Affinage

Showing SLC9A6 — NHE6 is a alias.

SLC9A6

Sodium/hydrogen exchanger 6 · UniProt Q92581

Length
701 aa
Mass
77.9 kDa
Annotated
2026-06-10
64 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC9A6 encodes NHE6, an electroneutral (Na+,K+)/H+ exchanger that resides predominantly in early and recycling endosomes, where its proton-leak activity raises luminal pH and thereby governs endosome maturation, cargo sorting, and lysosomal function in neurons (PMID:21881004, PMID:24035762, PMID:34526390). NHE6 is synthesized through the secretory pathway with an N-terminal cleavable signal peptide, is N-glycosylated, and matures into a homodimer of 13-transmembrane-helix protomers with a conserved cation-binding site that exchanges both Na+ and K+ for protons [PMID:11641397, PMID:bio_10.1101_2025.07.21.665523]. Endosomal targeting is directed by its cytoplasmic C-terminus through interaction with the adaptor GGA1, which routes NHE6 to endosomes rather than the Golgi, lysosomes, or the cell surface (PMID:39002678). By limiting endosomal acidification, NHE6 enables endosome maturation via 'inside-out' proton signaling: lowered pH inactivates the Rab7-GAP TBC1D5 with which NHE6 forms a complex, so loss of NHE6 overacidifies endosomes, collapses Rab7 GTPase cycling, blocks endosome-lysosome fusion, prematurely activates cathepsin D, disrupts M6PR recycling, and drives cargo to degradation and increased exosome secretion [PMID:34526390, PMID:bio_10.1101_2024.12.09.627558]. This pH control sustains receptor signaling and synaptic trafficking — supporting BDNF/TrkB signaling and neuronal arborization, and the trafficking of AMPA receptors during long-term potentiation (PMID:24035762, PMID:31175985, PMID:39341363). Loss-of-function mutations in SLC9A6 cause Christianson syndrome, an X-linked disorder with intellectual disability, microcephaly, epilepsy, and ataxia, and NHE6-null animals develop lysosome deficiency followed by neurodegeneration with tau and amyloid-β deposition (PMID:18342287, PMID:21964919, PMID:34928329). Disease alleles act through multiple molecular failures — ER retention, impaired glycosylation, accelerated proteasomal/lysosomal degradation, defective endosomal sorting, and endosomal overacidification — while a rare gain-of-function variant instead alkalinizes endosomes, establishing endosomal pH set-point as the critical output (PMID:27590723, PMID:30296617, PMID:32277048). Beyond its canonical endosomal role, NHE6 scaffolds CDK5/p35 and regulates surface expression of the TRPV1 channel (PMID:42051037, PMID:32569089), and hypoxia-driven relocalization of NHE6 to the plasma membrane via the PKC-RACK1 complex hyperacidifies endosomes to confer chemoresistance (PMID:28635961).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2001 High

    Established how NHE6 is made and where it first goes, defining it as a glycosylated, secretory-pathway membrane protein rather than a cytosolic exchanger.

    Evidence GFP-fusion localization, in vitro signal peptide assay, cell fractionation and endoglycosidase H treatment in COS7 cells and rat liver

    PMID:11641397

    Open questions at the time
    • Did not establish the steady-state endosomal compartment
    • No ion transport activity demonstrated
  2. 2006 High

    Demonstrated that NHE6 is a functional cation/H+ exchanger capable of Na+-independent, K+-dependent proton exchange, defining its biochemical activity.

    Evidence Heterologous expression in yeast exchanger-null strains plus intracellular pH imaging and ion substitution in vestibular hair cells

    PMID:17005858

    Open questions at the time
    • Did not resolve physiological localization vs plasma-membrane activity
    • Stoichiometry not defined
  3. 2008 High

    Linked SLC9A6 to human disease, establishing NHE6 loss of function as the cause of an X-linked neurodevelopmental syndrome.

    Evidence Linkage analysis and sequencing of patient families identifying deletion and point mutations

    PMID:18342287

    Open questions at the time
    • No mechanism connecting transporter loss to neuronal phenotype
    • No cellular model of pathogenesis
  4. 2010 High

    Connected NHE6 ion transport to its physiological output by showing reciprocal control of recycling-endosome luminal pH and a defined membrane-maintenance phenotype.

    Evidence siRNA knockdown and overexpression with live-cell pH imaging in polarized HepG2 cells

    PMID:20130086

    Open questions at the time
    • Did not address neuronal relevance
    • Mechanism of cargo misdirection not yet defined
  5. 2011 High

    Defined the core pathogenic mechanism in animals — NHE6 loss causes endolysosomal storage and neurodegeneration phenocopying lysosomal storage disorders.

    Evidence Slc9a6 KO mouse with histochemistry, β-hexosaminidase assays, and histopathology

    PMID:21964919

    Open questions at the time
    • Molecular link between endosomal pH and lysosomal enzyme failure unresolved
    • Cell-autonomous vs non-autonomous effects unclear
  6. 2011 High

    Showed that NHE6 ion-transport activity is required to set endosomal pH and support clathrin-mediated endocytosis, using transport-dead mutants to separate function from mere presence.

    Evidence siRNA knockdown plus WT and transport-deficient mutant rescue with transferrin uptake and endosomal pH measurement in HeLa cells

    PMID:21881004

    Open questions at the time
    • Did not identify the regulatory partners controlling localization
    • Neuronal cargo not examined
  7. 2013 High

    Identified TrkB/BDNF signaling as a key NHE6-dependent neuronal pathway and showed proton-leak activity is required for neuronal arborization.

    Evidence NHE6 KO mice with proton-leak mutagenesis, phospho-TrkB blots, and BDNF rescue

    PMID:24035762

    Open questions at the time
    • Mechanism of TrkB endosomal mis-sorting not defined
    • Did not address synaptic cargo beyond TrkB
  8. 2013 Medium

    Placed NHE6 at glutamatergic synapses with activity-dependent trafficking during LTP, implicating it in synaptic plasticity.

    Evidence Quantitative immunofluorescence and LTP induction in mouse hippocampal slices

    PMID:23303939

    Open questions at the time
    • No loss-of-function in the same study
    • Causal role in plasticity not yet tested
  9. 2015 Medium

    Connected NHE6-controlled endosomal pH to amyloid precursor protein processing, linking the transporter to amyloid-β production.

    Evidence Reciprocal overexpression/knockdown in APP-expressing cells with endosomal pH and Aβ ELISA

    PMID:25561733

    Open questions at the time
    • Human brain data correlational only
    • In vivo causality not established here
  10. 2009 Medium

    Showed how a patient deletion allele fails (dual proteasomal/lysosomal degradation) and revealed functional redundancy with NHE9 in endosomal acidification.

    Evidence Stability assays with proteasome/lysosome inhibitors and siRNA co-depletion in HeLa cells

    PMID:19619532

    Open questions at the time
    • Redundancy mapped only by co-depletion
    • Single cell-line context
  11. 2016 High

    Extended the disease-allele logic by showing a Christianson variant triggers ubiquitination, degradation, endosomal overacidification, and neuronal apoptosis.

    Evidence Multi-cell-line and primary neuron assays of maturation, ubiquitination, pH, trafficking and apoptosis

    PMID:27590723

    Open questions at the time
    • Did not map structural basis of misfolding
    • Apoptotic trigger downstream of pH not defined
  12. 2018 High

    Demonstrated that endosomal pH set-point, not transporter presence per se, is the critical variable — a gain-of-function variant alkalinizes endosomes yet still impairs neurons.

    Evidence Transfected non-neuronal cells and hippocampal neurons with pH, trafficking, exosome and dendritic spine assays

    PMID:30296617

    Open questions at the time
    • Structural basis of G218R activity change not resolved
    • In vivo phenotype of gain-of-function untested
  13. 2019 High

    Provided the mechanistic link from NHE6 loss to synaptic failure: misdirection of AMPA receptors to lysosomes, partially rescuable by blocking lysosomal degradation.

    Evidence ΔES NHE6 in hippocampal neurons with LTP electrophysiology and lysosomal-inhibitor rescue

    PMID:31175985

    Open questions at the time
    • Did not define the sorting machinery diverting cargo to lysosomes
    • Other plasticity cargos not enumerated
  14. 2020 High

    Systematically mapped disease-causing dysfunction to the ion-translocation domain and C-terminal regulatory domain across multiple variants.

    Evidence Heterologous expression of six variants in NHE6-null AP-1 cells with maturation, pH, trafficking and apoptosis assays

    PMID:32277048

    Open questions at the time
    • Did not test variants in vivo
    • Structural correlates inferred, not solved
  15. 2020 Medium

    Broadened NHE6 function beyond CNS development to nociception, showing it controls TRPV1 surface expression via endosomal trafficking.

    Evidence Nhe6 KO behavioral pain assays, TRPV1 fractionation, and Ca2+ imaging in nociceptors

    PMID:32569089

    Open questions at the time
    • Mechanism of TRPV1 sorting not detailed
    • Single lab
  16. 2020 Medium

    Extended TrkB-pathway dependence to cochlear neurons and tied NHE6 loss to altered Rab GTPase balance and hearing loss.

    Evidence Nhe6 KO auditory brainstem response with TrkB/Akt phospho-blots and Rab expression in organ of Corti

    PMID:32107410

    Open questions at the time
    • Rab changes correlative
    • Causality of Rab dysregulation untested here
  17. 2021 High

    Identified SCAMP5 as a direct C-terminal partner controlling axonal/presynaptic delivery of NHE6 and synaptic-vesicle pH, with NHE6 KO epistasis confirming the pathway.

    Evidence Domain-mapped Co-IP, shRNA knockdown, quantal-size electrophysiology and NHE6 KO occlusion

    PMID:33372133

    Open questions at the time
    • How SCAMP5 directs axonal targeting mechanistically unclear
    • Relationship to GGA1-dependent sorting not addressed
  18. 2021 Medium

    Showed SCAMP5-dependent NHE6 recruitment to synaptic vesicles is enhanced by chemical LTP, linking the partnership to activity-dependent plasticity.

    Evidence cLTP protocol with SCAMP5 knockdown, bouton imaging and quantal-size recording in hippocampal neurons

    PMID:33663553

    Open questions at the time
    • Functional consequence of increased boutons unresolved
    • Follow-up from same lab
  19. 2021 High

    Defined the cell-biological cascade of NHE6 loss: failed endosome-lysosome fusion, premature cathepsin D activation, M6PR mis-recycling and elevated exosome release driving lysosome deficiency.

    Evidence NHE6-null neuron TIRF fusion imaging, cathepsin D assays, M6PR staining and exosome characterization

    PMID:34526390

    Open questions at the time
    • The pH-sensitive molecular switch on maturation not yet identified here
    • Retromer involvement inferred
  20. 2021 Medium

    Provided genetic-epistasis evidence that NHE6-driven endosomal acidification interacts with ApoE and amyloid pathology, with NHE6 loss suppressing plaque deposition.

    Evidence Slc9a6 KO crossed with ApoE4 and amyloid model mice with plaque and synaptic readouts

    PMID:34617884

    Open questions at the time
    • Apparent protective direction conflicts with neurodegenerative phenotype in other models
    • Mechanism of occlusion not molecularly resolved
  21. 2022 High

    Ordered the pathogenic sequence in vivo: lysosome deficiency precedes neurodegeneration which precedes amyloid-β and tau aggregation.

    Evidence CRISPR NHE6-null rat with longitudinal histopathology, lysosomal/autophagy and aggregate biochemistry

    PMID:34928329

    Open questions at the time
    • Trigger converting lysosome defect into aggregation not defined
    • Cell-type specificity of progression incomplete
  22. 2024 High

    Identified GGA1 as the C-terminal adaptor that targets NHE6 to endosomes, explaining how the transporter avoids the surface, Golgi and lysosomes.

    Evidence Yeast two-hybrid, endogenous Co-IP from brain, hybrid constructs, and GGA1 KO fractionation with Golgi pH measurement

    PMID:39002678

    Open questions at the time
    • How GGA1 selectivity for organellar NHEs is encoded not fully defined
    • Interplay with SCAMP5 routing untested
  23. 2024 Medium

    Defined a transcriptional control axis (HDAC4 represses NHE6) whose pharmacological reversal corrects endosomal pH, LRP1 trafficking and amyloid burden.

    Evidence HDAC4 nuclear-translocation assays, vorinostat treatment, LRP1 trafficking and plaque quantification in 5xFAD mice

    PMID:41933339

    Open questions at the time
    • Direct vs indirect transcriptional repression not fully separated
    • Single lab
  24. 2024 Medium

    Implicated NHE6 in HIV immune evasion by showing its depletion acidifies endosomes and that restoring NHE6 impairs Nef-driven MHC-I downmodulation.

    Evidence HIV-1 infection of primary T cells with NHE6 overexpression, pH and MHC-I assays, and Nef Co-IP (preprint)

    PMID:bio_10.1101_2024.12.17.628989

    Open questions at the time
    • Preprint, not peer-reviewed
    • Direct NHE6–Nef pathway mechanism not fully resolved
  25. 2024 High

    Revealed the molecular switch coupling pH to endosome maturation: NHE6 acidification controls the Rab7-GAP TBC1D5 with which it forms a complex, gating Rab7 cycling.

    Evidence pH-dependent GAP assays, NHE6/TBC1D5/Rab7 Co-IP, proton-efflux-defective knockin neurons and epistatic TBC1D5 knockdown (preprint)

    PMID:bio_10.1101_2024.12.09.627558

    Open questions at the time
    • Preprint, not peer-reviewed
    • Whether TBC1D5 is the sole pH-sensitive effector unresolved
  26. 2024 Medium

    Confirmed TrkB as the actionable downstream effector by rescuing NHE6 KO synaptic plasticity with a selective TrkB agonist.

    Evidence Nhe6 KO neurons with 7,8-DHF rescue of spine density and LTP electrophysiology

    PMID:39341363

    Open questions at the time
    • Did not address non-TrkB cargo contributions
    • Confirmatory of prior pathway
  27. 2025 High

    Provided the atomic architecture: a homodimeric 13-TM transporter with a conserved inward-open cation site, a lipid-bound C-terminal helix, and a disordered distal C-terminus, while confirming dual Na+/K+ for proton exchange.

    Evidence Cryo-EM at 3.4 Å, in vitro ion-exchange assays, NMR and SAXS (preprint)

    PMID:bio_10.1101_2025.07.21.665523

    Open questions at the time
    • Preprint, not peer-reviewed
    • Structural basis of disease alleles not mapped onto the model
  28. 2026 Medium

    Established a transport-independent scaffolding role: NHE6 binds CDK5/p35 and promotes their membrane localization and surface accumulation of CDK5-regulated TRPV1.

    Evidence Yeast two-hybrid, Co-IP and subcellular fractionation with TRPV1 surface assay in CHO/SH-SY5Y cells

    PMID:42051037

    Open questions at the time
    • Physiological significance of scaffolding in vivo untested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how NHE6's distinct partner systems (GGA1 sorting, SCAMP5 axonal delivery, TBC1D5/Rab7 maturation, CDK5 scaffolding) are coordinated and how disease alleles map onto the new structural model to produce graded endosomal pH dysregulation.
  • No integrated model linking sorting adaptors to the pH-sensing TBC1D5/Rab7 switch
  • Disease variants not yet interpreted on the cryo-EM structure
  • Tissue-specific partner usage undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-112316 Neuronal System 2 R-HSA-162582 Signal Transduction 2
Partners
AGTR2CDK5GGA1RAB7RACK1SCAMP5TBC1D5

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 NHE6 is targeted to the ER membrane via an N-terminal signal peptide (H1) that directs translocation and is processed off; the second hydrophobic segment (H2) halts translocation and becomes a transmembrane segment. The full-length protein localizes to the ER and cell surface and is fully N-glycosylated. Cell fractionation shows NHE6 in microsomal membranes of rat liver with endoglycosidase H-resistant sugar chains, indicating transit through the Golgi. GFP-fusion constructs in COS7 cells, in vitro signal peptide assay, cell fractionation, endoglycosidase H treatment, Western blot with C-terminal antibody The Journal of biological chemistry High 11641397
2006 NHE6 (and NHE9) can mediate K+/H+ exchange at the plasma membrane of vestibular hair bundles, supporting pH recovery in a Na+-independent, K+-dependent manner. Heterologous expression of NHE6 in yeast lacking endogenous exchangers conferred pH-dependent tolerance to high KCl and NaCl, demonstrating its cation/H+ exchange activity. Heterologous expression in yeast exchanger-null strains, intracellular pH imaging in hair cells, ion substitution experiments, immunolocalization The Journal of neuroscience : the official journal of the Society for Neuroscience High 17005858
2008 Loss-of-function mutations in SLC9A6 (encoding NHE6) cause X-linked mental retardation with microcephaly, epilepsy, and ataxia, establishing NHE6 as the disease gene for what became Christianson syndrome. Linkage analysis, DNA sequencing of patient samples identifying deletion and point mutations in SLC9A6 American journal of human genetics High 18342287
2009 A patient-derived 6-bp deletion mutant NHE6Δ255-256 is degraded via two independent pathways: proteasomal and lysosomal degradation, in contrast to wild-type NHE6 which traffics stably to the plasma membrane and early endosomes. Co-depletion of NHE6 and NHE9 (but not NHE6 alone) caused enhanced acidification of early endosomes, indicating functional redundancy between the two isoforms. Immunoblot stability assays, proteasome/lysosome inhibitors, siRNA co-depletion, endosomal pH measurement in HeLa cells Experimental cell research Medium 19619532
2010 NHE6.1, a variant localizing to recycling endosomes, modulates endosome luminal pH; knockdown decreases and overexpression increases recycling endosome pH. NHE6.1 is required for maintenance (but not de novo biogenesis) of apical bile canalicular plasma membranes in polarized HepG2 hepatoma cells; its loss promotes progressive loss of bulk membrane lipids from the apical surface. NHE6.1 siRNA knockdown, overexpression, live-cell pH imaging, immunofluorescence, apical surface integrity assays in HepG2 cells Molecular biology of the cell High 20130086
2010 An in-frame 9-bp deletion in SLC9A6 disrupts the NHE6 protein (localized to endosomal vesicles) and causes widespread neuronal tau deposition with 4R tau isoform predominance, including paired helical filaments, in post-mortem brain tissue, linking endosomal NHE6 dysfunction to cytoskeletal/tau pathology. Linkage analysis, DNA sequencing, post-mortem neuropathology, electron microscopy of tau filaments, biochemical tau isoform analysis Brain : a journal of neurology Medium 20395263
2011 Slc9a6 knockout mice show loss of NHE6 function leading to abnormal accumulation of GM2 ganglioside and unesterified cholesterol in late endosomes/lysosomes of specific neuronal populations, undetectable β-hexosaminidase activity in those neurons, neuroaxonal dystrophy, and progressive Purkinje cell loss — phenocopying lysosomal storage disorders and demonstrating that NHE6 is required for normal endosomal-lysosomal function. Slc9a6 KO mouse model, histochemical staining for gangliosides and cholesterol, β-hexosaminidase activity assays, behavioral testing, histopathology Brain : a journal of neurology High 21964919
2011 NHE6 regulates clathrin-dependent endocytosis of transferrin via endosomal pH regulation. NHE6 knockdown decreases transferrin uptake and acidifies transferrin-positive endosomes; NHE6 colocalizes with clathrin and transferrin at 2 min after endocytosis onset. Overexpression of wild-type but not ion-transport-deficient mutant NHE6 increases transferrin uptake and alkalinizes transferrin-positive endosomes, showing that ion transport activity is required. NHE6 siRNA knockdown in HeLa cells, transferrin uptake assays, endosomal pH measurement, immunofluorescence colocalization, overexpression of WT and transport-dead mutant NHE6 American journal of physiology. Cell physiology High 21881004
2005 The Angiotensin II receptor AT2 physically interacts with NHE6 in a ligand-dependent manner. Yeast two-hybrid assay mapped the interaction to the third intracellular loop/C-terminal cytoplasmic tail of AT2 and a 182-aa region spanning the predicted 5th intracellular loop and initial C-terminus of NHE6. Co-immunoprecipitation confirmed the AT2-NHE6 complex in MCF-7 cells upon AngII stimulation. Yeast two-hybrid screen, co-immunoprecipitation from MCF-7 cells with HA-tagged NHE6 upon AngII treatment Peptides Medium 15808917
2013 NHE6 loss of function leads to overacidification of the endosomal compartment, attenuated TrkB signaling in response to BDNF, and reduced axonal/dendritic branching and synapse number in mouse neurons. TrkB colocalizes with NHE6-associated endosomes; site-directed mutagenesis shows the proton-leak (ion transport) function of NHE6 is required for neuronal arborization. Exogenous BDNF rescues arborization defects. NHE6 knockout mice, site-directed mutagenesis of NHE6 proton-leak function, TrkB co-localization, phospho-TrkB western blot, BDNF rescue experiments, endosomal pH measurement Neuron High 24035762
2013 NHE6 localizes to recycling endosomes and partially colocalizes with early/recycling endosome markers and the AMPAR subunit GluA1 in CA1 pyramidal neuron dendritic spines. NHE6-containing vesicles show enhanced translocation to dendritic spine heads during NMDA receptor-dependent long-term potentiation (LTP), suggesting NHE6 participates in activity-dependent endosomal trafficking at glutamatergic synapses. Quantitative immunofluorescence microscopy, dual immunolabeling in mouse hippocampal slices, LTP induction protocol, developmental expression analysis in area CA1 The Journal of neuroscience : the official journal of the Society for Neuroscience Medium 23303939
2013 An NHE6 ΔWST (Trp370-Ser-Thr372 deletion) mutation causes ER retention of the protein, dramatically reduced oligosaccharide maturation and half-life, negligible trafficking to recycling endosomes, and reduced clathrin-mediated transferrin uptake. In primary hippocampal neurons, ΔWST displays diffuse reticular pattern (ER retention) versus wild-type punctate distribution, and ΔWST expression markedly reduces dendritic arborization. Transfected CHO and SH-SY5Y cells, primary mouse hippocampal neurons, immunoblot (stability/glycosylation), transferrin uptake assay, immunofluorescence Neurochemistry international Medium 24090639
2015 NHE6 co-expression or monensin treatment shifts APP localization from the trans-Golgi network to early/recycling endosomes and alkalinizes the endosomal lumen, significantly attenuating APP processing and Aβ secretion. NHE6 knockdown elevates Aβ production. NHE6 transcript and protein levels are reduced in Alzheimer brains. NHE6 overexpression and knockdown in HEK293/SH-SY5Y cells stably expressing APP, endosomal pH measurement, Aβ ELISA, Western blot The Journal of biological chemistry Medium 25561733
2016 A Christianson syndrome-linked ΔES (E287-S288 deletion) mutation in NHE6 causes reduced oligosaccharide maturation, enhanced ubiquitination, proteasomal/lysosomal degradation, reduced clathrin-mediated endocytosis, excessive endosomal acidification, and induces apoptosis in AP-1 cells. In primary mouse hippocampal neurons, ΔES impairs membrane trafficking, reduces dendritic length/area/arborization, and triggers apoptotic cell death. Transfected CHO/AP-1, HeLa, SH-SY5Y cells and primary hippocampal neurons; immunoblot, ubiquitination assay, endosomal pH measurement, transferrin uptake, apoptosis assays, confocal microscopy Molecular neurodegeneration High 27590723
2017 Hypoxia induces relocalization of NHE6 from endosomes to the plasma membrane, causing endosome hyperacidification and intravesicular drug trapping (chemoresistance). The NHE6 translocation to the plasma membrane involves binding to the activated PKC–RACK1 complex. Immunofluorescence and subcellular fractionation under hypoxia, pH-sensitive dyes for endosomal pH, drug accumulation assays, co-immunoprecipitation of NHE6 with PKC/RACK1 Nature communications High 28635961
2017 NHE6 is localized to the luminal plasma membrane domain of choroid plexus epithelial cells, identified by immunolocalization and FACS-based proteomics, suggesting a role in CSF pH regulation. FACS isolation of choroid plexus epithelial cells, mass spectrometry proteomics, RT-PCR, immunolocalization American journal of physiology. Cell physiology Low 29351414
2018 A de novo gain-of-function NHE6 variant (G218R) in the ion translocation domain causes endosomes to be atypically alkaline (rather than overacidified as in loss-of-function), impairs uptake of recycling endosomal cargo, and redirects NHE6 from recycling endosomes to multivesicular bodies/late endosomes and exosomes. In hippocampal neurons, G218R-containing endosomes show attenuated acidification, diminished dendritic branching, reduced spine density, and increased filopodia. Transfected non-neuronal cells and primary hippocampal neurons; endosomal pH measurement, glycosylation/stability assays, ubiquitination assay, transferrin uptake, exosome isolation, confocal microscopy of dendritic spines Neurobiology of disease High 30296617
2019 The ΔES NHE6 mutation attenuates synapse density and structural/functional LTP in hippocampal neurons by misdirecting AMPA receptors (and other cargos) to lysosomes, preventing their trafficking during synaptic remodeling. Inhibition of lysosomal acidification (bafilomycin) or proteolysis (leupeptin) partially rescues synapse density and LTP. Primary mouse hippocampal neurons transfected with fluorescently-tagged ΔES NHE6, live imaging, LTP electrophysiology, AMPA receptor trafficking assays, lysosomal inhibitor rescue experiments Neurobiology of disease High 31175985
2020 NHE6 is expressed in nociceptors and cortical neurons involved in pain processing. Loss of NHE6 in Nhe6 KO mice reduces TRPV1 expression at the plasma membrane of nociceptors and decreases capsaicin-induced Ca2+ influx, explaining elevated pain tolerance in KO mice. NHE6 regulates surface expression of the TRPV1 channel through endosomal trafficking. Nhe6 KO mouse behavioral pain assays, NHE6 immunolabeling in DRG neurons, TRPV1 plasma membrane fractionation, Ca2+ imaging in primary nociceptors Pain Medium 32569089
2020 NHE6 deficiency in Nhe6 KO mice leads to hearing loss associated with reduced TrkB and Akt phosphorylation in the organ of Corti, altered Rab GTPase expression (decreased Rab7, increased Rab11), and cochlear nerve axon loss, demonstrating that NHE6 is required for BDNF/TrkB endosomal signaling in cochlear neurons. Nhe6 KO mouse auditory brainstem response, immunohistochemistry, Western blot for TrkB/Akt phosphorylation, Rab GTPase expression, anti-neurofilament staining in cochlea Scientific reports Medium 32107410
2020 Six NHE6 variants associated with Christianson syndrome were characterized: A9S and R568Q behave largely like wild-type; L188P, G383D, E547*, and W570* show variable deficiencies in post-translational maturation (glycosylation), membrane sorting to recycling endosomes, endosomal pH homeostasis, and cargo trafficking, and trigger apoptosis. This maps disease-causing dysfunction to the membrane ion translocation domain and the C-terminal regulatory domain. Heterologous expression in NHE6-deficient AP-1 cells, immunoblot, endosomal pH measurement, transferrin uptake, apoptosis assays The Journal of biological chemistry High 32277048
2021 SCAMP5 directly interacts with NHE6 via its 2/3 loop domain binding to the C-terminal region of NHE6. SCAMP5 knockdown or perturbation of the SCAMP5/NHE6 interaction inhibits axonal trafficking and presynaptic localization of NHE6, leading to hyperacidification of synaptic vesicles and reduced quantal size of glutamate release. NHE6 knockout occludes the effect of SCAMP5 knockdown. Co-IP, truncation constructs for domain mapping, shRNA knockdown, optical imaging of NHE6 localization, electrophysiological recording of quantal size, NHE6 KO epistasis Proceedings of the National Academy of Sciences of the United States of America High 33372133
2021 SCAMP5-dependent recruitment of NHE6 to synaptic vesicles is enhanced during chemical LTP (cLTP), with increased NHE6-positive presynaptic boutons at existing and newly formed synapses. SCAMP5 knockdown abolishes cLTP-induced enhancement of NHE6 recruitment. Despite increased NHE6-positive boutons, quantal size of glutamate release remains unaltered after cLTP. Chemical LTP protocol in hippocampal neurons, SCAMP5 shRNA knockdown, quantitative immunofluorescence of NHE6-positive boutons, electrophysiological quantal size measurement Molecular brain Medium 33663553
2021 Loss of NHE6 in null mouse neurons causes defective endosome maturation and trafficking: decreased endosome-lysosome fusion, premature activation of cathepsin D (CatD) in endosomes, reduced CatD activity/levels in lysosomes, accumulation of M6PRs in late endosomes suggesting defective M6PR recycling/retromer function, and increased exosome secretion via enhanced MVB-plasma membrane fusion. These endosome trafficking defects underlie lysosome deficiency. NHE6-null mouse neurons in vitro, live-cell TIRF imaging for MVB-plasma membrane fusion, cathepsin D activity assays, M6PR immunostaining, lysosomal proteolysis assays, exosome characterization The Journal of neuroscience : the official journal of the Society for Neuroscience High 34526390
2021 NHE6 depletion in mice (Slc9a6 KO) enhances endosomal acidification, which restores vesicular trafficking and normalizes synaptic homeostasis in the context of ApoE4. Loss of NHE6 also suppresses amyloid deposition even in the absence of ApoE4, demonstrating that accelerated EE acidification caused by NHE6 absence occludes ApoE effects on amyloid plaque formation. Slc9a6 KO mice crossed with ApoE4 and amyloid model mice; amyloid plaque quantification, synaptic marker analysis, endosomal trafficking assays eLife Medium 34617884
2022 NHE6-null rat brains show early lysosome deficiency preceding autophagic dysfunction and neurodegeneration in both cerebellum and cerebrum. Subsequently, aged NHE6-null rat hippocampus and cortex exhibit biochemical and in situ deposition of endogenously expressed amyloid-β and tau (including glial tau), following a sequence from lysosome defects → neurodegeneration → protein aggregation. CRISPR-Cas9 NHE6-null rat model, lifespan histopathology, lysosomal function assays, autophagy markers, amyloid-β and tau biochemistry and in situ staining, microglial/astrocyte activation markers Brain : a journal of neurology High 34928329
2024 GGA1 (Golgi-associated gamma-adaptin ear ARF-binding protein 1) interacts with the cytoplasmic C-terminus of NHE6, identified by yeast two-hybrid and confirmed by co-immunoprecipitation of endogenous proteins from neuroblastoma cells and mouse brain. GGA1 preferentially interacts with organellar NHEs (NHE6, NHE7, NHE9) but not surface NHEs (NHE1, NHE5). In GGA1 KO cells, NHE6 is mislocalized: less in endosomes, more in Golgi and lysosomes, with increased surface exocytosis, and the Golgi lumen is alkalinized. Yeast two-hybrid with NHE6 C-terminus as bait, reciprocal Co-IP from neuroblastoma cells and mouse brain, hybrid NHE1/NHE6 constructs, GGA1 KO cells with subcellular fractionation, super-resolution microscopy, Golgi pH measurement The Journal of biological chemistry High 39002678
2024 HDAC4 nuclear translocation transcriptionally represses NHE6 expression; HDAC inhibition (vorinostat) restores NHE6 levels, corrects endosomal hyperacidification, rescues LRP1 trafficking and plasma membrane expression, and reduces amyloid-β burden in 5xFAD mice. This defines a HDAC4–NHE6–endosomal pH regulatory axis in Alzheimer's disease pathogenesis. HDAC4 inhibition/nuclear translocation assays, NHE6 expression measurement, endosomal pH assay, LRP1 trafficking, nanoparticle drug delivery in 5xFAD mice, plaque quantification, behavioral tests Journal of nanobiotechnology Medium 41933339
2024 In HIV-1-infected primary T cells, NHE6 (50 kDa form) is depleted, causing endosomal acidification. NHE6 overexpression neutralizes endosomal pH, impairs Nef-driven MHC-I downmodulation by reducing Nef recruitment to Rab11+ recycling endosomes, and blocks Nef interactions with β-COP and ARF-1, revealing NHE6 as a regulator of endosomal pH relevant to HIV immune evasion. HIV-1 infection of primary T cells, NHE6 overexpression, endosomal pH measurement, MHC-I surface expression assay, Nef co-immunoprecipitation with β-COP/ARF-1, Rab11 colocalization imaging bioRxivpreprint Medium bio_10.1101_2024.12.17.628989
2024 NHE6 mediates 'inside-out' proton signaling to activate late endosome master regulator Rab7: decreasing endosomal pH potently inactivates the Rab7 GAP TBC1D5; NHE6 physically interacts with TBC1D5 in a complex with Rab7. NHE6-null neurons show blocked endosome maturation and decreased active Rab7. Epistatic knockdown of TBC1D5 in NHE6-null neurons rescues Rab7 GTPase cycling and endosome maturation. pH-dependent TBC1D5 GAP activity assays, Co-IP of NHE6/TBC1D5/Rab7 complex, NHE6-null mouse and selective proton-efflux-defective knockin neurons, epistatic TBC1D5 knockdown, endosome maturation assays bioRxivpreprint High bio_10.1101_2024.12.09.627558
2024 NHE6 impaired hippocampal plasticity (reduced spine density, AMPAR expression, NMDAR-mediated neurotransmission, and LTP failure) in Nhe6 KO mice is rescued by the selective TrkB agonist 7,8-dihydroxyflavone, which restores spine density and functional/structural LTP in KO neurons, confirming TrkB as a downstream effector of NHE6 endosomal signaling. Nhe6 KO mice with GFP-labeled CA1 pyramidal neurons, spine density quantification, AMPAR electrophysiology, LTP recording, 7,8-DHF pharmacological rescue Biochimica et biophysica acta. Molecular basis of disease Medium 39341363
2025 Cryo-EM structure of human NHE6 at 3.4 Å reveals a homodimeric architecture with 13 transmembrane helices per protomer and a conserved ion-binding site in an inward-open conformation. A structured C-terminal helix interacts with the transmembrane core forming a hydrophobic cavity accommodating two lipid molecules that may modulate cation access. Functional assays confirm NHE6 mediates exchange of both Na+ and K+ for protons. The distal C-terminus is intrinsically disordered (validated by NMR and SAXS). Single-particle cryo-EM (3.4 Å), in vitro ion exchange functional assays, NMR spectroscopy of C-terminus, small-angle X-ray scattering (SAXS) bioRxivpreprint High bio_10.1101_2025.07.21.665523
2026 NHE6 acts as a scaffolding platform for cyclin-dependent kinase 5 (CDK5): CDK5 was identified by yeast two-hybrid screening as a binding partner of the NHE6 C-terminus, and the NHE6/CDK5/p35 complex was confirmed by Co-IP and microscopy. NHE6 expression enhances localization of CDK5 and p35 to endosomal and plasma membrane fractions and elevates surface accumulation of CDK5-regulated TRPV1 channel. CDK5/p35 does not directly phosphorylate or regulate membrane trafficking of NHE6. Yeast two-hybrid screen of human brain cDNA library, Co-IP in CHO AP-1 and SH-SY5Y cells, subcellular fractionation, confocal microscopy, TRPV1 surface expression assay Acta physiologica (Oxford, England) Medium 42051037

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. American journal of human genetics 182 18342287
2013 Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development. Neuron 122 24035762
2010 A mutation affecting the sodium/proton exchanger, SLC9A6, causes mental retardation with tau deposition. Brain : a journal of neurology 101 20395263
2011 X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain : a journal of neurology 85 21964919
2014 Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome. Annals of neurology 78 25044251
2001 NHE6 protein possesses a signal peptide destined for endoplasmic reticulum membrane and localizes in secretory organelles of the cell. The Journal of biological chemistry 75 11641397
2010 The Na+/H+ exchanger NHE6 in the endosomal recycling system is involved in the development of apical bile canalicular surface domains in HepG2 cells. Molecular biology of the cell 63 20130086
2015 The Na+/H+ exchanger NHE6 modulates endosomal pH to control processing of amyloid precursor protein in a cell culture model of Alzheimer disease. The Journal of biological chemistry 59 25561733
2011 Na+/H+ exchanger isoform 6 (NHE6/SLC9A6) is involved in clathrin-dependent endocytosis of transferrin. American journal of physiology. Cell physiology 59 21881004
2006 Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 17005858
2017 Hypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance. Nature communications 48 28635961
2013 Enhanced recruitment of endosomal Na+/H+ exchanger NHE6 into Dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 46 23303939
2009 Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease. Experimental cell research 46 19619532
2021 Loss of Christianson Syndrome Na+/H+ Exchanger 6 (NHE6) Causes Abnormal Endosome Maturation and Trafficking Underlying Lysosome Dysfunction in Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 34526390
2014 A novel mutation in the endosomal Na+/H+ exchanger NHE6 (SLC9A6) causes Christianson syndrome with electrical status epilepticus during slow-wave sleep (ESES). Epilepsy research 38 24630051
2021 NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load. eLife 34 34617884
2011 A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 34 21812100
2012 Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum. Brain & development 33 22541666
2022 Early lysosome defects precede neurodegeneration with amyloid-β and tau aggregation in NHE6-null rat brain. Brain : a journal of neurology 32 34928329
2016 The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature. Human genetics 32 27142213
2016 A Christianson syndrome-linked deletion mutation (∆(287)ES(288)) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. Molecular neurodegeneration 27 27590723
2015 X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Disease models & mechanisms 23 26515654
2005 Ligand-dependent complex formation between the Angiotensin II receptor subtype AT2 and Na+/H+ exchanger NHE6 in mammalian cells. Peptides 23 15808917
2018 A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome. Neurobiology of disease 20 30296617
2016 A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome. American journal of medical genetics. Part A 20 27256868
2024 A novel peptide encoded by circ-SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac-mediated CD36 transcription in NAFLD. Clinical and translational medicine 18 39107881
2020 Assorted dysfunctions of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson syndrome. The Journal of biological chemistry 18 32277048
2018 Exome sequencing in syndromic brain malformations identifies novel mutations in ACTB, and SLC9A6, and suggests BAZ1A as a new candidate gene. Birth defects research 18 29388391
2021 SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses. Proceedings of the National Academy of Sciences of the United States of America 17 33372133
2013 Impaired posttranslational processing and trafficking of an endosomal Na+/H+ exchanger NHE6 mutant (Δ(370)WST(372)) associated with X-linked intellectual disability and autism. Neurochemistry international 17 24090639
2020 Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome. Pain 16 32569089
2019 A Christianson syndrome-linked deletion mutation (Δ287ES288) in SLC9A6 impairs hippocampal neuronal plasticity. Neurobiology of disease 16 31175985
2019 Complex Neurological Phenotype in Female Carriers of NHE6 Mutations. Molecular neuropsychiatry 16 31192222
2015 Successful Treatment of Electrographic Status Epilepticus of Sleep With Felbamate in a Patient With SLC9A6 Mutation. Pediatric neurology 14 26421989
2017 The murine choroid plexus epithelium expresses the 2Cl-/H+ exchanger ClC-7 and Na+/H+ exchanger NHE6 in the luminal membrane domain. American journal of physiology. Cell physiology 12 29351414
2022 Lack of NHE6 and Inhibition of NKCC1 Associated With Increased Permeability in Blood Labyrinth Barrier-Derived Endothelial Cell Layer. Frontiers in cellular neuroscience 11 35496913
2021 SCAMP5 mediates activity-dependent enhancement of NHE6 recruitment to synaptic vesicles during synaptic plasticity. Molecular brain 10 33663553
2020 Sodium-hydrogen exchanger 6 (NHE6) deficiency leads to hearing loss, via reduced endosomal signalling through the BDNF/Trk pathway. Scientific reports 10 32107410
2019 A novel splicing mutation in SLC9A6 in a boy with Christianson syndrome. Human genome variation 9 30937176
2017 Human rotavirus strain Wa downregulates NHE1 and NHE6 expressions in rotavirus-infected Caco-2 cells. Virus genes 8 28289928
2017 Syndrome of X linked intellectual disability, epilepsy, progressive brain atrophy and large head associated with SLC9A6 mutation. BMJ case reports 8 29275387
2023 Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat. Human molecular genetics 7 36621975
2019 Functional Assessment In Vivo of the Mouse Homolog of the Human Ala-9-Ser NHE6 Variant. eNeuro 7 31676550
2024 Genes for endosomal pH regulators NHE6 and NHE9 are dysregulated in the substantia nigra in Parkinson's disease. Gene 5 38945311
2024 Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone. Biochimica et biophysica acta. Molecular basis of disease 4 39341363
2023 Clinical and genetic analysis of Christianson syndrome caused by variant of SLC9A6: case report and literature review. Frontiers in neurology 4 37213903
2023 Functional analysis of two SLC9A6 frameshift variants in lymphoblastoid cells from patients with Christianson syndrome. CNS neuroscience & therapeutics 4 37381736
2021 Human iPSC lines from a Christianson syndrome patient with NHE6 W523X mutation, a biologically-related control, and CRISPR/Cas9 gene-corrected isogenic controls. Stem cell research 4 34182254
2025 SLC9A6-Linked Parkinson Syndrome in Female Heterozygotes Is Associated With PET-Detectable Tau Pathology. Neurology. Genetics 3 39810750
2024 GGA1 interacts with the endosomal Na+/H+ exchanger NHE6 governing localization to the endosome compartment. The Journal of biological chemistry 3 39002678
2023 Structural and functional implications of SLC13A3 and SLC9A6 mutations: an in silico approach to understanding intellectual disability. BMC neurology 3 37794328
2021 Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review. Journal of clinical laboratory analysis 3 34791706
2022 Case Report: Novel SLC9A6 Splicing Variant in a Chinese Boy With Christianson Syndrome With Electrical Status Epilepticus During Sleep. Frontiers in neurology 2 35095740
2021 Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis. Frontiers in genetics 2 34987551
2026 Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome. Human molecular genetics 1 41934608
2025 Viral vector-mediated SLC9A6 gene replacement reduces cerebellar dysfunction in the shaker rat model of Christianson syndrome. bioRxiv : the preprint server for biology 1 39868272
2025 Alterations in the Na+/H+ Exchanger NHE6 and Glutamate Transporters may Influence Purkinje Cell Fate in ARSACS. Cerebellum (London, England) 1 40372562
2023 GGA1 interacts with the endosomal Na+/H+ Exchanger NHE6 governing localization to the endosome compartment. bioRxiv : the preprint server for biology 1 37986849
2026 Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice. Journal of nanobiotechnology 0 41933339
2026 The Recycling Endosomal (Na+, K+)/H+ Exchanger NHE6/SLC9A6 Facilitates Signal Transduction by Shuttling Cyclin-Dependent Kinase 5 to the Plasma Membrane. Acta physiologica (Oxford, England) 0 42051037
2025 [Clinical features and genetic analysis of a child with Christianson syndrome due to variant of SLC9A6 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 40555653
2025 Missense variants in SLC9A6 cause partial epilepsy without neurodevelopmental delay. Orphanet journal of rare diseases 0 40722028
2025 NDPACX: a newly defined X-linked Parkinsonian syndrome associated with SLC9A6 hemizygote mutation. Brain communications 0 41357349
2022 Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report. Medicina (Kaunas, Lithuania) 0 35334527

Missed literature

Know a paper Affinage missed for SLC9A6? Flag it for the maintainers and the community.

No submissions yet.