Affinage

SLC9A1

Sodium/hydrogen exchanger 1 · UniProt P19634

Length
815 aa
Mass
90.8 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9A1 encodes NHE1, a ubiquitously expressed plasma membrane Na+/H+ exchanger that functions as a homodimeric secondary active transporter utilizing an elevator-like conformational mechanism to electroneutrally exchange extracellular Na+ for intracellular H+, thereby governing intracellular pH, cell volume, and downstream pH-sensitive signaling (PMID:34108458, PMID:20974853). Its ~315-residue cytosolic C-terminal tail serves as a multivalent regulatory scaffold: it is phosphorylated by p38 MAPK, ERK/p90RSK, and Sgk1 to tune transport rate, binds PI(4,5)P2 to integrate lipid signaling, and anchors ERM proteins to couple the actin cytoskeleton to the plasma membrane—dual functions (ion transport and cytoskeletal anchoring) that are independently required for cell polarity, directed migration, and invadopodium-driven invasion (PMID:12486114, PMID:11604491, PMID:24891603, PMID:24531551, PMID:22216126). CHP1 is an obligate biosynthetic partner that promotes NHE1 glycosylation, membrane targeting, and pH sensitivity, and loss of either NHE1 or CHP1 function causes cerebellar ataxia and sensorineural deafness (Lichtenstein–Knorr syndrome) (PMID:34108458, PMID:23904602, PMID:25205112, PMID:29379881). In cardiomyocytes, NHE1 activation underlies the slow force response to stretch and contributes to oxidative-stress-induced calcium overload, linking its activity to cardiac contractility and pathological remodeling (PMID:21659487, PMID:12124207).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 Medium

    Establishing where NHE1 resides in polarized epithelia revealed its basolateral targeting, distinguishing it from apical NHE isoforms and showing it is subject to PKA-mediated inhibition.

    Evidence Transfection of NHE1 into polarized OK cells with intracellular pH fluorimetry and pharmacological dissection

    PMID:8272382

    Open questions at the time
    • Basolateral targeting determinants not mapped
    • PKA phosphorylation site on NHE1 not identified
  2. 1994 High

    Defining the biochemical features of mature NHE1 showed that Asn75 is the sole N-glycosylation site; glycosylation distinguishes ER from surface forms but is dispensable for transport, while the C-terminal cytosolic domain is required for ATP-dependent regulation and cytoskeletal association.

    Evidence Site-directed mutagenesis of glycosylation sites, glycosidase treatment, truncation mutants, ATP depletion, and cytochalasin D treatment in expression systems

    PMID:8068684 PMID:8132605

    Open questions at the time
    • Identity of cytoskeletal binding partners unknown
    • Mechanism linking ATP to transport regulation undefined
  3. 2001 High

    Identifying p38 MAPK as a direct NHE1 kinase (Thr717/Ser722/Ser725/Ser728) established a paradigm for stress-responsive phosphoregulation of the exchanger, linking trophic factor withdrawal to NHE1 activation and intracellular alkalinization.

    Evidence In vitro kinase assay, mass spectrometry of phosphosites, dominant-negative p38 expression

    PMID:11604491

    Open questions at the time
    • Relative contribution of individual phosphosites not resolved
    • Whether p38 phosphorylation changes set-point or Vmax unclear
  4. 2002 High

    Demonstrating that NHE1 polarizes to lamellipodia and serves dual roles—ion transporter and ERM-mediated actin anchor—with separation-of-function mutants resolved how NHE1 directs cell migration through two independent mechanisms.

    Evidence Site-directed mutagenesis separating ERM binding from transport, wound-healing assays, subcellular imaging in fibroblasts

    PMID:12486114

    Open questions at the time
    • Signal directing NHE1 polarization to leading edge unknown
    • Whether ERM-binding mutant affects pH gradient at leading edge not tested
  5. 2004 High

    Revealing that the NHE1-ERM complex recruits PI3K and Akt during apoptotic stress established NHE1 as a survival signaling scaffold beyond its transport function.

    Evidence Co-immunoprecipitation, NHE1-null cell rescue, apoptosis assays with ERM-binding-deficient mutant

    PMID:15096511

    Open questions at the time
    • Direct versus indirect recruitment of PI3K to NHE1-ERM complex not distinguished
    • Structural basis of the scaffolding interaction unknown
  6. 2006 High

    Identifying PP2A as a direct NHE1 phosphatase (acting on RSK-phosphorylated residues) recruited via adenosine A1 receptor/Gi signaling provided the first defined dephosphorylation mechanism for NHE1 in cardiomyocytes.

    Evidence In vitro dephosphorylation of GST-NHE1 by purified PP2A, co-IP and confocal co-localization at intercalated discs

    PMID:16707501

    Open questions at the time
    • Specific PP2A holoenzyme (B subunit identity) targeting NHE1 not defined
    • Whether PP2A regulates p38-dependent phosphosites unknown
  7. 2007 High

    Showing that DNA damage upregulates NHE1, driving intracellular alkalinization that triggers Bcl-xL deamidation and apoptosis, established a pH-dependent cell death pathway in which NHE1 is the effector.

    Evidence NHE1-deficient cells, pharmacological inhibition, enforced alkalinization, deamidation assay in thymocytes

    PMID:17177603

    Open questions at the time
    • Transcriptional mechanism of NHE1 upregulation after DNA damage not identified
    • Generalizability beyond thymocytes untested
  8. 2010 High

    EPR spectroscopy on TM IV and TM XI confirmed their close proximity and pH/inhibitor-dependent rearrangement, providing the first direct biophysical evidence for the conformational change mechanism of NHE1 ion translocation.

    Evidence EPR distance measurements between spin-labeled cysteine pairs, cariporide binding, Arg425 mutagenesis with transport assays

    PMID:20974853

    Open questions at the time
    • Full transport cycle intermediates not captured
    • No high-resolution structure available at this time
  9. 2011 High

    Multiple studies converged to show that NHE1 integrates into oncogenic signaling: B-Raf(V600E) directly binds and activates NHE1 to raise intracellular pH in melanoma, while p90RSK phosphorylation of NHE1 drives invadopodium formation under hypoxia, and NHE1 is required for the cardiac slow force response to stretch.

    Evidence Co-IP and in vitro pulldown (B-Raf–NHE1), shRNA knockdown with pH imaging and invadopodium assays, lentiviral NHE1 knockdown in rat myocardium with contractile force measurement

    PMID:21345796 PMID:21659487 PMID:22216126

    Open questions at the time
    • B-Raf binding site on NHE1 C-tail not mapped to specific residues
    • Whether stretch-induced NHE1 activation is phosphorylation-dependent or conformational unclear
  10. 2013 High

    Genetic studies in mice and humans established that CHP1 is required for NHE1 biosynthetic maturation and membrane targeting, and that loss-of-function mutations in either SLC9A1 (p.Gly305Arg) or CHP1 cause cerebellar ataxia with sensorineural hearing loss, defining the NHE1–CHP1 axis as essential for neuronal homeostasis.

    Evidence Homozygosity mapping, whole-exome sequencing, glycosylation analysis (NHE1 G305R), positional cloning of CHP1 vac mutant, genetic epistasis with NHE1 null

    PMID:23904602 PMID:25205112 PMID:29379881

    Open questions at the time
    • Precise neuronal subtype vulnerability (Purkinje cell specificity) mechanism not fully explained
    • Whether CHP1 regulates NHE1 transport kinetics independently of maturation not resolved
  11. 2014 High

    Demonstrating that PI(4,5)P2 binds the NHE1 cytosolic domain and that long-chain acyl-CoA competes for this site linked lipid metabolism to NHE1-dependent cell survival, while talin–moesin–NHE1 complex recruitment to invadopodia established the cytoskeletal scaffolding mechanism for local pH control during invasion.

    Evidence Direct binding/competition assays (PI(4,5)P2 vs. LC-CoA), mouse kidney disease models; talin–moesin pulldown with live-cell pH imaging and in vivo metastasis assay

    PMID:24531551 PMID:24891603

    Open questions at the time
    • Structural basis of PI(4,5)P2 binding to NHE1 C-tail unknown
    • Whether LC-CoA regulation is tissue-specific not determined
  12. 2021 High

    Cryo-EM structures of the NHE1–CHP1 complex in inward- and outward-facing states resolved the homodimeric elevator mechanism, identified the cariporide binding site, and showed conformational-state-dependent CHP1 association, providing an atomic framework for NHE1 regulation and drug design.

    Evidence Cryo-EM at near-atomic resolution of human NHE1–CHP1 complex in two conformational states with functional validation

    PMID:34108458

    Open questions at the time
    • Structure of the full-length cytosolic regulatory tail not resolved
    • Lipid-bound and phosphorylated structures not available
  13. 2022 High

    Establishing that NHE1 and SWELL1 polarize to opposite cell poles to drive osmotic water flux (Osmotic Engine Model) unified NHE1's ion transport and polarity roles into a biophysical mechanism for confined cell migration and metastatic extravasation.

    Evidence Live-cell polarization imaging, optogenetic Cdc42/RhoA activation, dual siRNA knockdown, in vivo metastasis assay

    PMID:36253369

    Open questions at the time
    • Whether the Osmotic Engine Model applies to all confined migration contexts unknown
    • Mechanism of Cdc42-dependent NHE1 polarization not molecularly defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the NHE1 cytosolic tail's multipartner scaffolding (ERM, PI(4,5)P2, kinases), how phosphorylation at distinct sites differentially tunes transport versus scaffolding functions, and whether mitochondrial NHE1 represents a physiologically relevant pool.
  • No high-resolution structure of the full cytosolic regulatory domain
  • Mitochondrial NHE1 localization reported by a single lab awaits independent confirmation
  • Phosphosite-specific effects on transport kinetics vs. protein interactions not systematically dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 8 GO:0005856 cytoskeleton 4
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-382551 Transport of small molecules 5 R-HSA-5357801 Programmed Cell Death 2
Partners
BRAFCHP1EZRMSNNHERF1PPP2CARDXTLN1
Complex memberships
NHE1-CHP1 homodimerNHE1-ERM-PI3K-Akt survival complexTalin-moesin-NHE1 invadopodium complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Cryo-EM structures of the human NHE1-CHP1 complex were solved in both inward-facing and inhibitor (cariporide)-bound outward-facing conformations, revealing that NHE1 assembles as a symmetrical homodimer and undergoes an elevator-like conformational change during cation exchange. The cariporide binding site was identified. CHP1 differentially associates with the two conformational states of each NHE1 monomer, underlying CHP1 regulation of NHE1 pH-sensitivity. Cryo-EM structural determination with functional validation Nature communications High 34108458
2002 NHE1 is predominantly localized in lamellipodia of migrating fibroblasts, where it functions as a plasma membrane anchor for actin filaments through direct binding of ERM (ezrin/radixin/moesin) proteins. Mutations that independently disrupt ERM binding/cytoskeletal anchoring or ion transport each impair cell polarity and migration, demonstrating that both functions are required for directed migration. Site-directed mutagenesis, wound-healing migration assays, subcellular localization imaging The Journal of cell biology High 12486114
2001 p38 MAPK directly phosphorylates the C-terminus of NHE1 within a 40-amino-acid region after trophic factor (IL-7 or IL-3) withdrawal. Mass spectrometry identified four phosphorylation sites: Thr717, Ser722, Ser725, and Ser728, leading to NHE1 activation, intracellular alkalinization, and cell death. In vitro kinase assay, mass spectrometry, dominant-negative kinase expression, pharmacological inhibition Molecular and cellular biology High 11604491
2004 Under apoptotic stress, NHE1 physically associates with phosphorylated ERM proteins within the cytoskeleton-enriched fraction, recruiting a signaling complex that includes PI3K and Akt, thereby promoting cell survival. ERM-binding-deficient NHE1 abolishes this Akt activation and survival signaling. Co-immunoprecipitation, dominant-negative constructs, apoptosis assays, NHE1-null cell rescue The Journal of biological chemistry High 15096511
1994 NHE1 contains N-linked glycosylation exclusively at Asn75 (first extracellular loop) and O-linked oligosaccharide also restricted to the first extracellular domain. The mature 110-kDa form at the cell surface carries both N- and O-linked sugars, while the 85-kDa ER form carries only N-linked high-mannose oligosaccharide. Glycosylation is not required for transport activity. Site-directed mutagenesis of N-glycosylation sites, glycosidase treatment, immunoblotting, functional transport assays Biochemistry High 8068684
1994 ATP depletion profoundly inhibits NHE1 transport without detectable changes in NHE1 phosphorylation or surface expression, but causes redistribution of NHE1 away from focal accumulations at the plasma membrane. The C-terminal cytosolic domain of NHE1 is required for its ATP dependence. NHE1 co-localizes with F-actin and redistributes when actin is disassembled, indicating interaction with the cytoskeleton. Truncation mutants, cell-surface biotinylation, immunofluorescence, cytochalasin D treatment, ATP depletion assays The Journal of biological chemistry High 8132605
2014 Talin C-terminus binds directly to the moesin FERM domain, recruiting a moesin-NHE1 complex to invadopodia. Silencing talin reduces cytosolic pH at invadopodia and blocks cofilin-dependent actin polymerization, impairing invadopodium stability and matrix degradation. Direct binding assay (pulldown), siRNA knockdown, live-cell pH imaging, invadopodium assays, in vivo metastasis assay The Journal of cell biology High 24891603
2013 The p.Gly305Arg missense mutation in SLC9A1 (NHE1 transmembrane segment 8) causes near-complete de-glycosylation, mis-targeting, and loss of proton-pumping activity of NHE1, resulting in Lichtenstein-Knorr syndrome (ataxia and sensorineural hearing loss). Homozygosity mapping, whole-exome sequencing, functional transport assay, glycosylation analysis Human molecular genetics High 25205112
2013 CHP1 assists in full glycosylation and membrane localization (biosynthetic maturation) of NHE1 required for Purkinje cell axon homeostasis. Truncated CHP1 isoforms are defective in stimulating NHE1 maturation; loss of membrane-localized NHE1 at axon terminals precedes Purkinje cell axon degeneration. Positional cloning, mouse genetics (vac mutant), subcellular fractionation, immunolocalization, NHE1 null genetic ablation The Journal of neuroscience High 23904602
2006 Adenosine A1 receptor stimulation recruits PP2A catalytic subunit to the particulate (NHE1-containing) fraction via Gi proteins. Purified PP2A dephosphorylates a GST-NHE1 fusion protein (aa 625-747) pre-phosphorylated by RSK in vitro. In intact cardiomyocytes, PP2A co-localizes with NHE1 at intercalated discs and its inhibition prevents CPA-mediated attenuation of NHE1 phosphorylation and activity. In vitro phosphatase assay with purified proteins, co-immunoprecipitation, confocal immunofluorescence, subcellular fractionation The Journal of biological chemistry High 16707501
2010 An EPR/structural modeling study confirmed that TM IV and TM XI of NHE1 are in close proximity (~15 Å between spin labels A173C and I461C). This distance decreases at low pH and in the presence of cariporide, consistent with TM IV–TM XI rearrangements during ion translocation and inhibitor binding. Mutation of Arg425 that stabilizes this arrangement causes partial loss of function. EPR spectroscopy with spin-labeled cysteine mutants, structural modeling (NhaA template), site-directed mutagenesis, functional transport assays The Journal of biological chemistry High 20974853
2011 B-Raf associates with the cytosolic regulatory tail (C-terminal 182 aa) of NHE1 in vivo (co-immunoprecipitation from HeLa and HEK cells) and in vitro (purified protein pulldown). The constitutively active B-Raf(V600E) oncogenic mutant increases NHE1 activity and raises resting intracellular pH in melanoma cells; inhibition of B-Raf (sorafenib, PLX4720, or siRNA) abolishes ERK phosphorylation and decreases NHE1 activity. Co-immunoprecipitation, in vitro pulldown with purified proteins, pharmacological inhibition, siRNA knockdown, intracellular pH measurement The Journal of biological chemistry High 21345796
2011 NHE1 is expressed in cardiac mitochondrial membranes. shRNA-mediated knockdown of NHE1 reduced mitochondrial NHE1 by ~60% and significantly reduced Ca2+-induced mitochondrial permeability transition pore (MPTP) opening/swelling by 64%, demonstrating a functional role of mitochondrial NHE1 in MPTP regulation. Lentiviral shRNA knockdown, mitochondrial fractionation, electron microscopy, immunostaining, mitochondrial swelling assay American journal of physiology. Heart and circulatory physiology Medium 21297023
2002 H2O2 activates NHE-1 activity through ERK1/2-dependent phosphorylation of the NHE-1 carboxyl tail, and this NHE-1 activation mediates ~50% of H2O2-induced intracellular Ca2+ overload in cardiomyocytes. Intracellular Ca2+ measurement (fura-2), ERK inhibitor (U0126), NHE-1 inhibitor (HOE-642), phosphorylation analysis American journal of physiology. Heart and circulatory physiology Medium 12124207
2013 EGF promotes complex formation of EGFR with NHE1 via the scaffolding protein NHERF1 (Na+/H+ exchanger regulatory factor 1), engaging EGFR in a negative transregulatory loop that controls EGFR oncogenic signaling duration and stimulates NHE1 activity in pancreatic cancer cells. Co-immunoprecipitation, 3D growth and invasion assays, NHE1 inhibition, lipid raft fractionation Neoplasia Medium 25748234
2011 Hypoxia activates p90 ribosomal S6 kinase (p90RSK), which phosphorylates NHE-1 at specific sites to increase Na+/H+ exchange rate and intracellular pH, thereby stimulating invadopodium formation and cancer cell invasion. shRNA depletion of NHE-1, live-cell pH imaging, invadopodium assays, p90RSK inhibition/knockdown, phosphorylation analysis PloS one Medium 22216126
2007 DNA damage in thymocytes upregulates NHE-1 expression, which is necessary and sufficient for subsequent intracellular alkalinization, Bcl-xL deamidation at Asn52/Asn66, and apoptosis. Enforced intracellular alkalinization mimics DNA damage effects. NHE-1-deficient cell lines, pharmacological inhibition, enforced alkalinization, deamidation assay, apoptosis assays PLoS biology High 17177603
2014 NHE1 interacts with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] through its cytosolic domain to promote proximal tubule cell survival. Long-chain acyl-CoA (LC-CoA) metabolites directly interact with the NHE1 cytosolic domain with affinity comparable to PI(4,5)P2 and compete with PI(4,5)P2 for NHE1 binding, disrupting NHE1-PI(4,5)P2 interaction and lowering the apoptotic threshold. Direct binding assay (LC-CoA vs. PI(4,5)P2 competition), inhibition of LC-CoA catabolism/generation, functional NHE1 activity assay, mouse models of kidney disease The Journal of clinical investigation High 24531551
2013 Phosphorylation of NHE1 at Ser703 by Sgk1 (serum- and glucocorticoid-inducible kinase 1) is required for dexamethasone-stimulated NHE1 activation. In sgk1-knockout mice, dexamethasone fails to increase NHE1 phosphorylation at Ser703 or NHE1 activity. Sgk1 knockout mice, phospho-specific antibody (P-Ser703), NHE1 activity measurement (BCECF), Sgk1 pharmacological inhibition Cellular physiology and biochemistry Medium 23860121
2010 NaV1.5 sodium channels and NHE1 are co-localized in caveolin-1-containing membrane rafts in breast cancer cells. NaV1.5 functionally couples to NHE1 to increase H+ efflux; inhibiting either reduces invasiveness by a similar magnitude with no additive effect when inhibited simultaneously. Co-localization by immunofluorescence, membrane raft fractionation, Matrigel invasion assay, pharmacological inhibition Oncogene Medium 21170089
2022 NHE1 polarizes to the leading edge and SWELL1 to the trailing edge of confined migrating cells, mediating asymmetric water influx and efflux (Osmotic Engine Model) to drive cell protrusion and migration. Optogenetic RhoA activation at the cell front triggers SWELL1 redistribution and migration reversal in a SWELL1-dependent manner. Cdc42 controls NHE1 repolarization. Dual NHE1/SWELL1 knockdown inhibits breast cancer cell extravasation and lung metastasis in vivo. Live-cell polarization imaging, optogenetics (RhoA, Cdc42), siRNA knockdown, mathematical modeling, in vivo metastasis assay Nature communications High 36253369
1993 When NHE1 is transfected into opossum kidney (OK) epithelial cells, it is expressed at the basolateral membrane (whereas endogenous NHE is apical). PKA activation by forskolin inhibits both apical and basolateral NHE activity, while PTH inhibits only apical NHE and phorbol ester (PKC activation) preferentially reduces apical NHE. Transfection into polarized cells, intracellular pH fluorimetry, pharmacological dissection of regulatory pathways Pflugers Archiv Medium 8272382
2013 Phosphorylation of NHE1 at the p90RSK/14-3-3 site (S703A mutation) is required for maintaining the mesenchymal phenotype of TNBC cells; the S703A mutation converts cells to an epithelial-like morphology with reduced vimentin expression, and markedly reduces migration, invasion, and metastatic potential. Site-directed mutagenesis of NHE1 regulatory phosphosites, morphological analysis, migration/invasion assays, vimentin expression analysis Oncotarget Medium 27049728
2013 Acute sustained intracellular acidosis (SIA) activates NHE1 in kidney cells through an ERK-dependent pathway; in MDCK cells, amino acids Ser771, Ser776, Thr779, and Ser785 in the cytosolic regulatory tail are important for NHE1 phosphorylation and activation after SIA. Site-directed mutagenesis of NHE1 cytosolic tail, isoform-specific inhibitors, MEK inhibitor (U0126), intracellular pH measurement American journal of physiology. Renal physiology Medium 23678047
2010 Insulin stimulates PI3K-dependent translocation of NHE1 to the cardiomyocyte sarcolemma. Hypoxia, mitochondrial metabolic inhibition, and electrical contraction also translocate NHE1 to the sarcolemma through a PI3K-independent process, providing an additional level of activation beyond intrinsic catalytic regulation. Immunofluorescence microscopy, cell-surface biotinylation, PI3K inhibition, subcellular fractionation The Biochemical journal Medium 20868366
2018 Biallelic mutation (p.K19del) in CHP1 causes mutant CHP1 to fail integration into functional protein complexes and aggregate, leading to diminished soluble CHP1 and reduced membrane targeting of NHE1, resulting in autosomal recessive cerebellar ataxia. Whole-exome sequencing, subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, zebrafish morpholino model with mRNA rescue Neurology. Genetics High 29379881
1996 The NHE-1 promoter contains a functional AP-2 binding site that is critical for promoter activity in neonatal rat cardiomyocytes. Deletion or mutation of this AP-2 site reduces or eliminates promoter activity. Purified AP-2 protein and AP-2-like protein from myocyte nuclear extracts bind the AP-2 site by gel mobility shift assay. Deletion analysis, mutation of AP-2 site, gel mobility shift assay with purified AP-2 and nuclear extracts The American journal of physiology Medium 8769760
2003 An alternatively spliced variant of NHE1 lacking the amiloride binding site is expressed in human reticulocytes and erythrocytes. Transfection of this spliced variant restores amiloride-insensitive, phloretin-sensitive sodium-lithium countertransport (SLC) activity, identifying this alternative splice form as the molecular basis of SLC. RT-PCR cloning, transfection functional assay, pharmacological profiling Diabetes Medium 12765964
2008 Deficiency of the NHE1 gene prevents hypoxia-induced pulmonary hypertension and vascular remodeling in mice, associated with decreased Rho kinase (ROCK1 and ROCK2) expression and increased p27 expression in NHE1-null mice. NHE1 knockout mice, hemodynamic measurements, right ventricular weight, histomorphometry, Western blot of downstream signaling American journal of respiratory and critical care medicine Medium 18310478
2011 Lentiviral shRNA-mediated NHE-1 knockdown in the myocardium abolishes the slow force response (SFR) to myocardial stretch, establishing NHE-1 activation as a key determinant of the contractile SFR (in vitro Anrep effect), even when ERK1/2 phosphorylation is preserved. Lentiviral shRNA NHE1 knockdown in rat myocardium, intracellular pH measurement, contractile force measurement, ERK1/2 phosphorylation analysis Journal of applied physiology Medium 21659487
2010 NHE1 inhibition suppresses HIF-1α-induced angiogenesis in HUVECs by modulating calpain activity: NHE1 siRNA decreased intracellular pH, reduced calpain-2 (but not calpain-1) expression and calpain activity, and inhibited HIF-1α-driven proliferation, migration, and tube formation. The inhibitory effect was reversed by VEGF and the reversal was abrogated by a calpain inhibitor. siRNA knockdown of NHE1, calpain activity assay, intracellular pH measurement, Matrigel tube formation assay, epistasis with VEGF and calpain inhibitor Microvascular research Medium 21185840
2010 NHE-1 associates with the Na-K-ATPase α1-subunit, and ouabain-stimulated Na-K-ATPase activity depends on this NHE-1 interaction. Inhibition or absence of NHE-1 prevents ouabain-mediated stimulation of Na-K-ATPase tyrosine phosphorylation and (86)Rb uptake; re-expression of wild-type NHE-1 in NHE-1-deficient cells restores ouabain regulation. Co-immunoprecipitation, NHE-1 inhibitor (EIPA), wild-type NHE-1 expression rescue in HK-2 cells, 86Rb uptake, tyrosine phosphorylation assay American journal of physiology. Renal physiology Medium 20427472

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 407 11807182
2002 Cell migration requires both ion translocation and cytoskeletal anchoring by the Na-H exchanger NHE1. The Journal of cell biology 370 12486114
2010 Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H(+) efflux in caveolae. Oncogene 154 21170089
2004 The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival. The Journal of biological chemistry 142 15096511
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 127 24195657
1994 Immunolocalization of anion exchanger AE2 and cation exchanger NHE-1 in distinct adjacent cells of gastric mucosa. The American journal of physiology 127 8141271
1994 The Na+/H+ exchanger NHE-1 possesses N- and O-linked glycosylation restricted to the first N-terminal extracellular domain. Biochemistry 123 8068684
2006 Role of the Na/H exchanger NHE1 in cell migration. Acta physiologica (Oxford, England) 117 16734751
2008 The role of NHE-1 in myocardial hypertrophy and remodelling. Journal of molecular and cellular cardiology 97 18329039
2002 H(2)O(2)-induced Ca(2+) overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway. American journal of physiology. Heart and circulatory physiology 91 12124207
2005 Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation 90 16216978
1994 ATP dependence of NHE-1, the ubiquitous isoform of the Na+/H+ antiporter. Analysis of phosphorylation and subcellular localization. The Journal of biological chemistry 90 8132605
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 72 34108458
2011 Hypoxia-induced invadopodia formation involves activation of NHE-1 by the p90 ribosomal S6 kinase (p90RSK). PloS one 71 22216126
2015 A novel NHE1-centered signaling cassette drives epidermal growth factor receptor-dependent pancreatic tumor metastasis and is a target for combination therapy. Neoplasia (New York, N.Y.) 70 25748234
2018 The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms. International journal of cancer 64 29363134
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
2022 Direct cardio-protection of Dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling. Acta pharmacologica Sinica 60 35217813
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
2006 A novel role for protein phosphatase 2A in receptor-mediated regulation of the cardiac sarcolemmal Na+/H+ exchanger NHE1. The Journal of biological chemistry 59 16707501
2022 Polarized NHE1 and SWELL1 regulate migration direction, efficiency and metastasis. Nature communications 58 36253369
2009 Repression of NHE1 expression by PPARgamma activation is a potential new approach for specific inhibition of the growth of tumor cells in vitro and in vivo. Cancer research 55 19887620
2009 Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. Journal of molecular and cellular cardiology 53 19318234
2012 Anti-proliferative effect of atrial natriuretic peptide on colorectal cancer cells: evidence for an Akt-mediated cross-talk between NHE-1 activity and Wnt/β-catenin signaling. Biochimica et biophysica acta 51 22387884
2016 Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelial-mesenchymal transition of triple-negative breast cancer cells. Oncotarget 50 27049728
2014 Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. The Journal of clinical investigation 50 24531551
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 49 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
2013 Sgk1-dependent stimulation of cardiac Na+/H+ exchanger Nhe1 by dexamethasone. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 48 23860121
2002 Structure and function of the NHE1 isoform of the Na+/H+ exchanger. Biochemistry and cell biology = Biochimie et biologie cellulaire 48 12440691
2005 Extracellular pH Controls NHE1 expression in epidermis and keratinocytes: implications for barrier repair. The Journal of investigative dermatology 46 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 44 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 43 30849956
2014 Mutation of SLC9A1, encoding the major Na⁺/H⁺ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome. Human molecular genetics 41 25205112
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 40 28055960
2015 Physiological Functions and Regulation of the Na+/H+ Exchanger [NHE1] in Renal Tubule Epithelial Cells. Kidney & blood pressure research 40 26304834
2010 Structural modeling and electron paramagnetic resonance spectroscopy of the human Na+/H+ exchanger isoform 1, NHE1. The Journal of biological chemistry 39 20974853
2007 NHE1, NHE2, and NHE4 contribute to regulation of cell pH in T84 colon cancer cells. Pflugers Archiv : European journal of physiology 39 17943310
2001 Immunolocalization of anion exchanger AE2, Na(+)/H(+) exchangers NHE1 and NHE4, and vacuolar type H(+)-ATPase in rat pancreas. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 39 11259449
1996 Cellular distribution and regulation of NHE-1 isoform of the NA-H exchanger in the avian osteoclast. Bone 39 8833201
2011 Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening. American journal of physiology. Heart and circulatory physiology 37 21297023
2007 The Na+/H+ exchanger, NHE1, differentially regulates mitogen-activated protein kinase subfamilies after osmotic shrinkage in Ehrlich Lettre Ascites cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 17982256
2004 Comparative biology of the ubiquitous Na+/H+ exchanger, NHE1: lessons from erythrocytes. Journal of experimental zoology. Part A, Comparative experimental biology 37 15229867
2010 Suppression of NHE1 by small interfering RNA inhibits HIF-1α-induced angiogenesis in vitro via modulation of calpain activity. Microvascular research 36 21185840
2009 Chronic NHE-1 blockade induces an antiapoptotic effect in the hypertrophied heart. Journal of applied physiology (Bethesda, Md. : 1985) 36 19179646
2009 Computational identification and experimental validation of PPRE motifs in NHE1 and MnSOD genes of human. BMC genomics 36 19958503
2015 Na (+)/H (+)exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis? The International journal of developmental biology 35 26679950
2008 Estrogen exerts concentration-dependent pro-and anti-hypertrophic effects on adult cultured ventricular myocytes. Role of NHE-1 in estrogen-induced hypertrophy. Journal of molecular and cellular cardiology 35 19111554
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
1998 Colitis-induced changes in the expression of the Na+/H+ exchanger isoform NHE-1. The Journal of pharmacology and experimental therapeutics 35 9580638
2014 Physiological cardiac hypertrophy: critical role of AKT in the prevention of NHE-1 hyperactivity. Journal of molecular and cellular cardiology 34 25240639
2013 Inside out: targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Chemical biology & drug design 33 23253131
2011 B-Raf associates with and activates the NHE1 isoform of the Na+/H+ exchanger. The Journal of biological chemistry 33 21345796
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
1994 Enhanced Na(+)-H+ exchanger activity and NHE-1 mRNA levels in human lymphocytes during metabolic acidosis. The American journal of physiology 31 7511337
1993 Na/H exchange activities in NHE1-transfected OK-cells: cell polarity and regulation. Pflugers Archiv : European journal of physiology 31 8272382
2024 Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2. Basic research in cardiology 30 39046464
2018 The role of CD44, hyaluronan and NHE1 in cardiac remodeling. Life sciences 30 30089233
2020 Empagliflozin Decreases Lactate Generation in an NHE-1 Dependent Fashion and Increases α-Ketoglutarate Synthesis From Palmitate in Type II Diabetic Mouse Hearts. Frontiers in cardiovascular medicine 29 33344518
2018 A novel SLC9A1 mutation causes cerebellar ataxia. Journal of human genetics 29 30018422
2018 Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity. Acta physiologica (Oxford, England) 28 31595734
2013 Acidosis-mediated regulation of the NHE1 isoform of the Na⁺/H⁺ exchanger in renal cells. American journal of physiology. Renal physiology 28 23678047
2008 Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes. American journal of physiology. Heart and circulatory physiology 28 18263712
2000 Localization of Idd11 using NOD congenic mouse strains: elimination of Slc9a1 as a candidate gene. Immunogenetics 28 10663560
2013 Extracellular matrix composition and interstitial pH modulate NHE1-mediated melanoma cell motility. International journal of oncology 27 24173371
2011 In vivo key role of reactive oxygen species and NHE-1 activation in determining excessive cardiac hypertrophy. Pflugers Archiv : European journal of physiology 27 21870055
2010 Translocation of the Na+/H+ exchanger 1 (NHE1) in cardiomyocyte responses to insulin and energy-status signalling. The Biochemical journal 27 20868366
2015 Na+-H+ exchanger-1 (NHE1) regulation in kidney proximal tubule. Cellular and molecular life sciences : CMLS 26 25680790
2012 Identification of a potent sodium hydrogen exchanger isoform 1 (NHE1) inhibitor with a suitable profile for chronic dosing and demonstrated cardioprotective effects in a preclinical model of myocardial infarction in the rat. Journal of medicinal chemistry 26 22803959
2010 A novel chimeric natriuretic peptide reduces cardiomyocyte hypertrophy through the NHE-1-calcineurin pathway. Cardiovascular research 26 20679416
1999 Cloning and expression of the Na+/H+ exchanger from Amphiuma RBCs: resemblance to mammalian NHE1. The American journal of physiology 26 10329949
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
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
2014 High glucose concentration stimulates NHE-1 activity in distal nephron cells: the role of the Mek/Erk1/2/p90RSK and p38MAPK signaling pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 24557342
2018 Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. International journal of molecular medicine 23 30592266
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
2000 Expression of the Na(+)/H(+) exchanger isoform NHE1 in rat skeletal muscle and effect of training. Acta physiologica Scandinavica 23 10971224
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
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
2018 Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. Neurology. Genetics 20 29379881
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
2021 Advances in research on the regulatory mechanism of NHE1 in tumors. Oncology letters 19 33717270
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 18 31015514
2016 Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells. The Journal of biological chemistry 18 27629415
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