Affinage

Showing SLC4A3 — AE3 is a alias.

SLC4A3

Anion exchange protein 3 · UniProt P48751

Length
1232 aa
Mass
135.8 kDa
Annotated
2026-06-10
50 papers in source corpus 22 papers cited in narrative 22 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

SLC4A3 (AE3) is a plasma-membrane Cl-/HCO3- anion exchanger that catalyzes electroneutral exchange of intracellular bicarbonate for extracellular chloride to regulate intracellular pH in brain, heart, and retina (PMID:7923606, PMID:10548554). The gene produces tissue-specific isoforms—a full-length brain form and a shorter cardiac form (cAE3)—generated by alternative promoter usage and an alternative first exon, with additional truncated variants arising from alternative RNA processing (PMID:1560021, PMID:8126106, PMID:7931579). Functionally, AE3 mediates lower-rate exchange than AE1 or AE2 owing to inefficient plasma-membrane processing dictated by its cytoplasmic domain, but unlike AE2 it is insensitive to inhibition by acidic intracellular pH, allowing it to drive pHi recovery across a wide pH range (PMID:10548554, PMID:12578559). Its transport activity is upregulated by PKA and is functionally coupled to extracellular carbonic anhydrases CA4 and CA14, which enhance AE3-dependent pH regulation in neurons (PMID:19279262, PMID:19605733). In the hippocampus AE3 mediates neuronal HCO3- efflux that shapes pHi homeostasis, indirectly modulates astrocytic pH regulation, and limits seizure susceptibility, as AE3-null mice show reduced seizure thresholds (PMID:16354689, PMID:27353306). In cardiomyocytes AE3-mediated acid loading is required for the pro-hypertrophic cascade, the force-frequency response, and protection against hypertrophic decompensation, acting together with NKCC1 to control Ca2+ handling and phosphatase regulation (PMID:18779325, PMID:21056571, PMID:25047106). Loss-of-function SLC4A3 mutations cause short QT syndrome by producing intracellular alkalinization that decreases ICa-L, increases INCX, shortens action potential duration, and provokes delayed afterdepolarizations, with alkalinization established as the proximate arrhythmogenic cause; a gain-of-function variant produces SQTS by the reciprocal mechanism (PMID:29167417, PMID:36806574, PMID:41780556, PMID:40439641). AE3 is additionally required for retinal integrity, as its disruption causes progressive retinal degeneration in mice and dogs (PMID:17786210, PMID:21738669).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1992 High

    Established the molecular basis for AE3 tissue diversity by showing distinct brain and cardiac isoforms arise from alternative promoter and first-exon usage, explaining how one gene serves multiple tissues.

    Evidence cDNA cloning, genomic characterization, primer extension and S1 nuclease protection

    PMID:1560021

    Open questions at the time
    • Functional differences between isoforms not yet tested
    • Truncated/alternative-processing variants not yet characterized
  2. 1993 Medium

    Identified additional truncated AE3 isoforms by tissue-specific RNA processing, revealing that an N-terminal cytoplasmic-only product may associate with the cytoskeleton independent of transport.

    Evidence Molecular cloning, epitope-specific immunoblot, detergent solubility fractionation

    PMID:8126106

    Open questions at the time
    • Cytoskeletal partner not identified
    • Functional role of truncated isoform unknown
    • Single-lab structural inference
  3. 1994 High

    Confirmed that both major AE3 isoforms are functional anion exchangers and that the cardiac form is the dominant species in heart, anchoring AE3 as a bona fide Cl- transporter.

    Evidence Xenopus oocyte 36Cl- uptake, CHO overexpression, immunoblot of human cardiac membranes

    PMID:7923606

    Open questions at the time
    • pH dependence not quantified
    • Regulatory mechanisms not addressed
  4. 1994 High

    Mapped retinal isoform distribution, showing full-length AE3 in Müller glia and cardiac-type AE3 in horizontal neurons with developmental regulation, linking AE3 to retinal cell biology.

    Evidence Isoform-specific antibody immunoblot and immunohistochemistry in rat retina

    PMID:7931579

    Open questions at the time
    • Functional significance of cell-type segregation untested
    • Human relevance not established
  5. 1999 High

    Defined the distinctive pH behavior of AE3, showing it sustains anion exchange even at acidic pHi unlike AE2, identifying its role in pHi recovery after acid loading.

    Evidence HEK-293 transfection with pH clamping and intracellular Cl-/pH measurement across AE isoforms

    PMID:10548554

    Open questions at the time
    • Structural basis of pH insensitivity unknown
    • Reason for low transport rate not yet explained
  6. 2003 High

    Explained AE3's low activity as inefficient surface processing governed by its cytoplasmic domain rather than glycosylation, localizing the regulatory determinant within the protein.

    Evidence AE2-AE3 chimera expression, cell-surface labeling, confocal microscopy, tunicamycin treatment

    PMID:12578559

    Open questions at the time
    • Trafficking machinery interacting with cytoplasmic domain unidentified
    • In vivo relevance of trafficking inefficiency unclear
  7. 2005 High

    Demonstrated a physiological role for AE3 in the brain by linking its anion exchange to seizure threshold, establishing CNS pHi regulation as an AE3 function.

    Evidence Slc4a3 knockout mice, hippocampal ion transport measurement, multiple pharmacological seizure paradigms

    PMID:16354689

    Open questions at the time
    • Cell-autonomous neuronal vs glial contribution not resolved here
    • Molecular signaling linking pH to excitability unknown
  8. 2007 High

    Established AE3 as required for retinal function in vivo, with KO mice showing inner-retina defects and photoreceptor apoptosis plus compensatory upregulation of other acid-base transporters.

    Evidence Slc4a3-/- mice, electroretinography, TUNEL, immunoblot

    PMID:17786210

    Open questions at the time
    • Mechanism connecting AE3 loss to apoptosis unknown
    • Which retinal cell type drives degeneration unresolved
  9. 2008 High

    Revealed genetic redundancy in heart, showing AE3 loss is compensated unless NKCC1 is also removed, after which Ca2+ handling and phosphatase regulation are disrupted.

    Evidence AE3/NKCC1 double-knockout mice, in vivo cardiac performance, myocyte Ca2+ transients, NCX activity, PLN/phosphatase immunoblots

    PMID:18779325

    Open questions at the time
    • Direct physical interaction between AE3 and NKCC1 not shown
    • Mechanism of PP2A methylation change unexplained
  10. 2009 High

    Identified CA4 and CA14 as functional partners that enhance AE3-mediated bicarbonate transport, defining a transport metabolon for neuronal pH regulation.

    Evidence AE3-null neurons, benzolamide and isoform-specific antibody inhibition, intracellular pH measurement, single-cell PCR

    PMID:19279262

    Open questions at the time
    • Direct physical binding of CA4/CA14 to AE3 not demonstrated
    • Stoichiometry of metabolon undefined
  11. 2009 High

    Linked an AE3 variant to epilepsy at the functional level and showed PKA upregulates AE3 transport, identifying a regulatory input on the exchanger.

    Evidence HEK-293 transport assay of A867D variant, H89 and 8-Br-cAMP pharmacology, surface expression analysis

    PMID:19605733

    Open questions at the time
    • PKA phosphorylation site on AE3 not mapped
    • Human epilepsy causality from single variant not established
  12. 2010 High

    Showed AE3 is required to maintain contractile reserve in a hypertrophic cardiomyopathy background, separating its role in decompensation from hypertrophy itself.

    Evidence AE3-null × TM180 double-mutant mice, echocardiography, Ca2+ imaging, PLN phosphorylation immunoblot

    PMID:21056571

    Open questions at the time
    • Direct link between pHi change and PLN phosphorylation reserve unproven
    • Translation to human HCM unknown
  13. 2011 Medium

    Provided in vivo genetic causation for retinal disease by showing a SLC4A3 frameshift causes progressive retinal atrophy in dogs, strengthening the retinal requirement seen in mice.

    Evidence GWAS, frameshift sequencing, pedigree segregation in Golden Retrievers

    PMID:21738669

    Open questions at the time
    • Cellular mechanism of degeneration not addressed
    • Single natural model
  14. 2014 Medium

    Established AE3-mediated acid loading as required for cardiomyocyte hypertrophy and demonstrated its specific role in pHi recovery from alkalosis.

    Evidence ae3-/- mice and cultured cardiomyocyte hypertrophic stimulation with BCECF pH imaging

    PMID:25047106

    Open questions at the time
    • Downstream pro-hypertrophic signaling effectors unidentified
    • Single lab
  15. 2014 Medium

    Showed AE3 is needed for the force-frequency response and mechanosensory signaling under acute biomechanical stress, broadening its cardiac role beyond steady-state pH.

    Evidence In vivo cardiac pacing, intraventricular pressure, Akt/AMPK phosphoprotein immunoblot in AE3-null mice

    PMID:24427143

    Open questions at the time
    • Causal link between pH changes and Akt/AMPK signaling not proven
    • Single study
  16. 2014 High

    Characterized zebrafish Ae3 as a single-isoform DIDS-sensitive exchanger with substrate properties distinct from Ae2, validating the model organism used for later disease studies.

    Evidence Xenopus oocyte 36Cl- exchange, pharmacology, in situ hybridization

    PMID:24668450

    Open questions at the time
    • pH sensitivity differs from mammalian AE3
    • Tissue-specific isoforms absent in zebrafish
  17. 2016 High

    Dissected AE3's bidirectional impact on neuronal pHi and revealed neuron-dependent enhancement of astrocytic pH regulation, refining the CNS mechanism.

    Evidence AE3-/- neuron-astrocyte co-cultures, pH imaging across multiple acid/alkali load paradigms

    PMID:27353306

    Open questions at the time
    • Molecular signal coupling neuronal AE3 to astrocytic NBCe1 unidentified
    • In vivo relevance of co-culture findings untested
  18. 2017 High

    Established SLC4A3 as a short QT syndrome gene, demonstrating that reduced bicarbonate transport raises cardiac pHi and shortens the QT interval, with mutant rescue failing in zebrafish.

    Evidence Zebrafish knockdown with WT/mutant rescue, intracellular pH measurement, patch-clamp QTc, transport assay

    PMID:29167417

    Open questions at the time
    • Detailed ionic mechanism not yet resolved in this study
    • Human cardiomyocyte confirmation pending
  19. 2017 Low

    Inferred from transcriptomics that AE3 may participate in cardiac CO2 disposal, raising a metabolic hypothesis for its cardiac function.

    Evidence RNA-seq of AE3-null vs WT mouse hearts, GO analysis

    PMID:28779178

    Open questions at the time
    • CO2 disposal conclusion inferred from gene expression, not directly demonstrated
    • No direct flux measurement
    • Causation vs compensation not separated
  20. 2023 High

    Expanded and confirmed the SQTS allelic spectrum by functionally validating multiple loss-of-function variants via variant-specific zebrafish rescue, solidifying the alkaline-cytosol arrhythmia mechanism.

    Evidence Zebrafish knockdown with variant-specific human rescue, pH and QTc measurement, multicenter cohort

    PMID:36806574

    Open questions at the time
    • Cell-level electrophysiology not measured for each variant here
    • Penetrance and clinical variability not explained
  21. 2025 Medium

    Demonstrated that a gain-of-function SLC4A3 variant also causes SQTS, showing the QT-shortening phenotype can arise from either increased or decreased transport.

    Evidence Whole-exome sequencing, HEK-293 transport assay, structural modeling, clinical ECG

    PMID:40439641

    Open questions at the time
    • Cardiomyocyte-level consequences of gain-of-function not directly tested
    • Single lab, single variant
  22. 2026 High

    Pinpointed intracellular alkalinization as the proximate cause of SQTS arrhythmia, showing patient hiPSC-CMs with AE3 loss recapitulate the electrophysiology that is reproduced by simple alkalinization of wild-type cells.

    Evidence Patient hiPSC-CMs with isogenic CRISPR correction, patch-clamp, Ca2+ imaging, optical mapping, NH4Cl alkalinization

    PMID:41780556

    Open questions at the time
    • Molecular link from pH to ICa-L/INCX channel modulation not detailed
    • Therapeutic pH-correction strategies untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AE3 physically assembles with its functional partners (CA4/CA14, NKCC1) and how its cytoplasmic domain integrates PKA regulation, trafficking, and possible cytoskeletal anchoring into tissue-specific pHi control remains unresolved.
  • No direct structural model of AE3 or its complexes
  • PKA phosphosite and binding interfaces unmapped
  • Molecular coupling of pH change to channel function undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-397014 Muscle contraction 3
Partners
CA14CA4NKCC1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 The AE3 gene generates two isoforms (brain AE3 and cardiac AE3/cAE3) via alternative promoter usage and alternative first exon (exon C1) within the sixth intron of the brain transcription unit; the cardiac isoform encodes a unique 73 amino acid N-terminus replacing the first 270 amino acids of the brain form. cDNA cloning, genomic characterization, primer extension, S1 nuclease protection assays The Journal of biological chemistry High 1560021
1994 Both cardiac (cAE3, 1034 aa) and brain (bAE3, 1232 aa) isoforms of human AE3 mediate Cl- transport when expressed in Xenopus oocytes, confirming functional anion exchange activity. In human cardiac membranes, only cAE3 polypeptides were detected by immunoblot. Xenopus oocyte expression with 36Cl- uptake assay, immunoblot of human cardiac membranes, CHO cell overexpression Circulation research High 7923606
1993 Two novel truncated AE3 isoforms are generated by tissue-specific alternative RNA processing. The 14-AE3 isoform (74 kDa) encodes only the N-terminal cytoplasmic domain and lacks the transmembrane anion exchange channel. Unlike full-length AE3, 14-AE3 is insoluble in non-ionic detergent, suggesting association with the cytoskeleton. Molecular cloning, immunoblotting with N- and C-terminus-specific antibodies, detergent solubility fractionation Journal of cell science Medium 8126106
1994 AE3 is expressed as two distinct isoforms in the rat retina: a 165 kDa isoform (bAE3/full-length) restricted to Müller glia with polarized distribution highest in basal endfoot processes, and a 125 kDa isoform (cAE3) expressed in horizontal neurons. These isoforms show distinct developmental expression patterns, with the neuronal isoform undetectable until postnatal day 10-15. Immunoblotting and immunohistochemistry with antipeptide antibodies specific for NH2-terminal and COOH-terminal epitopes, developmental expression analysis The Journal of neuroscience High 7931579
1999 Full-length AE3 and cAE3 mediate Cl-/HCO3- exchange when expressed in HEK-293 cells, but at lower transport activity than AE1 or AE2 (AE3: 9 mM H+/min; cAE3: 4; vs AE1: 24; AE2: 32). Unlike AE2, AE3 and cAE3 are essentially insensitive to inhibition by acid intracellular pH across the range 6.0-9.0, indicating they can contribute to pHi recovery after acid loading regardless of pH. Transient transfection in HEK-293 cells, intracellular pH monitoring, intracellular chloride concentration measurement, pH clamping experiments The Biochemical journal High 10548554
2003 The low anion-transport activity of AE3 in HEK-293 cells is due to inefficient processing to the plasma membrane (~8-fold less efficient than AE2), and this inefficiency is determined by the cytoplasmic domain (amino acids 322-677 of AE2 being dominant). Glycosylation has little or no role in cell-surface processing or transport activity of AE2 or AE3. AE2-AE3 chimeric protein expression in HEK-293 cells, chemical cell-surface labeling, confocal microscopy, glycosylation inhibitor (tunicamycin) treatment, transport activity assays The Biochemical journal High 12578559
2006 Disruption of Slc4a3 (AE3 knockout) abolishes sodium-independent Cl-/HCO3- exchange in pyramidal cell layer of hippocampal CA3 region and reduces the seizure threshold in mice exposed to bicuculline, pentylenetetrazole, or pilocarpine, with increased seizure-induced mortality. AE3 KO mice do not develop spontaneous seizures but show increased susceptibility. Targeted gene disruption (knockout mouse), electrocorticography, pharmacological seizure induction, ion transport measurements in hippocampal slices Molecular and cellular biology High 16354689
2007 AE3-null (Slc4a3-/-) mice develop inner retina defects including electroretinogram b-wave reduction, optic nerve and retinal vessel anomalies, and late-onset photoreceptor apoptosis (4-6 months). Compensatory upregulation of NBC1, carbonic anhydrase II, and CAXIV protein expression was detected in null retinas, indicating that AE3-mediated Cl-/HCO3- exchange is required for normal retinal function. Electroretinography, TUNEL staining, immunoblotting, Slc4a3-/- knockout mouse model PloS one High 17786210
2008 Loss of AE3 alone in mice does not impair cardiac contractility or ischemia-reperfusion injury; however, combined knockout of AE3 and NKCC1 causes impaired cardiac contraction and relaxation, enhanced Na+/Ca2+ exchanger activity, reduced phospholamban phosphorylation, and altered protein phosphatase 2A methylation/localization, demonstrating that AE3 and NKCC1 together affect Ca2+ handling and cardiac phosphatase regulation. AE3/NKCC1 double knockout mice, in vivo cardiac performance, isolated ventricular myocyte Ca2+ transients, Na+/Ca2+ exchanger activity, immunoblotting for phospholamban and protein phosphatases The Journal of biological chemistry High 18779325
2009 Extracellular carbonic anhydrases CA4 and CA14 both facilitate AE3-mediated Cl-/HCO3- exchange in hippocampal neurons. Inhibition of CA4 or CA14 by benzolamide or isoform-specific antibodies enhanced NH4+-induced alkalinization in WT neurons, but this effect was absent in AE3-knockout neurons, placing CA4/CA14 as functional partners that enhance AE3-dependent pH regulation. AE3-null mouse hippocampal neurons, pharmacological CA inhibition (benzolamide), isoform-specific inhibitory antibodies, intracellular pH measurements, quantitative PCR, single-cell PCR The Journal of neuroscience High 19279262
2009 The epilepsy-associated AE3 variant A867D has significantly reduced Cl-/HCO3- exchange transport activity (~54% of wild-type) when expressed in HEK-293 cells, without differences in expression level or plasma membrane trafficking. PKA activation (by 8-Br-cAMP) increases transport activity of both WT and A867D AE3 to a similar degree, demonstrating PKA-dependent regulation of AE3 transport activity. Transient transfection in HEK-293 cells, intracellular pH-based transport assay, PKA inhibitor (H89) treatment, 8-Br-cAMP stimulation, surface expression analysis American journal of physiology. Cell physiology High 19605733
2010 In a hypertrophic cardiomyopathy model (α-tropomyosin E180G mutation), loss of AE3 caused rapid decompensation and heart failure with reduced Ca2+ transient amplitude and decay, impaired β-adrenergic response, and blunted PLN phosphorylation reserve, without affecting hypertrophy per se. Phospholamban Ser16 phosphorylation was sharply increased under basal conditions in both single and double mutants. AE3-null × TM180 hypertrophic cardiomyopathy double-mutant mice, echocardiography, Ca2+ transient imaging, immunoblotting for PLN phosphorylation and protein phosphatases Journal of molecular and cellular cardiology High 21056571
2011 A frameshift mutation in SLC4A3 in Golden Retriever dogs causes progressive retinal atrophy (PRA) with a recessive inheritance pattern and full penetrance, establishing SLC4A3 as causally required for retinal integrity in vivo. Genome-wide association study, sequencing identification of frameshift mutation, pedigree segregation analysis in affected dogs PloS one Medium 21738669
2013 AE3-null mice show blunted frequency-dependent inotropy (force-frequency response) during in vivo pacing, with elevated Akt phosphorylation and reduced AMPK phosphorylation in paced null hearts, suggesting AE3-mediated HCO3- extrusion is required for normal mechanosensory signaling during acute biomechanical stress. Intraventricular pressure analysis, in vivo cardiac pacing, phosphoprotein immunoblotting, Ca2+ transient analysis in AE3-null mice Frontiers in physiology Medium 24427143
2014 AE3-deficient (ae3-/-) cardiomyocytes are resistant to hypertrophic stimulation (no increase in cell growth or fetal gene program reactivation), and show a significantly slower rate of pHi recovery from imposed alkalosis, establishing AE3-mediated acid loading as required for the pro-hypertrophic cascade in cardiomyocytes. ae3-/- knockout mice, echocardiography, cultured cardiomyocyte hypertrophic stimulation assays, intracellular pH measurement with BCECF-AM dye BMC cardiovascular disorders Medium 25047106
2014 Zebrafish Ae3 (Slc4a3) encodes a single 1170 aa polypeptide that mediates low-rate DIDS-sensitive 36Cl-/Cl- exchange at the Xenopus oocyte surface. Unlike Ae2, zebrafish Ae3 Cl- transport is insensitive to NH4Cl and hypertonicity, though it is similarly inhibited by acidic pH and stimulated by alkaline pH. Xenopus oocyte expression, 36Cl- influx/efflux assays, pharmacological characterization (DIDS, NH4Cl, hypertonicity, pH), epitope-tagging, whole mount in situ hybridization Pflugers Archiv : European journal of physiology High 24668450
2016 AE3 in hippocampal neurons (not astrocytes) mediates HCO3- efflux that: (1) enhances pHi acidification rate during alkali loads and early metabolic acidosis, (2) limits the extent of pHi decrease during metabolic acidosis, and (3) paradoxically speeds re-alkalization after metabolic acidosis removal. AE3 knockout also impairs pHi homeostasis in adjacent astrocytes, which requires the presence of neurons, suggesting indirect enhancement of astrocytic NBCe1 activity by neuronal AE3. AE3-/- knockout mouse hippocampal neuron-astrocyte co-cultures, intracellular pH fluorescence imaging during CO2/HCO3- manipulations, metabolic acid loading/removal protocols, ammonium prepulse assays The Journal of physiology High 27353306
2017 A missense mutation in SLC4A3 causes SQTS by reducing surface expression of AE3 and reducing membrane bicarbonate transport. Slc4a3 knockdown in zebrafish increases cardiac pHi, shortens QTc, and reduces systolic duration; these phenotypes are rescued by wildtype but not mutated SLC4A3. An increase in pHi and decrease in intracellular [Cl-] shortens the action potential duration. Slc4a3 zebrafish knockdown with rescue experiments (WT vs. mutant SLC4A3), intracellular pH measurement, patch clamp for QTc, bicarbonate transport assay in transfected cells, surface expression analysis Nature communications High 29167417
2017 RNA-seq analysis of AE3-null mouse hearts reveals upregulation of hypoxia response genes and angiogenesis/vasodilation genes, and metabolic shifts toward glucose utilization and away from fatty acid utilization, supporting the hypothesis that AE3 functions in active CO2 disposal by extruding CO2 as HCO3- from cardiac myocytes. RNA-seq of AE3-null vs. wild-type mouse hearts, Gene Ontology analysis, PubMatrix analysis of differentially expressed genes Scientific reports Low 28779178
2023 Nonsynonymous SLC4A3 variants (p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, p.Arg952His, p.Arg370His) are loss-of-function mutations causing SQTS; knockdown of slc4a3 in zebrafish shortens QTc intervals rescued by native human SLC4A3 but not by the mutant variants, establishing pathogenicity of each variant. SLC4A3 dysfunction is associated with alkaline cytosol and shortened cardiomyocyte action potential. Zebrafish slc4a3 knockdown with variant-specific rescue, intracellular pH measurement, QTc measurement in zebrafish Heart rhythm High 36806574
2025 A novel SLC4A3 variant p.R1016G causes SQTS via a gain-of-function mechanism (increased transport activity) in HEK-293 cells, in contrast to previously described loss-of-function SQTS variants, demonstrating that both gain- and loss-of-function of AE3 can shorten the QT interval. Whole-exome sequencing, functional transport assay in HEK-293 cells, computational structural modeling, clinical ECG analysis JACC. Clinical electrophysiology Medium 40439641
2026 SLC4A3 loss-of-function mutations (p.Arg370Cys, p.Lys531Thr) in patient-derived hiPSC-CMs cause intracellular alkalinization, decreased L-type calcium channel current (ICa-L), increased Na+/Ca2+ exchange current (INCX), shortened action potential duration, and frequent delayed afterdepolarizations. Experimental alkalinization of WT hiPSC-CMs by NH4Cl recapitulated all these electrophysiological changes, establishing that alkalinization downstream of AE3 loss-of-function is the proximate cause of APD shortening and arrhythmia. Patient hiPSC-CMs with CRISPR/Cas9 isogenic correction, patch-clamp, Ca2+ imaging, single-cell contraction analysis, intracellular pH measurement, optical mapping in organoids, NH4Cl alkalinization of WT cells European heart journal High 41780556

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold. Molecular and cellular biology 106 16354689
1994 Molecular cloning, expression, and chromosomal localization of two isoforms of the AE3 anion exchanger from human heart. Circulation research 106 7923606
2017 Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nature communications 91 29167417
1999 Transport activity of AE3 chloride/bicarbonate anion-exchange proteins and their regulation by intracellular pH. The Biochemical journal 83 10548554
1992 The predicted translation product of a cardiac AE3 mRNA contains an N terminus distinct from that of the brain AE3 Cl-/HCO3- exchanger. Cloning of a cardiac AE3 cDNA, organization of the AE3 gene, and identification of an alternative transcription initiation site. The Journal of biological chemistry 81 1560021
1987 Comparison of keratin monoclonal antibodies MAK-6, AE1:AE3, and CAM-5.2. American journal of clinical pathology 79 2443001
1994 AE3 anion exchanger isoforms in the vertebrate retina: developmental regulation and differential expression in neurons and glia. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 7931579
1984 The use of aIF, AE1, and AE3 monoclonal antibodies for the identification and classification of mammalian epithelial keratins. Differentiation; research in biological diversity 71 6083891
2009 Carbonic anhydrases CA4 and CA14 both enhance AE3-mediated Cl--HCO3- exchange in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 62 19279262
2008 NKCC1 and AE3 appear to accumulate chloride in embryonic motoneurons. Journal of neurophysiology 62 19036864
2011 A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations. PloS one 50 21738669
2008 Immunohistochemical markers to distinguish between hemangioblastoma and metastatic clear-cell renal cell carcinoma in the brain: utility of aquaporin1 combined with cytokeratin AE1/AE3 immunostaining. The American journal of surgical pathology 40 18496143
2007 Blindness caused by deficiency in AE3 chloride/bicarbonate exchanger. PloS one 40 17786210
1995 Conservation of an AE3 Cl-/HCO3- exchanger cardiac-specific exon and promoter region and AE3 mRNA expression patterns in murine and human hearts. Circulation research 37 7895333
2003 Differential expression pattern of chloride transporters NCC, NKCC2, KCC1, KCC3, KCC4, and AE3 in the developing rat auditory brainstem. Cell and tissue research 34 12712325
2008 Impaired cardiac contractility in mice lacking both the AE3 Cl-/HCO3- exchanger and the NKCC1 Na+-K+-2Cl- cotransporter: effects on Ca2+ handling and protein phosphatases. The Journal of biological chemistry 30 18779325
2014 An EP4 antagonist ONO-AE3-208 suppresses cell invasion, migration, and metastasis of prostate cancer. Cell biochemistry and biophysics 28 24744183
2009 Characterization of an epilepsy-associated variant of the human Cl-/HCO3(-) exchanger AE3. American journal of physiology. Cell physiology 28 19605733
2010 Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure. Journal of molecular and cellular cardiology 26 21056571
2009 Expression of prostaglandin E2 receptors in oral squamous cell carcinomas and growth inhibitory effects of an EP3 selective antagonist, ONO-AE3-240. International journal of oncology 25 19212690
2023 Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome. Heart rhythm 24 36806574
2003 Transport activity of chimaeric AE2-AE3 chloride/bicarbonate anion exchange proteins. The Biochemical journal 23 12578559
1994 Molecular cloning and physical and genetic mapping of the human anion exchanger isoform 3 (SLC2C) gene to chromosome 2q36. Genomics 23 8001971
2022 Rhabdomyosarcoma with TFCP2 Rearrangement or Typical Co-expression of AE1/AE3 and ALK: Report of Three New Cases in the Head and Neck Region and Literature Review. Head and neck pathology 20 36374445
2016 Role of Cl- -HCO3- exchanger AE3 in intracellular pH homeostasis in cultured murine hippocampal neurons, and in crosstalk to adjacent astrocytes. The Journal of physiology 17 27353306
1987 Structural distinctions among human breast epithelial cells revealed by the monclonal antikeratin antibodies AE1 and AE3. The Journal of pathology 16 2447254
2014 Resistance to cardiomyocyte hypertrophy in ae3-/- mice, deficient in the AE3 Cl-/HCO3- exchanger. BMC cardiovascular disorders 15 25047106
1993 Generation of truncated brain AE3 isoforms by alternate mRNA processing. Journal of cell science 15 8126106
2016 Cytokeratin AE1/AE3 immunostaining and 3D-histology: improvement of diagnosis in desmoplastic squamous cell carcinoma of the skin. Archives of dermatological research 13 27864629
2004 Immunocytochemical analysis of AE1/AE3, CK 14, Ki-67 and p53 expression in benign, premalignant and malignant oral tissue to establish putative markers for progression of oral carcinoma. British journal of biomedical science 13 15462255
2013 Loss of the AE3 Cl(-)/HCO(-) 3 exchanger in mice affects rate-dependent inotropy and stress-related AKT signaling in heart. Frontiers in physiology 11 24427143
2014 The murine Cl⁻/HCO⁻₃ exchanger Ae3 (Slc4a3) is not required for acid-base balance but is involved in magnesium handling by the kidney. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 9 25402438
2017 RNA SEQ Analysis Indicates that the AE3 Cl-/HCO3- Exchanger Contributes to Active Transport-Mediated CO2 Disposal in Heart. Scientific reports 8 28779178
2025 A Gain-of -Function SLC4A3 Mutation Causes Short-QT Syndrome: From Molecular Analysis to Novel Diagnostic Testing. JACC. Clinical electrophysiology 7 40439641
2023 SATB2, CKAE1/AE3, and synaptophysin as a sensitive immunohistochemical panel for the detection of lymph node metastases of Merkel cell carcinoma. Virchows Archiv : an international journal of pathology 7 38066198
2008 Histopathological and immunohistochemical (cytokeratins AE1/AE3) study of the parametrium of patients with early stage cervical cancer. European journal of obstetrics, gynecology, and reproductive biology 7 18938023
2014 Molecular cloning and functional characterization of zebrafish Slc4a3/Ae3 anion exchanger. Pflugers Archiv : European journal of physiology 6 24668450
2005 Detection of lymph nodes micrometastases in Dukes' A and B colorectal cancer using anti-cytokeratin antibodies AE1/AE3. World journal of gastroenterology 6 15962393
2024 Expression Patterns of Cytokeratins (CK7, CK20, CK19, CK AE1/AE3) in Atypical Endometrial Hyperplasia Coexisting with Endometrial Cancer. International journal of molecular sciences 4 39201770
2017 Changes in histopathology and cytokeratin AE1/AE3 expression in skin graft with different time on Indonesian local cats. Veterinary world 4 28717319
2023 Detection of micro-metastasis using cytokeratins (AE1/AE3) in haematoxylin & eosin-stained N0 lymph nodes of oral squamous cell carcinoma. The Indian journal of medical research 3 37282394
2010 AE1/AE3, vimentin and p63 immunolocalization in canine mammary gland tumours: roles in differentiation between luminal epithelial and myoepithelial lineages. Asian Pacific journal of cancer prevention : APJCP 3 20593961
1984 A monoclonal antibody (AE3.d3) with mitogenic properties for murine B cells. Journal of immunology (Baltimore, Md. : 1950) 3 6384364
2022 Allele frequency of SLC4A3 (PRA1), TTC8 (PRA2), and PRA-prcd mutations in golden retrievers in Brazil. Frontiers in veterinary science 2 36325094
2026 SLC4A3-related short QT syndrome assessed in human induced pluripotent stem cell-derived cardiomyocytes: mechanisms of ventricular arrhythmia and sudden cardiac death. European heart journal 1 41780556
2025 A Novel Variant in SLC4A3 Gene Mutation Associated With Familial Short QT Syndrome and Sudden Death. Journal of cardiovascular electrophysiology 1 41039816
2025 POU4F3 Plus Keratin AE1/AE3 or Pan-keratin: An Optimal Sentinel Lymph Node Protocol for Merkel Cell Carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 1 41380848
2017 A Plasma Cell Myeloma With Post-Therapy Anaplastic Morphology, Osteomyelosclerosis, and Strong Pan-Cytokeratin (AE1/AE3) Expression: A Potential Diagnostic Pitfall. International journal of surgical pathology 1 29278963
2002 Genomic cloning and promoter analysis of a mouse anion exchanger 3 (AE3) gene. DNA sequence : the journal of DNA sequencing and mapping 1 12592704
2025 Multiscale computational elucidation of Interleukin-17 receptor A-E3 ubiquitin ligase TRAF3IP2 signaling nexus: structural dynamics and hotspots for targeted autoimmune and anti-inflammatory therapeutics. International journal of biological macromolecules 0 41067334

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