunoblot for ERK1/2 phosphorylation Journal of applied physiology Medium 21659487
2013 Stress 70 chaperone protein STCH directly interacts with NHE1 (confirmed by co-immunoprecipitation), and STCH siRNA impairs NHE1-dependent pHi recovery from acidification in HSG cells. The NHE1-STCH interaction is dependent on a specific 45-amino-acid region of STCH. Yeast two-hybrid (for NBCe1-B identification), co-immunoprecipitation, siRNA knockdown, pHi recovery assay The Journal of biological chemistry Medium 23303189
2010 NHE1 directly associates with Na-K-ATPase α1-subunit (co-immunoprecipitation). Ouabain stimulates Na-K-ATPase activity through an NHE1-dependent mechanism: EIPA inhibition of NHE1 blocks ouabain-mediated Na-K-ATPase stimulation, and wild-type NHE1 expression in NHE1-deficient HK-2 cells restores this regulation. Co-immunoprecipitation (NHE1–Na-K-ATPase α1), NHE1 rescue expression in deficient cells, 86Rb uptake, pharmacological inhibition American journal of physiology. Renal physiology Medium 20427472
2006 HIF-1 is required for hypoxia-induced NHE1 mRNA and protein upregulation, increased NHE activity, and intracellular alkalinization in pulmonary arterial smooth muscle cells. PASMCs from mice with partial HIF-1α deficiency lacked these hypoxic responses, and HIF-1 overexpression in normoxia was sufficient to increase NHE1 expression. HIF-1α heterozygous knockout mice, ex vivo hypoxia exposure, HIF-1 overexpression, NHE1 mRNA/protein quantification, NHE activity and pHi measurements American journal of physiology. Lung cellular and molecular physiology Medium 16766575
2008 NHE1 deficiency (NHE1-null mice) prevents hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and vascular remodeling. In NHE1-null mice, Rho kinase (ROCK1 and ROCK2) expression was decreased and p27 expression increased under hypoxia, placing NHE1 upstream of ROCK signaling in pulmonary vascular remodeling. NHE1-null (NHE1-/-) mice, hypoxia exposure, right ventricular pressure measurement, morphometry, Western blot for ROCK1/ROCK2/p27 American journal of respiratory and critical care medicine Medium 18310478
2010 NHE1 regulates Ca2+ oscillation in CNS pericytes through modulation of Ca2+ release from the endoplasmic reticulum. NHE1 knockdown by siRNA or pharmacological NHE inhibition abolished spontaneous Ca2+ oscillation and attenuated pericyte proliferation. siRNA knockdown, pharmacological inhibition, Ca2+ imaging (fura-2), proliferation assay American journal of physiology. Heart and circulatory physiology Medium 18263712
2022 NHE1 preferentially polarizes at the leading edge and SWELL1 at the trailing edge of confined migrating cells. NHE1 and SWELL1 cooperate in the Osmotic Engine Model to mediate cell volume regulation, confined migration, and cell dissemination from spheroids. Cdc42 controls NHE1 repolarization during directional reversal. Dual NHE1/SWELL1 knockdown inhibited breast cancer cell extravasation and metastasis in vivo. shRNA knockdown, optogenetic RhoA/Cdc42 activation, live imaging of confined migration, spheroid dissemination assay, in vivo extravasation/metastasis assay Nature communications Medium 36253369
2010 In Dictyostelium lacking the NHE ortholog (Ddnhe1-), intracellular pH is lower, F-actin assembly is attenuated, and chemotaxis is impaired. Full-length Aip1 (actin-interacting protein 1), which promotes cofilin-dependent actin remodeling, suppresses the chemotaxis defect of Ddnhe1- cells and restores F-actin assembly, whereas the C-terminal fragment of Aip1 (which binds cofilin but not F-actin) enhances the defect. This establishes that NHE1-mediated H+ efflux enables cofilin-dependent actin dynamics necessary for chemotaxis. Dictyostelium NHE null mutant (Ddnhe1-), genetic modifier screen, expression of Aip1 fragments, F-actin assembly assay, chemotaxis assay Molecular biology of the cell Medium 20668166
1996 Biosynthesis studies in A6 epithelial cells showed that newly synthesized core-glycosylated (90 kDa, endoglycosidase H-sensitive) NHE1 is delivered to both apical and basolateral membranes, while mature 110 kDa NHE1 is selectively delivered to and retained at the basolateral membrane, indicating a post-biosynthetic sorting mechanism for basolateral NHE1 localization. Pulse-chase biosynthesis, endoglycosidase H sensitivity, domain-specific surface biotinylation The American journal of physiology Medium 8944647
2002 Thyroid hormone receptor TRα1 binds to a -841/-800 nt element of the NHE1 promoter (shown by EMSA) and, when added exogenously, increases transcriptional activity of this element. Treatment with T3 increases NHE1 protein in cardiac myocytes, and hypothyroid rats have decreased NHE1 protein. EMSA, promoter-reporter transfection with TRα1, Western blot in hypothyroid rats The Journal of biological chemistry Medium 12039959
1996 AP-2 transcription factor (or AP-2-like protein from myocyte nuclear extracts) binds to a critical AP-2 site in the NHE1 promoter (shown by gel mobility shift assay). Deletion or mutation of this AP-2 site reduces NHE1 promoter activity by ~75-100% in neonatal cardiomyocytes. Serum deprivation reduces NHE1 promoter activity. Promoter deletion/mutation analysis, reporter assay in cardiomyocytes, gel mobility shift assay The American journal of physiology Medium 8769760
2020 β1 integrin, KV11.1 (hERG1), and NHE1 co-immunoprecipitate in colorectal cancer cells seeded on collagen I, suggesting formation of a macromolecular complex following integrin-mediated adhesion. KV11.1 and NHE1 cooperatively regulate β1 integrin-dependent pHi increase and cell motility in colorectal cancer cells. Co-immunoprecipitation, pharmacological inhibition, pHi measurement (BCECF), migration assay Frontiers in pharmacology Low 32587517
2003 An alternatively spliced form of NHE1 lacking the amiloride binding site was identified in human reticulocytes and erythrocytes. Transfection of this spliced variant into cells restores amiloride-insensitive, phloretin-sensitive sodium-lithium countertransport activity, demonstrating that this splice form mediates this transport mode. RT-PCR identification of splice variant, transfection into cells, 22Na+/Li+ transport assay Diabetes Low 12765964

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annual review of pharmacology and toxicology 408 11807182
2002 Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. The Journal of cell biology 370 12486114
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
2006 HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes. American journal of physiology. Lung cellular and molecular physiology 174 16766575
2010 Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene 154 21170089
2004 Na(+)/H(+) exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes. American journal of physiology. Cell physiology 140 15355855
2001 Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Molecular and cellular biology 137 11604491
2013 Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis. Cancer research 133 23393197
2013 Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. Journal of translational medicine 129 24195657
2012 Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy. Current pharmaceutical design 120 22360557
2006 Role of the Na/H exchanger NHE1 in cell migration. Acta physiologica (Oxford, England) 118 16734751
2016 Roles of pH and the Na+/H+ exchanger NHE1 in cancer: From cell biology and animal models to an emerging translational perspective? Seminars in cancer biology 108 28007556
2010 NBCn1 and NHE1 expression and activity in DeltaNErbB2 receptor-expressing MCF-7 breast cancer cells: contributions to pHi regulation and chemotherapy resistance. Experimental cell research 102 20542029
2008 Protein kinase B/Akt phosphorylates and inhibits the cardiac Na+/H+ exchanger NHE1. Circulation research 102 18757828
2006 The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Archiv : European journal of physiology 100 16586098
2008 The role of NHE-1 in myocardial hypertrophy and remodelling. Journal of molecular and cellular cardiology 98 18329039
2003 Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes. Hypertension (Dallas, Tex. : 1979) 93 14610099
1994 Na+/H+ exchanger isoforms NHE-2 and NHE-1 in inner medullary collecting duct cells. Expression, functional localization, and differential regulation. The Journal of biological chemistry 91 7961730
2005 Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Molecular biology of the cell 89 15843433
2014 Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. The Journal of cell biology 88 24891603
2008 Protons extruded by NHE1: digestive or glue? European journal of cell biology 80 18328592
2010 Expression of mitochondrial fusion-fission proteins during post-infarction remodeling: the effect of NHE-1 inhibition. Basic research in cardiology 78 20886221
2021 Structure and mechanism of the human NHE1-CHP1 complex. Nature communications 74 34108458
2011 Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PloS one 71 22216126
2012 NHE-1: a promising target for novel anti-cancer therapeutics. Current pharmaceutical design 64 22360552
2022 Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling. Acta pharmacologica Sinica 62 35217813
2010 Ginseng inhibits cardiomyocyte hypertrophy and heart failure via NHE-1 inhibition and attenuation of calcineurin activation. Circulation. Heart failure 62 20971938
2022 Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis. Nature communications 61 36253369
2008 Deficiency of the NHE1 gene prevents hypoxia-induced pulmonary hypertension and vascular remodeling. American journal of respiratory and critical care medicine 61 18310478
2007 DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. PLoS biology 61 17177603
2010 Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells. American journal of physiology. Renal physiology 59 20427472
2014 Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. The Journal of clinical investigation 53 24531551
2009 Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. Journal of molecular and cellular cardiology 53 19318234
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
2005 NHE-1-dependent intracellular sodium overload in hypertrophic hereditary cardiomyopathy: prevention by NHE-1 inhibitor. Journal of molecular and cellular cardiology 52 15808834
2020 Adipose Mesenchymal Stem Cell-Derived Exosomal microRNA-1236 Reduces Resistance of Breast Cancer Cells to Cisplatin by Suppressing SLC9A1 and the Wnt/β-Catenin Signaling. Cancer management and research 50 33061571
2018 The acid-base transport proteins NHE1 and NBCn1 regulate cell cycle progression in human breast cancer cells. Cell cycle (Georgetown, Tex.) 49 29895196
2002 Structure and function of the NHE1 isoform of the Na+/H+ exchanger. Biochemistry and cell biology = Biochimie et biologie cellulaire 49 12440691
2005 Extracellular pH Controls NHE1 expression in epidermis and keratinocytes: implications for barrier repair. The Journal of investigative dermatology 47 16185280
2020 Pyrazine ring-based Na+/H+ exchanger (NHE) inhibitors potently inhibit cancer cell growth in 3D culture, independent of NHE1. Scientific reports 45 32242030
2006 Regulation of mitogen-activated protein kinase pathways by the plasma membrane Na+/H+ exchanger, NHE1. Archives of biochemistry and biophysics 45 17321481
2019 Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC cancer 44 30849956
2017 Genetic disruption of the pHi-regulating proteins Na+/H+ exchanger 1 (SLC9A1) and carbonic anhydrase 9 severely reduces growth of colon cancer cells. Oncotarget 41 28055960
2015 Physiological Functions and Regulation of the Na+/H+ Exchanger [NHE1] in Renal Tubule Epithelial Cells. Kidney & blood pressure research 41 26304834
2014 Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome. Human molecular genetics 41 25205112
2021 Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells. Theranostics 40 33391535
2018 Ginsenoside Rg3 Decreases NHE1 Expression via Inhibiting EGF-EGFR-ERK1/2-HIF-1 Pathway in Hepatocellular Carcinoma: A Novel Antitumor Mechanism. The American journal of Chinese medicine 39 30525897
2007 NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells. Pflugers Archiv : European journal of physiology 39 17943310
1996 Cellular distribution and regulation of NHE-1 isoform of the NA-H exchanger in the avian osteoclast. Bone 39 8833201
2024 Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2. Basic research in cardiology 37 39046464
2011 Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening. American journal of physiology. Heart and circulatory physiology 37 21297023
2004 Comparative biology of the ubiquitous Na+/H+ exchanger, NHE1: lessons from erythrocytes. Journal of experimental zoology. Part A, Comparative experimental biology 37 15229867
2015 Na (+)/H (+)exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis? The International journal of developmental biology 36 26679950
2009 Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart. Journal of applied physiology (Bethesda, Md. : 1985) 36 19179646
2003 Zoniporide: a potent and selective inhibitor of the human sodium-hydrogen exchanger isoform 1 (NHE-1). Cardiovascular drug reviews 36 12595915
2006 Increased NHE1 expression is associated with serum deprivation-induced differentiation in immortalized rat proximal tubule cells. American journal of physiology. Renal physiology 35 16495213
2017 NHE1 is upregulated in gastric cancer and regulates gastric cancer cell proliferation, migration and invasion. Oncology reports 34 28098891
2013 Inside out: targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Chemical biology & drug design 33 23253131
2007 Regulation and role of the presynaptic and myocardial Na+/H+ exchanger NHE1: effects on the sympathetic nervous system in heart failure. Cardiovascular drug reviews 31 17614935
2001 alpha(1)-Adrenergic receptors activate NHE1 and NHE3 through distinct signaling pathways in epithelial cells. American journal of physiology. Renal physiology 31 11181403
1996 Biosynthesis and cell surface delivery of the NHE1 isoform of Na+/H+ exchanger in A6 cells. The American journal of physiology 31 8944647
1993 Na/H exchange activities in NHE1-transfected OK-cells: cell polarity and regulation. Pflugers Archiv : European journal of physiology 31 8272382
2018 The role of CD44, hyaluronan and NHE1 in cardiac remodeling. Life sciences 30 30089233
2018 A novel SLC9A1 mutation causes cerebellar ataxia. Journal of human genetics 29 30018422
2008 Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes. American journal of physiology. Heart and circulatory physiology 28 18263712
2013 Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility. International journal of oncology 27 24173371
2008 Late expression of Na+/H+ exchanger 1 (NHE1) and neuroprotective effects of NHE inhibitor in the gerbil hippocampal CA1 region induced by transient ischemia. Experimental neurology 27 18511042
2015 Na+-H+ exchanger-1 (NHE1) regulation in kidney proximal tubule. Cellular and molecular life sciences : CMLS 26 25680790
2010 A novel chimeric natriuretic peptide reduces cardiomyocyte hypertrophy through the NHE-1-calcineurin pathway. Cardiovascular research 26 20679416
2018 The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 29558744
2013 CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 23904602
2011 Silencing of NHE-1 blunts the slow force response to myocardial stretch. Journal of applied physiology (Bethesda, Md. : 1985) 25 21659487
2003 NHE-1 inhibition: from protection during acute ischaemia/reperfusion to prevention/reversal of myocardial remodelling. Naunyn-Schmiedeberg's archives of pharmacology 25 14504689
1996 Regulation of NHE-1 promoter in mammalian myocardium. The American journal of physiology 25 8769760
1995 NHE-1 isoform of the Na+/H+ antiport is expressed in the rat and rabbit esophagus. Gastroenterology 25 7557121
2020 KV11.1 Potassium Channel and the Na+/H+ Antiporter NHE1 Modulate Adhesion-Dependent Intracellular pH in Colorectal Cancer Cells. Frontiers in pharmacology 24 32587517
2018 Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. International journal of molecular medicine 23 30592266
2013 Chaperone stress 70 protein (STCH) binds and regulates two acid/base transporters NBCe1-B and NHE1. The Journal of biological chemistry 23 23303189
2011 NHE1 activity contributes to migration and is necessary for proliferation of human gastric myofibroblasts. Pflugers Archiv : European journal of physiology 23 22138972
2007 KCNA1 and TRPC6 ion channels and NHE1 exchanger operate the biological outcome of HGF/scatter factor in renal tubular cells. Growth factors (Chur, Switzerland) 23 18365869
2014 Suppression of PPARβ, and DHA treatment, inhibit NaV1.5 and NHE-1 pro-invasive activities. Pflugers Archiv : European journal of physiology 22 25017107
2014 RhoA and MAPK signal transduction pathways regulate NHE1-dependent proximal tubule cell apoptosis after mechanical stretch. American journal of physiology. Renal physiology 22 25080524
1998 Ontogeny of basolateral membrane sodium-hydrogen exchange (NHE) activity and mRNA expression of NHE-1 and NHE-4 in rat kidney and jejunum. Biochimica et biophysica acta 22 9518637
2021 Advances in research on the regulatory mechanism of NHE1 in tumors. Oncology letters 21 33717270
2012 DNA hypermethylation and 1p Loss silence NHE-1 in oligodendroglioma. Annals of neurology 21 22718548
2008 NHE-1: a molecular target for signalling and cell matrix interactions. Connective tissue research 21 18661333
2003 Alternative splicing of NHE-1 mediates Na-Li countertransport and associates with activity rate. Diabetes 21 12765964
2011 Structural analysis of the Na+/H+ exchanger isoform 1 (NHE1) using the divide and conquer approach. Biochemistry and cell biology = Biochimie et biologie cellulaire 20 21455270
2010 Expression of actin-interacting protein 1 suppresses impaired chemotaxis of Dictyostelium cells lacking the Na+-H+ exchanger NHE1. Molecular biology of the cell 20 20668166
2002 Thyroid hormone receptor alpha 1 regulates expression of the Na+/H+ exchanger (NHE1). The Journal of biological chemistry 20 12039959
2022 Voltage-Gated Sodium Channel NaV1.5 Controls NHE-1-Dependent Invasive Properties in Colon Cancer Cells. Cancers 19 36612049
2020 Roles of hsa-miR-12462 and SLC9A1 in acute myeloid leukemia. Journal of hematology & oncology 19 32703317
2019 The Na+/H+-Exchanger NHE1 Regulates Extra- and Intracellular pH and Nimodipine-sensitive [Ca2+]i in the Suprachiasmatic Nucleus. Scientific reports 19 31015514
2016 Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells. The Journal of biological chemistry 19 27629415
2023 SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 18 37770568
2015 A minireview on NHE1 inhibitors. A rediscovered hope in oncohematology. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 18 26725705
2011 NHE-1 participates in isoproterenol-induced downregulation of SERCA2a and development of cardiac remodeling in rat hearts. American journal of physiology. Heart and circulatory physiology 18 21856903
2020 An Inhibitor of the Sodium-Hydrogen Exchanger-1 (NHE-1), Amiloride, Reduced Zinc Accumulation and Hippocampal Neuronal Death after Ischemia. International journal of molecular sciences 17 32545865
2002 Differential role of Na+/H+ exchange isoforms NHE-1 and NHE-2 in a rat cortical collecting duct cell line. The Journal of membrane biology 17 12474076

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