Affinage

AQP4

Aquaporin-4 · UniProt P55087

Length
323 aa
Mass
34.8 kDa
Annotated
2026-06-09
100 papers in source corpus 27 papers cited in narrative 27 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

AQP4 is the principal water-selective channel of astrocytes and related epithelia, where it governs transmembrane water flux and the structural organization of perivascular membrane domains (PMID:8537439, PMID:8617713). Unlike AQP1, AQP4 adopts a six-transmembrane topology with cytoplasmic termini and N-glycosylation at N131, and forms an aqueous pore whose conductance depends on residues flanking its NPA motifs; dominant-negative tryptophan substitutions show its monomers interact functionally (PMID:7541239, PMID:8555225). AQP4 monomers assemble into tetramers, and the M23 isoform drives further aggregation into supramolecular orthogonal arrays of particles (OAPs), with the M1/M23 ratio setting OAP extent (PMID:8617713, PMID:24118484). OAP integrity, dependent on residue A25, is required for the polarized perivascular localization of AQP4 at astrocytic endfeet and is neuroprotective in edema models (PMID:36100398), and the M23/M1 balance also dictates whether glioma cells undergo apoptosis or adopt a migratory, MMP-9-high phenotype through C-terminal proline-dependent actin remodeling (PMID:30877104, PMID:40403843). Surface abundance and polarity are set by multiple post-transcriptional routes: SNX27-retromer recycling rescues endocytosed AQP4 from lysosomal degradation (PMID:34002021), MMP-9 cleavage of β-dystroglycan triggers AQP4 endocytosis (PMID:38512439, PMID:38421470), ubiquitin-dependent proteasomal turnover degrades AQP4 (PMID:18836575), the RNA helicase DDX17 represses AQP4 translation (PMID:34038017), and scaffolding through α-syntrophin, SNTA1, and the circadian protein Per2 (via α-dystrobrevin) directs perivascular targeting (PMID:38077948, PMID:37802998, PMID:40403843). AQP4 transcription is induced by NFAT5 under osmotic stress and by NF-κB/p65 downstream of inflammatory TNF-α signaling (PMID:23180003, PMID:35260880). Functionally, AQP4-driven water influx accelerates TRPV4-mediated calcium entry for glial volume regulation (PMID:26424896), and AQP4 polarity controls glymphatic clearance, which is disrupted when LRRK2 phosphorylates AQP4 (PMID:38296953).

Mechanistic history

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

    Establishing where AQP4 resides and that its tissue distribution matches orthogonal arrays of particles seeded the hypothesis that AQP4 is itself the OAP-forming protein.

    Evidence Immunogold EM and immunolocalization across rat astrocytes, ependyma, muscle, kidney, and glandular epithelia

    PMID:8537439

    Open questions at the time
    • Co-localization was correlative and did not prove AQP4 alone suffices to form OAPs
    • Functional role of OAPs in water transport not addressed
  2. 1995 High

    Determining AQP4's membrane topology distinguished it from AQP1 and defined its biosynthetic insertion and glycosylation, providing the structural framework for later pore and assembly studies.

    Evidence Cell-free translation with ER microsomes, protease protection, glycosylation mapping, and oocyte expression of chimeras

    PMID:7541239

    Open questions at the time
    • Topology determined in vitro and in oocytes, not native astrocytes
    • Did not address oligomerization or OAP assembly
  3. 1996 High

    Heterologous expression proved a single aquaporin is sufficient to form OAPs and that this property is AQP4-specific, settling the identity of the OAP protein.

    Evidence Stable CHO transfection with freeze-fracture EM, with AQP1 as negative control

    PMID:8617713

    Open questions at the time
    • Isoform requirement (M1 vs M23) for OAP assembly not yet resolved
    • Physiological consequence of OAPs unaddressed
  4. 1996 High

    Mutagenesis mapped the residues lining the water pore and showed dominant-negative behavior, establishing that AQP4 functions as an interacting oligomer rather than independent monomers.

    Evidence Site-directed mutagenesis with oocyte osmotic water permeability and HgCl2 dose-response assays

    PMID:8555225

    Open questions at the time
    • Atomic structure of the pore not determined
    • Link between oligomerization and OAP suprastructure not made
  5. 2013 Medium

    Defining the M23-driven tetramer-to-OAP hierarchy and its M1/M23 control connected AQP4 supramolecular structure to its clinical role as the NMO autoantigen.

    Evidence Cell-based assays, complement cytotoxicity assays, and isoform-ratio manipulation, including review synthesis

    PMID:24118484 PMID:24260168

    Open questions at the time
    • Quantitative determinants of in vivo M1/M23 ratio not defined
    • Mechanism by which OAP geometry enhances IgG avidity not resolved structurally
  6. 2013 Medium

    Linking AQP4 surface abundance to vesicle mobility under osmotic and cAMP stimulation introduced regulated trafficking as a determinant of channel availability.

    Evidence Live-cell vesicle imaging and membrane AQP4 quantification in rat astrocytes under osmotic and pharmacological stimulation

    PMID:23505074

    Open questions at the time
    • Trafficking machinery (motors, adaptors) not identified
    • Causality between vesicle mobility and membrane abundance correlative
  7. 2012 High

    Identifying NFAT5 as a direct promoter-binding activator established the transcriptional arm of osmotic AQP4 induction.

    Evidence ChIP, luciferase reporter, siRNA knockdown, and in vivo kainic acid edema model

    PMID:23180003

    Open questions at the time
    • Upstream osmosensing signaling to NFAT5 not delineated
    • Interaction with other promoter factors unaddressed
  8. 2015 High

    Reciprocal genetic and oocyte experiments showed AQP4 water influx accelerates TRPV4 calcium entry, defining a functional coupling for glial volume regulation.

    Evidence Trpv4-/- and Aqp4-/- mice, calcium imaging, oocyte co-expression with osmotic matching, and pharmacology

    PMID:26424896

    Open questions at the time
    • Physical proximity/scaffolding between AQP4 and TRPV4 not structurally defined
    • Downstream effectors of the calcium signal not fully mapped
  9. 2008 Medium

    Demonstrating AQP4 as a substrate of ubiquitin-dependent degradation, modulated by intraocular pressure, established proteostatic control of AQP4 levels.

    Evidence S5a affinity purification of ubiquitinated proteins with retinal injury models

    PMID:18836575

    Open questions at the time
    • E3 ligase responsible not identified
    • Ubiquitination sites on AQP4 not mapped
  10. 2017 High

    Showing B cells express and present AQP4 to delete autoreactive thymocytes revealed an unexpected role for AQP4 in B-cell-dependent central tolerance.

    Evidence B-cell conditional Aqp4 knockout with TCR repertoire analysis and thymic B-cell transcriptomics

    PMID:38383779

    Open questions at the time
    • Relation between this tolerance mechanism and CNS AQP4 channel function not connected
    • Why AQP4 is induced in activated B cells unexplained
  11. 2019 High

    Identifying AQP4 as a SNX27-retromer cargo and an isoform-dependent determinant of glioma fate connected recycling and aggregation state to AQP4 abundance and cell behavior.

    Evidence Co-IP, SNX27 knockdown/overexpression rescue, lysosomal block, Kidins220 mouse, and isoform-selective glioma expression with proline mutagenesis

    PMID:30877104 PMID:34002021

    Open questions at the time
    • Direct binding interface between AQP4 and SNX27 not mapped
    • How OAP aggregation state mechanically couples to F-actin not resolved
  12. 2020 Medium

    Connexin deletion and microglial cytokine experiments tied astrocytic coupling and paracrine inflammatory signaling to AQP4 isoform composition and expression.

    Evidence Cx43/Cx30 double-knockout immunogold and isoform western blot; astrocyte-microglia hypoxia co-culture with p38/NF-κB inhibitors

    PMID:29054452 PMID:32046059

    Open questions at the time
    • Mechanism linking gap junction coupling to isoform-specific AQP4 changes unclear
    • Direct vs indirect transcriptional effects of cytokines not separated
  13. 2021 High

    The M23-null model revealed translational control of AQP4 and identified DDX17 as a negative regulator and PTBP1 as a positive one, adding RNA-binding control to AQP4 regulation.

    Evidence CRISPR M23-null mouse, mRNA-protein pulldown with mass spectrometry, DDX17 knockdown, and astrocyte swelling assays

    PMID:34038017

    Open questions at the time
    • DDX17 binding site on AQP4 mRNA not mapped
    • Signals controlling RBP recruitment unknown
  14. 2022 High

    An OAP-disrupting A25Q knock-in proved that supramolecular structure, independent of expression level, is required for polarized endfeet localization and modulates edema outcome.

    Evidence AQP4-A25Q knock-in mouse with BN-PAGE, STORM, immunogold EM, and edema/MCAO models; plus stroke-associated AQP4ex loss analysis

    PMID:35163040 PMID:36100398

    Open questions at the time
    • Molecular anchor reading OAP geometry for polarized targeting not identified
    • Causal role of AQP4ex in OAP stability remains correlative
  15. 2022 Medium

    Defining TNF-α/NF-κB-p65 promoter binding established the inflammatory transcriptional pathway controlling AQP4 and astrocyte edema.

    Evidence Luciferase reporter, ChIP, NF-κB inhibitor, and p65 siRNA in astrocytes

    PMID:35260880

    Open questions at the time
    • Interaction with osmotic NFAT5 pathway not addressed
    • p65 binding site coordinates not finely mapped
  16. 2023 Medium

    Identifying AQP4ex/α-syntrophin interactions and Per2/α-dystrobrevin coupling clarified how scaffolding and circadian inputs direct perivascular AQP4 polarity.

    Evidence AQP4x dose-modulating transgenic lines with EM/MRI; Per2-Dtna Co-IP and CUMS/melatonin rescue

    PMID:37802998 PMID:38077948

    Open questions at the time
    • Direct binding of AQP4ex to α-syntrophin not biochemically resolved
    • How Per2 mechanistically regulates the anchoring complex unclear
  17. 2024 High

    Demonstrating LRRK2 directly phosphorylates AQP4 to cause depolarization linked a Parkinson's-associated kinase to glymphatic dysfunction and neuroinflammation.

    Evidence In vitro and in vivo kinase assays, LRRK2 R1441G mice, glymphatic tracer studies, and LRRK2 inhibitor rescue

    PMID:38296953

    Open questions at the time
    • AQP4 phosphosite(s) targeted by LRRK2 not specified
    • How phosphorylation disrupts OAP/anchoring mechanistically unresolved
  18. 2024 Medium

    Defining the MMP-9/β-dystroglycan axis and an AQP4-Nav1.6-PPARγ-autophagy circuit expanded the post-translational and downstream signaling control of AQP4 polarity and astrocyte fate.

    Evidence Diabetic and ICH models with MMP-9 inhibition, bafilomycin rescue, edaravone; AQP4 knockout with Ca2+/Nav1.6/PPAR-γ analysis in sepsis encephalopathy

    PMID:36922751 PMID:38421470 PMID:38512439

    Open questions at the time
    • Whether β-DG cleavage directly releases OAPs vs tetramers not resolved
    • Causal chain from AQP4 to Nav1.6 regulation incompletely defined
  19. 2025 Medium

    Isoform overexpression after stroke confirmed M23 corrects and M1 worsens AQP4 mis-localization, with SNTA1 enhancing polarity, reinforcing isoform balance as a therapeutic lever for glymphatic function.

    Evidence tMCAO mouse model with viral AQP4 isoform and SNTA1 overexpression, TGN-020 antagonist, MRI glymphatic tracer, and multi-omics

    PMID:40403843

    Open questions at the time
    • Mechanism by which SNTA1 modulates isoform expression not defined
    • Single-lab stroke-model findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers — transcriptional, translational, trafficking, scaffolding, phosphorylation, and OAP assembly — are integrated into a single quantitative control of perivascular AQP4 polarity, and the atomic structure governing OAP-dependent targeting, remain unresolved.
  • No structural model linking OAP geometry to its anchoring/targeting machinery
  • No unified hierarchy among the competing regulators of AQP4 surface polarity
  • Phosphosite and ubiquitination site maps incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005764 lysosome 2 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9609507 Protein localization 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
DDX17DTNALRRK2PER2PTBP1SNTA1SNX27TRPV4
Complex memberships
SNX27-retromer complexdystrophin-associated (α-syntrophin/α-dystrobrevin/β-dystroglycan) anchoring complexorthogonal arrays of particles (OAPs)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 AQP4 (MIWC) is expressed at the plasma membrane of astrocytes, ependymal cells lining the aqueductal system, skeletal muscle sarcolemma, kidney collecting duct basolateral membranes, gastric parietal cells, and glandular epithelia; its cellular distribution matches precisely the sites where orthogonal arrays of particles (OAPs) are observed by freeze-fracture electron microscopy, suggesting AQP4 is the OAP protein. Immunogold electron microscopy and immunolocalization in rat tissues Journal of cell science High 8537439
1995 AQP4 (MIWC) spans the endoplasmic reticulum membrane with six transmembrane domains and cytoplasmic N- and C-termini (distinct from the four-transmembrane topology of AQP1/CHIP28); membrane integration occurs after synthesis of the first hydrophobic region and N-linked glycosylation occurs at residue N131. Cell-free translation with ER microsomes, protease protection assays, N-linked glycosylation mapping, and Xenopus oocyte expression using cDNA chimeras with reporter epitopes Biochemistry High 7541239
1996 AQP4 (MIWC) spontaneously assembles into orthogonal arrays of particles (OAPs) in transfected CHO cell plasma membranes, demonstrating that a single aquaporin molecule is sufficient to form OAPs; AQP1 expression does not produce OAPs, showing OAP formation is AQP4-specific. Stable transfection of CHO cells, freeze-fracture electron microscopy, immunoblot, cell fractionation, stopped-flow light scattering for water permeability The Journal of biological chemistry High 8617713
1996 AQP4 is mercurial-insensitive because it lacks a cysteine residue near its NPA motifs; introduction of cysteine mutations at residues 70–73 or 189 (near the NPA motifs) confers HgCl2 sensitivity, identifying these residues as lining the aqueous pore. Bulky tryptophan substitutions at G72 or A188 abolish water transport and exert a dominant-negative effect, indicating AQP4 monomers interact functionally. Site-directed mutagenesis, Xenopus oocyte expression, osmotic water permeability assay (Pf), HgCl2 dose-response, quantitative immunofluorescence Biochemistry High 8555225
2013 AQP4 surface expression in astrocytes is regulated by vesicular trafficking; AQP4e isoform localizes to vesicles whose mobility correlates with AQP4 plasma membrane abundance. Hypoosmotic stimulation (mimicking brain edema) transiently reduces vesicle mobility and transiently changes AQP4 plasma membrane localization; increased cytosolic cAMP (reactive astrocyte model) increases AQP4 surface expression. Actin rearrangement accompanies reactive astrocyte stimulation and vimentin depolymerization accompanies hypoosmotic conditions. Live-cell imaging of vesicle mobility in cultured rat astrocytes, plasma membrane AQP4 quantification, cytoskeletal analysis under pharmacological and osmotic stimulation Glia Medium 23505074
2013 AQP4 monomers form tetramers in membranes, and M23-AQP4 tetramers further aggregate into supramolecular orthogonal arrays of particles (OAPs); the M1/M23 isoform ratio controls the extent of OAP assembly, and AQP4-IgG binding and complement-dependent cytotoxicity in NMO are greatly enhanced by OAP formation. Cell-based assays, complement cytotoxicity assays, isoform expression studies reviewed from multiple independent experiments Brain pathology (Zurich, Switzerland) Medium 24118484
2013 AQP4-IgG diagnostic sensitivity is highest with M23-AQP4 expressing cells (97.5%) versus M1-AQP4 (27.5%) in cell-based assays (CBA); the nucleotide at position -3 of the AUG of M1 greatly affects the M1/M23 protein ratio and NMO-IgG binding. An N-terminal fluorescent tag on M23-AQP4 disrupts AQP4 suprastructures and reduces test sensitivity. Cell-based assay (CBA) with systematic variation of AQP4 isoform, translation initiation signals, fluorescent tag position; NMO patient serum testing PloS one Medium 24260168
2015 AQP4 and TRPV4 colocalize in Müller glial endfeet and radial processes in mouse retina. AQP4-mediated water influx drives TRPV4-mediated calcium entry during hypo-osmotic swelling; conversely, calcium entry through TRPV4 modulates volume regulation and Aqp4 gene expression. In Xenopus oocytes co-expressing both channels, when swelling rate was osmotically matched, TRPV4 activation became independent of AQP4, demonstrating that AQP4's contribution is specifically through accelerating water influx. Genetic ablation (Trpv4-/- and Aqp4-/- mice), live calcium imaging, cell volume measurements, Xenopus oocyte co-expression, pharmacological TRPV4 agonist/antagonist studies, gene expression analysis The Journal of neuroscience High 26424896
2019 AQP4 aggregation state determines glioma cell fate: M23-AQP4 (OAP-forming isoform) triggers F-actin cytoskeletal changes and promotes apoptosis, while M1-AQP4 (tetramer-only) increases cell migration and MMP-9 activity. Two C-terminal proline residues (Pro254 and Pro296) mediate the relationship between AQP4 aggregation state and the actin cytoskeleton. Selective isoform expression in glioma cell lines, F-actin imaging, apoptosis assays, cell migration/invasion assays, MMP-9 activity assay, proline mutagenesis Cancer research Medium 30877104
2019 AQP4 is a novel cargo of the SNX27-retromer complex, which recycles endocytosed AQP4 back to the cell surface and prevents lysosomal degradation. Kidins220 deficiency causes SNX27-retromer downregulation leading to AQP4 lysosomal degradation; SNX27 silencing decreases AQP4 levels in wild-type astrocytes, while SNX27 overexpression restores AQP4 in Kidins220-deficient astrocytes. Co-immunoprecipitation, SNX27 knockdown and overexpression in astrocytes, lysosome inhibitor (bafilomycin) rescue, mouse genetic model (Kidins220 deficient), human iNPH patient tissue analysis Molecular psychiatry High 34002021
2021 In M23-AQP4 null (CRISPR/Cas9) mouse spinal cord, M1-AQP4 protein is drastically reduced without changes in M1-AQP4 transcription, splicing, or protein degradation, indicating translational control. mRNA-protein pulldown and quantitative mass spectrometry identified AQP4 mRNA-binding proteins (RBPs): polypyrimidine tract binding protein 1 (PTBP1, a positive translational regulator) shows increased interaction with AQP4 mRNA in M23-null, and RNA helicase DDX17 shows decreased interaction. DDX17 knockdown upregulates AQP4 protein and increases astrocyte swelling without affecting mRNA levels, identifying DDX17 as a negative translational regulator of AQP4. CRISPR/Cas9 M23-null mouse model, mRNA-protein pulldown, quantitative mass spectrometry, DDX17 siRNA knockdown, astrocyte primary culture swelling assay, western blot, RT-PCR Glia High 34038017
2020 Deletion of astrocytic connexins Cx43 and Cx30 causes substantial reduction of perivascular AQP4, downregulation of total AQP4 protein and mRNA, and isoform-specific effects: M23-AQP4 is reduced while M1-AQP4 and the AQP4ex isoform are increased, demonstrating a complex interdependence between astrocytic gap junction coupling and AQP4 membrane localization and isoform composition. Quantitative immunogold cytochemistry, isoform-specific western blot, mRNA analysis in connexin Cx43/Cx30 double knockout mice Cells Medium 32046059
2022 An AQP4-A25Q point mutation that depolymerizes OAPs (confirmed by blue native PAGE, super-resolution imaging, and immunogold EM) without affecting total AQP4 mRNA or protein expression reduces polarized perivascular expression of AQP4 at astrocytic endfeet and is neuroprotective in cerebral edema models (water intoxication and MCAO/reperfusion), demonstrating that OAP structure is required for polarized endfeet localization. Transgenic knock-in mouse (AQP4-A25Q), blue native PAGE, super-resolution imaging, immunogold EM, brain water content measurement, MCAO stroke model, behavioral scoring The Journal of neuroscience High 36100398
2022 Disassembly of supramolecular AQP4 complexes and loss of AQP4 from astrocytic endfoot membranes occurs at the border zone one week after ischemic stroke, mechanistically coupled to downregulation of the AQP4ex (readthrough) isoform, suggesting AQP4ex stabilizes OAPs at perivascular endfeet. Immunofluorescence and confocal analysis of murine stroke model at defined time points post-ischemia; isoform-specific analysis International journal of molecular sciences Medium 35163040
2023 The AQP4ex (readthrough) isoform preferentially localizes around the blood-brain barrier through interaction with the scaffolding protein α-syntrophin. Increasing AQP4ex dose enhances perivascular localization of both α-syntrophin and AQP4 without changing total protein expression. Complete AQP4x loss (NoXHom) alters BBB integrity (increased endothelial budding vesicles, leakier BBB by MRI). AQP4x plays a measurable role in recruiting structural/functional support proteins to blood vessels. AllX and NoX transgenic mouse lines (quantitative AQP4x modulation), immunofluorescence, electron microscopy, MRI, α-syntrophin colocalization analysis Frontiers in cellular neuroscience Medium 38077948
2024 LRRK2 directly interacts with and phosphorylates AQP4 in vitro and in vivo. LRRK2 R1441G-mediated AQP4 phosphorylation induces AQP4 depolarization and disrupts glymphatic clearance of IFNγ, leading to neuroinflammation and dopaminergic neurodegeneration. LRRK2 inhibition restores AQP4 polarity and improves glymphatic function. In vitro kinase assay, in vivo phosphorylation in transgenic mice, AQP4 polarization imaging, glymphatic tracer studies, LRRK2 inhibitor treatment, IFNγ clearance measurement NPJ Parkinson's disease High 38296953
2012 NFAT5 directly binds the AQP4 gene promoter (between -49 and -38 bp) and is required for transcriptional upregulation of AQP4 in astrocytes under swelling conditions (ammonia treatment). NFAT5 siRNA silencing significantly reduces AQP4 expression, and ChIP assay shows increased NFAT5 binding to the AQP4 promoter after ammonia treatment. Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, siRNA knockdown, in vivo kainic acid brain edema model, immunohistochemistry Cellular and molecular neurobiology High 23180003
2022 TNF-α activates the NF-κB pathway in astrocytes, causing p65 protein to bind the AQP4 gene promoter region, enhancing AQP4 transcription and causing astrocyte edema and reduced viability. The NF-κB inhibitor BAY 11-7082 blocks this effect, and p65 siRNA reduces AQP4 expression and improves astrocyte viability. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), NF-κB pathway inhibitor (BAY 11-7082), p65 siRNA, western blot, qPCR, cell viability assay (CCK-8) Bioscience reports Medium 35260880
2024 AQP4 endocytosis and lysosomal degradation is regulated by MMP-9 cleavage of β-dystroglycan (β-DG): MMP-9 cleaves β-DG, disrupting its anchorage of AQP4 on the astrocyte plasma membrane, leading to AQP4 endocytosis. Bafilomycin A1 (lysosome inhibitor) reverses AQP4 downregulation in diabetic mice; MMP-9/β-DG inhibition restores AQP4 surface expression and partially alleviates diabetic cognitive dysfunction. Diabetic mouse model (STZ), lysosome inhibitor rescue (bafilomycin A1), MMP-9 inhibition, β-DG cleavage analysis, western blot, immunofluorescence, behavioral tests Molecular neurobiology Medium 38512439
2024 MMP-9 activation downstream of oxidative stress in intracerebral hemorrhage cleaves β-dystroglycan, reducing AQP4 polarity. Edaravone (oxygen free radical scavenger) downregulates MMP-9 and upregulates β-DG, maintaining AQP4 polarity and reducing brain edema. MMP-9 inhibitor similarly maintains AQP4 polarity, confirming the OS/MMP9/β-DG/AQP4 pathway. Autologous blood ICH mouse model, edaravone and MMP9-inh treatment, immunofluorescence, western blot, ELISA, Evans blue permeability, brain water content, intracisternal tracer infusion Molecular neurobiology Medium 38421470
2023 The circadian protein Per2 directs AQP4 perivascular polarization in astrocytes through interactions with α-dystrobrevin (Dtna), a subunit of the AQP4 anchoring complex. Per2 expression negatively correlates with AQP4 polarization; CUMS mice with disrupted circadian rhythms show impaired AQP4 polarization, which is restored by melatonin treatment that normalizes Per2 expression. Co-immunoprecipitation of Per2 with Dtna in primary cultured astrocytes, CUMS mouse model, melatonin treatment, EEG sleep analysis, AQP4 polarization imaging, circadian protein expression analysis Translational psychiatry Medium 37802998
2025 AQP4-M23 isoform is a key regulator of AQP4 polarized distribution in astrocytic endfeet after stroke: M23 overexpression corrects AQP4 mis-localization while M1 overexpression exacerbates edema and motor dysfunction. SNTA1 (syntrophin alpha 1) overexpression enhances AQP4 polarity by modulating AQP4 isoform expression; AQP4 inhibition with TGN-020 restores polarized AQP4 in astrocyte end-feet and improves glymphatic function. tMCAO mouse model, viral vectors for AQP4 isoforms, SNTA1 overexpression, TGN-020 AQP4 antagonist, MRI glymphatic tracer, western blot, q-PCR, immunofluorescence, TEM, behavioral tests, transcriptomic and metabolomic analyses Journal of advanced research Medium 40403843
2008 AQP4 is a substrate for ubiquitin-dependent proteasomal degradation in the retina; AQP4 was detected in affinity-purified ubiquitinated proteins using an S5a column. Elevated IOP increased ubiquitination in retinal extracts (correlating with decreased AQP4) but decreased ubiquitination in optic nerve extracts (correlating with increased AQP4 in optic nerve astrocytes). S5a affinity column purification of ubiquitinated proteins, western blot, Q-PCR, immunohistochemistry in rat retinal injury models (Morrison IOP model and intravitreal endothelin-1) Molecular vision Medium 18836575
2024 AQP4 knockout in astrocytes activates autophagy, reduces neuroinflammation and cognitive impairment in sepsis-associated encephalopathy. Mechanistically, AQP4 knockout reduces intracellular Ca2+ accumulation by downregulating Nav1.6 channel activity in astrocytes, which activates PPAR-γ signaling to promote autophagy. CLP sepsis mouse model, AQP4 knockout, LPS-treated astrocytes in vitro, intracellular Ca2+ measurement, Nav1.6 channel activity assay, PPAR-γ signaling analysis, autophagy markers, behavioral tests Advanced science Medium 36922751
2017 B cells endogenously express AQP4 upon activation with anti-CD40 and IL-21, and can present self-AQP4 to AQP4-specific T cells. Thymic B cells (which emulate the CD40-stimulated transcriptome including AQP4 expression in both mice and humans) efficiently delete AQP4-reactive thymocytes from the TCR repertoire. Genetic ablation of Aqp4 specifically in B cells rescues AQP4-specific TCRs despite sufficient AQP4 expression in medullary thymic epithelial cells, demonstrating B-cell-dependent (not just mTEC-dependent) central tolerance to AQP4. B-cell conditional Aqp4 knockout, T cell receptor repertoire analysis, thymic B cell transcriptomics, anti-CD40/IL-21 stimulation of B cells, AQP4-specific T cell challenge, germinal center assay Nature High 38383779
2015 Genistein promotes AQP4 gene transcription in intestinal cells via PKA-mediated CREB phosphorylation (cAMP/PKA/CREB signaling pathway), reversing the downregulation of AQP4 caused by rotavirus infection in Caco-2 cells. RT-PCR, western blot, CREB phosphorylation assay, PKA activity assay (PepTag), genistein dose-response in Caco-2 cells infected with rotavirus Archives of virology Medium 25877820
2020 In hippocampal astrocytes, hypoxia-exposed microglia release TNF-α and IL-6, which upregulate AQP4 expression in astrocytes through p38 MAPK and NF-κB signaling pathways. Co-culture of hypoxia-exposed astrocytes and microglia showed AQP4 upregulation in astrocytes that was prevented by p38 inhibitor, NF-κB inhibitor, or puerarin. Astrocyte-microglia co-culture under hypoxia, p38 MAPK inhibitor, NF-κB inhibitor, ELISA for cytokines, western blot for AQP4 and signaling molecules, hypobaric rat model Life sciences Medium 29054452

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nature reviews. Neurology 356 20639914
1995 Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. Journal of cell science 341 8537439
1996 The mercurial insensitive water channel (AQP-4) forms orthogonal arrays in stably transfected Chinese hamster ovary cells. The Journal of biological chemistry 210 8617713
2015 TRPV4 and AQP4 Channels Synergistically Regulate Cell Volume and Calcium Homeostasis in Retinal Müller Glia. The Journal of neuroscience : the official journal of the Society for Neuroscience 195 26424896
2006 Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Experimental neurology 181 16445913
2020 Regulation of AQP4 in the Central Nervous System. International journal of molecular sciences 140 32111087
2016 Neuroimmunological Implications of AQP4 in Astrocytes. International journal of molecular sciences 129 27517922
2020 Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway. Signal transduction and targeted therapy 120 32296044
2017 Microstructural visual system changes in AQP4-antibody-seropositive NMOSD. Neurology(R) neuroimmunology & neuroinflammation 110 28255575
2016 Regulation of astrocyte glutamate transporter-1 (GLT1) and aquaporin-4 (AQP4) expression in a model of epilepsy. Experimental neurology 109 27155358
2023 Melatonin alleviates depression-like behaviors and cognitive dysfunction in mice by regulating the circadian rhythm of AQP4 polarization. Translational psychiatry 106 37802998
2009 AQP4 gene deletion in mice does not alter blood-brain barrier integrity or brain morphology. Neuroscience 105 19345723
2013 Biology of AQP4 and anti-AQP4 antibody: therapeutic implications for NMO. Brain pathology (Zurich, Switzerland) 94 24118484
2015 Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease. Journal of neurology, neurosurgery, and psychiatry 92 26645082
2010 Cell locations for AQP1, AQP4 and 9 in the non-human primate brain. Neuroscience 74 20226845
2019 AQP1 and AQP4 Contribution to Cerebrospinal Fluid Homeostasis. Cells 72 30813473
2010 AQP-4 in peritumoral edematous tissue is correlated with the degree of glioma and with expression of VEGF and HIF-alpha. Journal of neuro-oncology 63 20467785
2019 Astrogliogenesis in human fetal brain: complex spatiotemporal immunoreactivity patterns of GFAP, S100, AQP4 and YKL-40. Journal of anatomy 60 30901080
2023 Tumefactive Demyelination in MOG Ab-Associated Disease, Multiple Sclerosis, and AQP-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder. Neurology 59 36690455
2023 Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models. Acta neuropathologica communications 58 36653878
2013 Regulation of AQP4 surface expression via vesicle mobility in astrocytes. Glia 57 23505074
2012 Dynamics of expression patterns of AQP4, dystroglycan, agrin and matrix metalloproteinases in human glioblastoma. Cell and tissue research 57 22307776
2020 HLA association in MOG-IgG- and AQP4-IgG-related disorders of the CNS in the Dutch population. Neurology(R) neuroimmunology & neuroinflammation 56 32198229
2015 Remote ischemic post-conditioning improves neurological function by AQP4 down-regulation in astrocytes. Behavioural brain research 55 25907740
2024 B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4. Nature 54 38383779
2023 Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation. Theranostics 54 37554272
2017 Orientin Attenuates Cerebral Ischemia/Reperfusion Injury in Rat Model through the AQP-4 and TLR4/NF-κB/TNF-α Signaling Pathway. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 53 28645524
2023 AQP4 Aggravates Cognitive Impairment in Sepsis-Associated Encephalopathy through Inhibiting Nav 1.6-Mediated Astrocyte Autophagy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 52 36922751
2022 Long-term Efficacy of Satralizumab in AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder From SAkuraSky and SAkuraStar. Neurology(R) neuroimmunology & neuroinflammation 52 36724181
2020 Clinical utility of AQP4-IgG titers and measures of complement-mediated cell killing in NMOSD. Neurology(R) neuroimmunology & neuroinflammation 52 35413004
2017 Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life sciences 49 29054452
2008 Changes in ocular aquaporin-4 (AQP4) expression following retinal injury. Molecular vision 45 18836575
2019 AQP4 Aggregation State Is a Determinant for Glioma Cell Fate. Cancer research 43 30877104
2015 Regulation and Function of AQP4 in the Central Nervous System. Neurochemical research 42 25630715
1995 Distinct biogenesis mechanisms for the water channels MIWC and CHIP28 at the endoplasmic reticulum. Biochemistry 42 7541239
2012 Berberine increases the expression of NHE3 and AQP4 in sennosideA-induced diarrhoea model. Fitoterapia 41 22668974
2008 Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema. Acta neurochirurgica. Supplement 40 19388360
1996 Selected cysteine point mutations confer mercurial sensitivity to the mercurial-insensitive water channel MIWC/AQP-4. Biochemistry 40 8555225
2022 Targeting long noncoding RNA-AQP4-AS1 for the treatment of retinal neurovascular dysfunction in diabetes mellitus. EBioMedicine 39 35172268
2019 Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice. Stem cells (Dayton, Ohio) 39 31648394
2020 The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. International journal of molecular sciences 37 32059400
2022 TNF-α induces AQP4 overexpression in astrocytes through the NF-κB pathway causing cellular edema and apoptosis. Bioscience reports 34 35260880
2021 Rituximab-Induced Hypogammaglobulinemia and Infections in AQP4 and MOG Antibody-Associated Diseases. Neurology(R) neuroimmunology & neuroinflammation 34 33722933
2020 Coexisting systemic and organ-specific autoimmunity in MOG-IgG1-associated disorders versus AQP4-IgG+ NMOSD. Multiple sclerosis (Houndmills, Basingstoke, England) 33 32633603
2013 Aquaporin-4 autoantibodies in Neuromyelitis Optica: AQP4 isoform-dependent sensitivity and specificity. PloS one 33 24260168
2024 Very Low-Intensity Ultrasound Facilitates Glymphatic Influx and Clearance via Modulation of the TRPV4-AQP4 Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 32 39494466
2021 Optic chiasm involvement in AQP-4 antibody-positive NMO and MOG antibody-associated disorder. Multiple sclerosis (Houndmills, Basingstoke, England) 32 33975499
2017 Alterations in AQP4 expression and polarization in the course of motor neuron degeneration in SOD1G93A mice. Molecular medicine reports 32 28627708
2015 Genistein inhibits rotavirus replication and upregulates AQP4 expression in rotavirus-infected Caco-2 cells. Archives of virology 32 25877820
2012 NFAT5-dependent expression of AQP4 in astrocytes. Cellular and molecular neurobiology 31 23180003
2013 Propofol administration modulates AQP-4 expression and brain edema after traumatic brain injury. Cell biochemistry and biophysics 30 23494261
2010 Aquaporin expression in normal and pathological skeletal muscles: a brief review with focus on AQP4. Journal of biomedicine & biotechnology 30 20339523
2010 Expression of AQP1 and AQP4 in paediatric brain tumours. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 30 20965731
2020 AQP4-siRNA alleviates traumatic brain edema by altering post-traumatic AQP4 polarity reversal in TBI rats. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 29 33222898
2016 The role of AQP4 in neuromyelitis optica: More answers, more questions. Journal of neuroimmunology 29 27609277
2022 MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls. Annals of neurology 28 36088544
2017 Deletional tolerance prevents AQP4-directed autoimmunity in mice. European journal of immunology 28 28058717
2012 Differential expression of MMP-9 and AQP4 in human glioma samples. Folia neuropathologica 28 22773464
2022 Altered Expression of AQP1 and AQP4 in Brain Barriers and Cerebrospinal Fluid May Affect Cerebral Water Balance during Chronic Hypertension. International journal of molecular sciences 26 36293145
2021 The role of aquaporin 4 (AQP4) in spinal cord injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 34915672
2024 Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration. NPJ Parkinson's disease 25 38296953
2021 The role of AQP4 in the pathogenesis of depression, and possible related mechanisms. Brain, behavior, and immunity 25 34474133
2023 Rapid Immunodot AQP4 Assay for Neuromyelitis Optica Spectrum Disorder. JAMA neurology 24 37669037
2022 A Microfluidic Model of AQP4 Polarization Dynamics and Fluid Transport in the Healthy and Inflamed Human Brain: The First Step Towards Glymphatics-on-a-Chip. Advanced biology 24 35922370
2021 Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation. Molecular psychiatry 24 34002021
2018 Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke. International journal of molecular medicine 23 30592266
2024 Dexmedetomidine improves the circulatory dysfunction of the glymphatic system induced by sevoflurane through the PI3K/AKT/ΔFosB/AQP4 pathway in young mice. Cell death & disease 22 38918408
2024 Autoimmune astrocytopathy double negative for AQP4-IgG and GFAP-IgG: Retrospective research of clinical practice, biomarkers, and pathology. CNS neuroscience & therapeutics 21 39279053
2022 The pathogenesis of idiopathic normal pressure hydrocephalus based on the understanding of AQP1 and AQP4. Frontiers in molecular neuroscience 21 36204139
2024 Edaravone Maintains AQP4 Polarity Via OS/MMP9/β-DG Pathway in an Experimental Intracerebral Hemorrhage Mouse Model. Molecular neurobiology 20 38421470
2022 Disassembly and Mislocalization of AQP4 in Incipient Scar Formation after Experimental Stroke. International journal of molecular sciences 20 35163040
2018 Er Shen Wan extract reduces diarrhea and regulates AQP 4 and NHE 3 in a rat model of spleen-kidney Yang deficiency-induced diarrhea. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 29571254
2024 Neutrophil Extracellular Traps Induce Brain Edema Around Intracerebral Hematoma via ERK-Mediated Regulation of MMP9 and AQP4. Translational stroke research 19 39733198
2023 Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder. Neurology(R) neuroimmunology & neuroinflammation 19 38134369
2021 Regulation of aquaporin-4 expression in the central nervous system investigated using M23-AQP4 null mouse. Glia 19 34038017
2019 Sevoflurane enhanced the clearance of Aβ1-40 in hippocampus under surgery via up-regulating AQP-4 expression in astrocyte. Life sciences 19 30763576
2023 Single-cell RNA sequencing reveals changes in glioma-associated macrophage polarization and cellular states of malignant gliomas with high AQP4 expression. Cancer gene therapy 18 36599974
2020 Uncoupling of the Astrocyte Syncytium Differentially Affects AQP4 Isoforms. Cells 18 32046059
2024 AQP4 Endocytosis-Lysosome Degradation Mediated by MMP-9/β-DG Involved in Diabetes Cognitive Impairment. Molecular neurobiology 17 38512439
2024 Different Complement Activation Patterns Following C5 Cleavage in MOGAD and AQP4-IgG+NMOSD. Neurology(R) neuroimmunology & neuroinflammation 17 39133885
2023 Intradermal AQP4 peptide immunization induces clinical features of neuromyelitis optica spectrum disorder in mice. Journal of neuroimmunology 17 37210799
2023 T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 17 37463205
2023 Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer's disease and other proteinopathies. Alzheimer's research & therapy 17 37821965
2023 Evaluation of gliovascular functions of AQP4 readthrough isoforms. Frontiers in cellular neuroscience 17 38077948
2022 AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood-Brain Barrier. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 36100398
2024 NHH promotes Sepsis-associated Encephalopathy with the expression of AQP4 in astrocytes through the gut-brain Axis. Journal of neuroinflammation 16 38802927
2023 Moxibustion improves hypothalamus Aqp4 polarization in APP/PS1 mice: Evidence from spatial transcriptomics. Frontiers in aging neuroscience 16 36819717
2021 Evaluation of AQP4/TRPV4 Channel Co-expression, Microvessel Density, and its Association with Peritumoral Brain Edema in Intracranial Meningiomas. Journal of molecular neuroscience : MN 16 33538957
2014 Association of rs2075575 and rs9951307 polymorphisms of AQP-4 gene with leukoaraiosis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 16 24582793
2024 Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ. Acta neuropathologica 15 38658413
2025 Blood-Based Biomarkers for Identifying Disease Activity in AQP4-IgG-Positive Neuromyelitis Optica Spectrum Disorder. JAMA neurology 14 39714824
2025 The role of Neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in MS and AQP4-NMOSD: Advancing clinical applications. eNeurologicalSci 14 39866832
2024 AQP4 regulates ferroptosis and oxidative stress of Muller cells in diabetic retinopathy by regulating TRPV4. Experimental cell research 14 38735619
2020 Inhibition of NMDA Receptors Downregulates Astrocytic AQP4 to Suppress Seizures. Cellular and molecular neurobiology 14 32107753
2019 AQP4 and the Fate of Gliomas. Cancer research 14 31160309
2016 Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve. Experimental eye research 14 26772436
2010 Spatial and temporal dissociation of AQP4 and Kir4.1 expression during induction of refractive errors. Molecular vision 14 20806048
2021 Pathogenic antibodies to AQP4: Neuromyelitis optica spectrum disorder (NMOSD). Biochimica et biophysica acta. Biomembranes 13 34509490
2018 Changes in the Expression of AQP4 and AQP9 in the Hippocampus Following Eclampsia-Like Seizure. International journal of molecular sciences 13 29351212
2025 Aquaporin 4 and its isoforms regulation ameliorate AQP4 Mis-localization-induced glymphatic dysfunction in ischemic stroke. Journal of advanced research 12 40403843

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