Affinage

SLC4A4

Electrogenic sodium bicarbonate cotransporter 1 · UniProt Q9Y6R1

Round 2 corrected
Length
1079 aa
Mass
121.5 kDa
Annotated
2026-04-28
98 papers in source corpus 42 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC4A4 encodes NBCe1, the electrogenic sodium-bicarbonate cotransporter that mediates basolateral Na⁺/HCO₃⁻ uptake in kidney proximal tubule, pancreatic ducts, colon, corneal endothelium, airways, and astrocytes, with a cell-type-dependent 2:1 or 3:1 HCO₃⁻:Na⁺ stoichiometry regulated by PKA phosphorylation at Ser982 (PMID:9235899, PMID:11251043, PMID:12411514). Its 3.9 Å cryo-EM structure reveals an ion coordination site whose subtle mutagenesis can convert the symporter into an anion exchanger; Asp555 discriminates bicarbonate from chloride, and the cytoplasmic N-terminal domain controls HCO₃⁻ permeation through an intramolecular Glu91–Arg298 interaction (PMID:29500354, PMID:19336397, PMID:18441326). Basolateral targeting requires a C-terminal Phe1013-Leu1014 motif, and transporter activity is modulated by IRBIT-dependent activation of the pNBC1 isoform, carbonic anhydrase II/IV transport metabolon formation, PKC-dependent endocytosis, TGF-β/Smad4 transcriptional regulation, and WNK/SPAK-opposed IRBIT-PP1 dephosphorylation (PMID:15273250, PMID:16769890, PMID:14567693, PMID:18815229, PMID:28568893, PMID:21317537). Loss-of-function mutations cause permanent isolated proximal renal tubular acidosis with ocular abnormalities, and astrocyte-specific deletion disrupts blood–brain barrier integrity through a CCL2–NO signaling axis (PMID:10545938, PMID:38709635).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Molecular identity of the renal Na⁺/HCO₃⁻ cotransporter was established by cloning kNBC1 from human kidney, resolving how proximal tubule cells reabsorb filtered bicarbonate at the molecular level.

    Evidence cDNA cloning and functional expression in HEK-293 cells with Northern blot showing kidney/pancreas expression

    PMID:9235899

    Open questions at the time
    • Transport stoichiometry not determined in this study
    • Structural basis of ion selectivity unknown
    • Regulatory mechanisms not addressed
  2. 1998 High

    Identification of the pancreatic isoform (pNBC1) sharing the SLC4A4 locus but with an alternative N-terminus revealed that a single gene generates tissue-specific cotransporter variants with distinct regulatory properties.

    Evidence cDNA library screening, Xenopus oocyte functional expression, FISH mapping to 4q21

    PMID:10069984 PMID:9651366

    Open questions at the time
    • Functional consequence of N-terminal difference unknown
    • Isoform-specific regulation not yet explored
  3. 1999 High

    The demonstration that homozygous SLC4A4 mutations cause proximal renal tubular acidosis with ocular abnormalities established NBCe1 as the essential basolateral bicarbonate exit pathway in the proximal tubule and linked it to human disease.

    Evidence Human genetics with mutation identification in pRTA families

    PMID:10545938

    Open questions at the time
    • Mechanism by which specific mutations impair transport not characterized
    • Ocular pathogenesis unclear
  4. 2001 High

    Stoichiometry studies revealed that NBCe1 operates at either 2:1 or 3:1 HCO₃⁻:Na⁺ depending on cell type rather than isoform identity, implying that unidentified cellular factors control the electrogenicity mode.

    Evidence Transfection of kNBC1 and pNBC1 into proximal tubule vs. collecting duct cells with reversal potential measurement

    PMID:11251043

    Open questions at the time
    • Identity of stoichiometry-determining cellular factors unknown
    • No structural explanation for variable stoichiometry
  5. 2002 High

    Discovery of a CAII–NBCe1 transport metabolon and PKA-dependent stoichiometry switching established the first regulatory mechanism: CAII binds the C-terminus at two acidic clusters to enhance flux, while PKA phosphorylation of Ser982 shifts stoichiometry from 3:1 to 2:1.

    Evidence Isothermal titration calorimetry (Kd ~160 nM), site-directed mutagenesis, Ussing chamber electrophysiology

    PMID:12411514 PMID:15218065

    Open questions at the time
    • Whether CAII interaction is regulated in vivo unclear
    • Kinase/phosphatase balance at Ser982 not mapped
  6. 2003 High

    Identification of an extracellular CAIV–NBC1 interaction at Gly767 completing a bilateral transport metabolon (CAII cytoplasmic / CAIV extracellular) showed that bicarbonate supply on both membrane faces is coupled to transporter flux.

    Evidence GST pull-down, G767 mutagenesis abolishing interaction, pHi recovery assay in HEK293 cells

    PMID:14567693

    Open questions at the time
    • In vivo relevance of metabolon in tissues other than kidney not tested
    • Stoichiometric composition of metabolon in native membranes unknown
  7. 2004 High

    Basolateral targeting was mapped to a C-terminal QQPFLS motif with Phe1013-Leu1014 being the minimal essential signal; disease-causing mutations S427L and R510H were shown to cause pRTA through mistargeting or cytoplasmic retention, not just loss of intrinsic activity.

    Evidence GFP-tagged truncation/point mutants in polarized MDCK cells, confocal microscopy, oocyte functional assays

    PMID:15273250 PMID:15713912 PMID:17182531

    Open questions at the time
    • Adaptor proteins recognizing the FL motif not identified
    • Whether FL motif interacts with clathrin machinery unknown
  8. 2006 High

    NBC1 knockout mice established the physiological essentiality of NBCe1 for survival (lethal metabolic acidosis) and demonstrated its role in colonic HCO₃⁻ secretion, while IRBIT was identified as an obligate activator of the pNBC1 isoform, linking IP₃ receptor signaling to bicarbonate transport.

    Evidence Gene-targeted KO mice with Ussing chamber measurements; Co-IP/pulldown with oocyte electrophysiology for IRBIT

    PMID:16769890 PMID:17192275

    Open questions at the time
    • IRBIT phosphorylation sites required for binding not fully mapped
    • Tissue-specific IRBIT–NBCe1 interaction not explored beyond oocytes at this point
  9. 2008 High

    Structural insights into NBCe1 mechanism advanced with homology modeling revealing an intramolecular Glu91–Arg298 interaction controlling HCO₃⁻ permeation (validated by charge-reversal rescue), and discovery of PKC-dependent regulated endocytosis providing a rapid post-translational control mechanism.

    Evidence Charge-reversal mutagenesis in oocytes; surface biotinylation and confocal microscopy with PKC inhibitors in parotid acinar cells

    PMID:18441326 PMID:18815229

    Open questions at the time
    • No high-resolution structure available at this stage
    • Endocytic adaptor partners not identified
  10. 2009 High

    Asp555 was identified as the bicarbonate selectivity determinant: D555E mutation converted NBCe1 from a HCO₃⁻ symporter to a broadly permissive anion conductor, pinpointing the ion discrimination mechanism.

    Evidence Site-directed mutagenesis with two-electrode voltage clamp and anion substitution in oocytes and HEK293 cells

    PMID:19336397

    Open questions at the time
    • Structural context of Asp555 within the pore not yet resolved at atomic level
  11. 2011 High

    NBCe1 was shown to couple membrane depolarization to intracellular alkalinization and glycolytic stimulation in astrocytes, establishing a neuron-to-astrocyte metabolic signaling role; separately, IRBIT was found to oppose WNK/SPAK kinase-mediated inhibition of NBCe1-B surface expression by recruiting PP1.

    Evidence FRET glycolysis reporter in WT vs. Slc4a4-null astrocytes with HEK293 reconstitution; siRNA epistasis with Co-IP and phosphorylation analysis in pancreatic ducts

    PMID:21317537 PMID:21976511

    Open questions at the time
    • Whether K⁺-glycolysis coupling operates in vivo during neuronal activity not directly shown
    • Full phosphorylation map of NBCe1 under WNK/SPAK regulation incomplete
  12. 2017 High

    TGF-β/Smad4 was identified as a direct transcriptional regulator of NBCe1 in astrocytes, with ChIP confirming Smad4 binding to the NBCe1 promoter; JNK and Src pathways also modulate NBCe1 expression, linking cytokine signaling to bicarbonate transport capacity.

    Evidence ChIP for Smad4, RT-PCR/immunoblotting, intracellular pH recording in WT and Slc4a4-null astrocytes, TGF-β reporter assay

    PMID:25755028 PMID:28568893

    Open questions at the time
    • Whether TGF-β regulation applies in non-CNS tissues unknown
    • Smad4 binding site in the NBCe1 promoter not mapped at single-nucleotide resolution
  13. 2018 High

    The 3.9 Å cryo-EM structure of the NBCe1 membrane domain dimer revealed the ion coordination site and accessibility pathway, and showed that minimal mutagenesis at the coordination site can switch NBCe1 from symport to exchange mode, unifying the mechanistic logic of SLC4 family transporters.

    Evidence Single-particle cryo-EM with atomic model building and functional mutagenesis validation

    PMID:29500354

    Open questions at the time
    • Cytoplasmic domains not resolved in structure
    • No substrate-bound or occluded-state structures available
    • Stoichiometry-determining mechanism not explained structurally
  14. 2022 High

    Physiological roles were extended to airway HCO₃⁻ secretion (Slc4a4-null mice show CF-like mucus accumulation) and to tumor biology (SLC4A4 inhibition in PDAC cells reduces glycolysis/lactate, raises extracellular pH, and restores anti-tumor immunity).

    Evidence siRNA/pharmacological inhibition in primary airway cells and Slc4a4-null mouse lungs; scRNA-seq-guided genetic/pharmacological targeting in PDAC mouse models with immune profiling

    PMID:35635440 PMID:36522548

    Open questions at the time
    • Clinical translatability of NBCe1 inhibition in PDAC unresolved
    • Whether airway phenotype is relevant to human CF pathogenesis needs confirmation
  15. 2024 High

    Astrocyte-specific Slc4a4 deletion was shown to disrupt blood–brain barrier integrity through increased CCL2 secretion and dysregulated arginine-NO metabolism, with rescue by CCL2-CCR2 pathway inhibition establishing a non-canonical role for NBCe1 in vascular homeostasis.

    Evidence Astrocyte-specific conditional KO, multi-omics (proteomics/metabolomics), ischemic stroke model, pharmacological/genetic CCL2-CCR2 rescue in vivo

    PMID:38709635

    Open questions at the time
    • How intracellular pH changes lead to CCL2 upregulation not mechanistically resolved
    • Relevance to human stroke outcomes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the identity of the cellular factor(s) that set 2:1 vs. 3:1 stoichiometry, the structural basis of stoichiometry regulation, substrate-bound and occluded-state structures, the adaptor machinery recognizing the basolateral FL targeting motif, and whether the astrocytic BBB-protective role is therapeutically targetable.
  • Stoichiometry-determining factor(s) remain unidentified after >20 years
  • No full-length NBCe1 structure with cytoplasmic domains resolved
  • FL motif receptor/adaptor unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 7
Localization
GO:0005886 plasma membrane 7 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-382551 Transport of small molecules 8 R-HSA-9609507 Protein localization 5 R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2
Partners
CA2CA4IRBITPPP1CASMAD4SPAKWNK1
Complex memberships
CAII-NBCe1 transport metabolonCAIV-NBCe1 extracellular metabolon

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 A human kidney Na+:HCO3- cotransporter (kNBC1/SLC4A4) was cloned and functionally expressed in HEK-293 cells, demonstrating Na+:HCO3- cotransport activity; Northern blot showed high expression in kidney and pancreas. cDNA cloning, functional expression in HEK-293 cells, Northern blot analysis The Journal of biological chemistry High 9235899
1998 The human pancreatic sodium bicarbonate cotransporter (pNBC1/SLC4A4) was cloned; it shares the same gene locus (chromosome 4q21) as kNBC1 but differs at the N-terminus (85 aa replacing 41 aa of kNBC1); functional expression in Xenopus oocytes confirmed Na+/HCO3- cotransport activity. cDNA library screening, functional expression in Xenopus oocytes, Northern blot, FISH chromosomal mapping The Journal of biological chemistry High 9651366
1999 hhNBC (heart/pancreas isoform of SLC4A4) is an electrogenic Na+/HCO3- cotransporter cloned from a human heart cDNA library; Xenopus oocyte expression showed membrane hyperpolarization and intracellular pH recovery upon CO2/HCO3- addition, Cl-independence, and DIDS sensitivity. cDNA cloning from heart library, two-electrode voltage clamp and intracellular pH measurements in Xenopus oocytes The American journal of physiology High 10069984
1999 Homozygous mutations in SLC4A4 (encoding NBCe1) cause permanent isolated proximal renal tubular acidosis with ocular abnormalities, establishing NBCe1 as the major renal bicarbonate reabsorber in the proximal tubule. Human genetics (mutation identification), functional characterization Nature genetics High 10545938
2000 The SLC4A4 gene spans ~450 kb with 26 exons; kNBC1 is transcribed from an alternative promoter in intron 3 (using last 313 nt of intron 3 coupled to exon 4), while pNBC1/hhNBC use exon 1 or a distinct first alternative exon. The proximal kNBC1 promoter region (-159 to +43) is sufficient for promoter activity. Genomic library screening, exon mapping, promoter deletion/reporter assays, transcription start site mapping Gene High 10876088
2000 NBC1 and NHE1 are the major basolateral base importers in rabbit duodenocytes; Na+/HCO3- cotransport and CO2 hydration/NHE1 exchange are equally important for duodenal HCO3- supply during cAMP-stimulated secretion; inhibition of either reduced basal HCO3- secretion by ~50%. Basolateral membrane vesicle 22Na+ uptake, semiquantitative RT-PCR, in vitro mucosa Ussing chamber measurements with pharmacological inhibitors Gastroenterology Medium 10930376
2001 Both kNBC1 and pNBC1 can exhibit either a 2HCO3-:1Na+ or 3HCO3-:1Na+ stoichiometry depending on the cell type (proximal tubule vs. collecting duct cells), not on their distinct N-termini; unidentified cellular factors modulate stoichiometry. Transfection of kNBC1 and pNBC1 into renal proximal tubule and collecting duct cells, Ussing chamber electrophysiology, reversal potential measurement at different Na+ gradients The Journal of physiology High 11251043
2001 A novel nonsense mutation Q29X in the unique 5'-end of kNBC1 (SLC4A4) in a patient with pRTA and bilateral glaucoma predicts a truncated protein lacking 1007 C-terminal amino acids, consistent with loss of cotransport function, while the pancreatic NBC1 isoform is unaffected. cDNA sequencing from peripheral lymphocytes, cosegregation analysis, allele frequency in controls Journal of the American Society of Nephrology Medium 11274232
2002 CAII binds to the C-terminus of kNBC1 (Kd ~160 nM, by isothermal titration calorimetry) at two acidic clusters (L958DDV and D986NDD); this interaction enhances flux through the cotransporter (transport metabolon). Asp986 and Asp988 are required for the phosphorylation-induced stoichiometry shift from 3:1 to 2:1, but CAII binding does not affect stoichiometry itself. PKA phosphorylation of Ser982 shifts stoichiometry from 3HCO3-:1Na+ to 2HCO3-:1Na+. Site-directed mutagenesis, isothermal titration calorimetry, Ussing chamber electrophysiology in mPCT cells, short-circuit current measurement The Journal of physiology High 12411514
2003 Carbonic anhydrase IV (CAIV) directly binds the fourth extracellular loop of NBC1 at residue G767 (by GST pull-down); this extracellular CAIV interaction increases NBC1-mediated pHi recovery rate by 44%. CAII interaction at the cytoplasmic face is also required for full NBC1 activity, forming a transport metabolon with CAIV and CAII flanking the transporter on both sides. Co-IP/GST pull-down, pHi recovery assay in NBC1-transfected HEK293 cells, site-directed mutagenesis of G767 Biochemistry High 14567693
2003 kNBC1 (but not pNBC1) is the dominant variant mediating bicarbonate absorption in human and rat renal proximal tubules, with exclusive basolateral membrane localization in proximal tubule cells; in renal cell carcinoma cells, kNBC1 labels both plasma membranes and intracellular organelles. Isoform-specific antibodies, Western blot, immunofluorescence, electron microscopy on human kidney and RCC tissues Biochemical and biophysical research communications Medium 14559244
2004 A novel missense mutation S427L in NBCe1 reduces Na+/HCO3- cotransport currents to ~10% of wild-type and abolishes NaHCO3 efflux mode; current-voltage analysis reveals no reversal potential in HCO3-, indicating voltage- and Na+-dependent transport is unfavorably altered, explaining both proximal RTA and glaucoma. Xenopus oocyte expression, microelectrode intracellular pH measurement, two-electrode voltage clamp, current-voltage analysis The Journal of biological chemistry High 15471865
2004 The molecular mechanism of kNBC1-CAII interaction involves two acidic clusters (L958DDV and D986NDD) in the C-terminus; mutations in these clusters reduce CAII binding and correlate with reduced transporter flux, confirming a functional transport metabolon in proximal tubule cells. Site-directed mutagenesis of kNBC1 C-terminus, CAII binding assays, functional flux measurements in mPCT cells The Journal of physiology High 15218065
2004 kNBC1 variant is differentially expressed at the basolateral membrane of renal proximal tubules (kNBC1) and basolateral membrane of acinar and duct cells in pancreas (pNBC1); some pancreatic duct cells also show apical pNBC1. Both N-terminal variants are co-expressed in kidney and pancreas. Anti-peptide antibodies against unique N-terminal epitopes, immunoblotting, immunohistochemistry, RT-PCR on rat kidney and pancreas Biochemical and biophysical research communications Medium 14733916
2004 A carboxyl-terminal motif QQPFLS (residues 1010-1015), specifically the Phe at position 1013, is essential for exclusive targeting of NBC1 to the basolateral membrane; deletion of 26+ C-terminal residues retargets NBC1 to the apical membrane while retaining transport function. GFP-tagged truncation and point mutants expressed in kidney epithelial cells, confocal microscopy, oocyte functional assays The Journal of biological chemistry High 15273250
2005 Three new NBC1 mutations (T485S, A799V, R881C) cause variable reductions in electrogenic activity (15-40% of WT); T485S and R510H show poor surface expression in oocytes but ~50% activity in ECV304 cells, indicating cell-type-dependent trafficking. All functional variants retain 2HCO3-:1Na+ stoichiometry and normal Na+ affinity. Xenopus oocyte electrophysiology, ECV304 cell expression, two-electrode voltage clamp, intracellular pH measurements Journal of the American Society of Nephrology High 15930088
2005 NBC1 mutations R510H and S427L cause proximal RTA through a combination of reduced transport activity and mistargeting: R510H is predominantly retained in the cytoplasm of polarized MDCK cells, while S427L is mistargeted to the apical membrane (instead of basolateral), with both reducing activity in oocytes. GFP-fusion constructs in polarized MDCK cells, confocal microscopy, oocyte Western blot membrane fractionation, membrane potential recording American journal of physiology. Renal physiology High 15713912
2006 NBC1 knockout (Slc4a4-/-) mice develop severe metabolic acidosis, growth retardation, and die before weaning; NBC1-/- proximal colon shows impaired HCO3- secretion under cAMP stimulation (detected with carbonic anhydrase inhibition), while NKCC1 activity increases compensatorily, demonstrating NBC1 is a basolateral HCO3- uptake mechanism for colonic anion secretion. Gene-targeted knockout mice, bioelectric measurements in Ussing chamber, intracellular pH measurement, pharmacological inhibitor studies The Journal of biological chemistry High 17192275
2006 A novel NBCe1 mutation L522P causes pRTA exclusively through inability of the protein to reach the plasma membrane (cytoplasmic retention in ECV304 and MDCK cells), in contrast to G486R and T485S which reach the basolateral membrane and retain partial activity (~50% of WT). Xenopus oocyte expression, ECV304 and MDCK cell expression, immunofluorescence, intracellular pH measurement Pflugers Archiv : European journal of physiology Medium 17661077
2006 IRBIT (IP3 receptor-binding protein released with IP3) specifically binds to the N-terminal domain of pNBC1 (but not kNBC1), in a phosphorylation-dependent manner; coexpression of IRBIT in Xenopus oocytes is required for pNBC1 to manifest substantial activity comparable to kNBC1. Co-IP, pulldown assays, Xenopus oocyte two-electrode voltage clamp, deletion mapping of binding domain Proceedings of the National Academy of Sciences of the United States of America High 16769890
2006 The R881C mutation in NBCe1-A reduces surface expression (not per-molecule activity) by causing retention in the endoplasmic reticulum in polarized MDCK cells, while WT localizes exclusively to the basolateral membrane. EGFP-tagged constructs, two-electrode voltage clamp with surface quantification in oocytes, confocal microscopy in MDCK-I cells American journal of physiology. Cell physiology High 16707554
2006 A novel Leu522Pro mutation in NBCe1 (L522P in kNBCe1) fails to induce electrogenic transport activity in oocytes because it is not effectively transported to the oocyte membrane. Xenopus oocyte expression, electrogenic transport activity assay, membrane trafficking assessment Molecular vision Medium 16636648
2006 A novel C-terminal cytoplasmic signal distinct from QQPFLS was identified: the FL motif (Phe1013-Leu1014) is essential for basolateral targeting; mutation of F1013A or L1014A retargets NBC1 to the apical membrane, while all mistargeted mutants remain functionally active in oocytes. Site-directed mutagenesis of FL motif, GFP-tagged constructs in MDCK cells, confocal microscopy, oocyte functional assays with microelectrode American journal of physiology. Renal physiology High 17182531
2008 Homology modeling of NBCe1 onto AE1/Band3 crystal structure predicted Arg298 to interact with Glu91 or Glu295 in a solvent-inaccessible pocket; charge-reversal mutagenesis (E91R/R298E) restored transport function, demonstrating these residues are interdependent and that the cytoplasmic N-terminal domain controls HCO3- permeation (a 'formula tunnel'). Homology modeling on AE1 crystal structure, site-directed mutagenesis, Xenopus oocyte expression with electrophysiological functional assay The Journal of biological chemistry High 18441326
2008 NBCe1 (SLC4A4) undergoes cholinergic-stimulated PKC-dependent endocytosis from the basolateral membrane to early endosomes in parotid acinar cells; constitutive recycling also occurs. NBCn1 (SLC4A7) does not undergo this regulated endocytosis, demonstrating isoform-specific membrane trafficking regulation. Confocal fluorescent microscopy, surface biotinylation assay, PKC inhibitor (GF-109203X), carbachol/PMA stimulation, monensin/W-13 treatment in polarized ParC5 cells American journal of physiology. Cell physiology High 18815229
2009 Asp555 in NBCe1 plays a role in HCO3- selectivity; substitution D555E induces an HCO3--independent chloride conductance (broadly permissive to NO3- and other anions), demonstrating that Asp555 discriminates between bicarbonate and chloride during transport. Site-directed mutagenesis, Xenopus oocyte two-electrode voltage clamp, immunohistochemistry, CO2/HCO3- pH recovery, fluorescent chloride transport assay in HEK293 cells, anion substitution experiments The Journal of biological chemistry High 19336397
2009 The precise position and orientation of the FL motif in the C-terminal tail of NBC1 is required for both basolateral targeting and alpha-helical secondary structure; shifting FL one residue downstream (PSFL) causes ER retention, while reversal (PLFS) has no effect on targeting. CD spectroscopy confirmed wild-type C-terminal peptide forms significant alpha-helical structure that is disrupted by certain FL motif alterations. Site-directed mutagenesis with positional shifts, confocal microscopy in MDCK cells, oocyte functional assays, circular dichroism spectroscopy of synthetic peptides The Journal of membrane biology High 19294449
2010 A homozygous 65-bp C-terminal deletion (Δ65bp/S982NfsX4) in NBCe1 causes near-total loss of transport activity in mammalian cells due to predominant cytosolic retention, and exerts a dominant negative effect through hetero-oligomer formation with wild-type NBCe1; near-total loss of NBCe1 activity in astrocytes can cause migraine through dysregulation of synaptic pH. Xenopus oocyte electrophysiology, mammalian cell expression with trafficking analysis, coexpression dominant-negative experiments, immunohistochemistry of patient astrocytes Proceedings of the National Academy of Sciences of the United States of America High 20798035
2011 NBCe1 (SLC4A4) mediates the K+-stimulated glycolytic response in astrocytes: extracellular K+ rise causes membrane depolarization → NBCe1-mediated intracellular alkalinization → glycolysis stimulation. This was absent in Slc4a4-null astrocytes and could be reconstituted in HEK293 cells by co-expressing NBCe1 with a constitutively open K+ channel. FRET-based glycolysis reporter in mouse astrocytes, pharmacological inhibition of NBCe1, comparison of WT vs. Slc4a4-null astrocytes, heterologous reconstitution in HEK293 cells with co-expression The Journal of neuroscience High 21976511
2011 NBC1(W516X) knock-in mice (modeling a patient nonsense mutation) show near-absent NBC1 mRNA and protein in kidney due to nonsense-mediated mRNA decay; isolated renal proximal tubules exhibit markedly reduced NBC1 activity and bicarbonate absorption rate; NaHCO3 (but not saline) administration prolongs survival, demonstrating that metabolic acidosis is the primary lethal mechanism. Knock-in mouse model, real-time PCR, Western blot, isolated proximal tubule bicarbonate absorption measurement, NaHCO3 vs. saline rescue experiment Kidney international High 21228764
2011 IRBIT antagonizes the WNK/SPAK kinase pathway by recruiting protein phosphatase 1 (PP1) to dephosphorylate NBCe1-B and CFTR, restoring their cell surface expression and activity; WNK kinases scaffold SPAK which phosphorylates NBCe1-B reducing its surface expression, while IRBIT opposes this to enable ductal HCO3- secretion. siRNA silencing in pancreatic ducts, surface expression assays, co-immunoprecipitation, phosphorylation analysis, ductal secretion measurements The Journal of clinical investigation High 21317537
2012 The A799V mutation in NBCe1-A causes a per-molecule transport defect plus an unusual HCO3--independent ion conductance; Ala799Ile (but not Ala799Gly or Ala799Ser) similarly generates this novel conductance, suggesting A799 position is critical for ion selectivity. A799V accumulates poorly in the plasma membrane and shows abnormal intracellular accumulation in a non-polarized renal cell line. Xenopus oocyte biotinylation and two-electrode voltage clamp, Cl--free solution ion substitution experiments, DIDS/tenidap sensitivity assays, renal cell-line trafficking analysis The Journal of physiology High 22331414
2015 4-Aminopyridine (4AP)-induced NBCe1 upregulation in astrocytes requires JNK and Src/ERK signaling pathways; both transcript and protein surface expression of NBCe1 increase after 4AP treatment, with increased rate and amplitude of intracellular H+ changes that are absent in Slc4a4-deficient astrocytes. Quantitative RT-PCR, immunoblotting, surface protein biotinylation, intracellular pH recording with BCECF, JNK/Src inhibitors, acute hippocampal slices and primary astrocyte cultures from WT and NBCe1-null mice Glia High 25755028
2015 SLC4A4/NBCe1 knockdown reduces pHi recovery from acidosis and impairs cell proliferation, survival under acid stress, and spheroid growth in colon cancer (LS174T) cells; in breast cancer (MDA-MB-231) cells, SLC4A4 knockdown strongly reduces proliferation, migration and invasion, and diminishes Na+/HCO3--dependent pHi recovery. shRNA knockdown of SLC4A4, intracellular pH recovery assays, cell proliferation/mortality assays, spheroid growth, migration/invasion assays Journal of cellular physiology Medium 25612232
2018 CryoEM structure of the human NBCe1 membrane domain dimer at 3.9 Å resolution revealed the ion accessibility pathway and ion coordination site; residues at the coordination site correspond to human disease-causing mutation positions. Functional mutagenesis of a small number of residues within the ion coordination site converted NBCe1 from a symporter to an anion exchanger, suggesting symporters and exchangers utilize comparable transport machinery with subtle differences in substrate-binding regions determining transport mode. Single-particle cryo-electron microscopy, atomic model building, site-directed mutagenesis with functional transport assays Nature communications High 29500354
2017 TGF-β directly regulates NBCe1 (SLC4A4) transcription via Smad4 binding to the NBCe1 promoter; TGF-β receptor activation upregulates NBCe1 transcript, protein, and surface expression through JNK and Smad signaling; 4AP-dependent NBCe1 regulation requires TGF-β; increased NBCe1 activity (rate and amplitude of intracellular H+ changes) was absent in Slc4a4-deficient astrocytes. RT-PCR, immunoblotting, immunofluorescence, intracellular H+ recording, chromatin immunoprecipitation (Smad4 binding to NBCe1 promoter), MLEC TGF-β reporter assay, Slc4a4-deficient mouse astrocytes Glia High 28568893
2018 The NBCe1-B splice variant of SLC4A4 is expressed in mouse kidney proximal tubules (in addition to NBCe1-A); its expression is upregulated in the proximal straight tubule of the outer stripe of the outer medulla in response to exogenous acid loading, suggesting it contributes to renal acid-base homeostasis. Splice variant-specific antibodies, immunohistochemistry, immunoblot, RT-PCR in NBCe1-A knockout mice, acid-loading experiments American journal of physiology. Renal physiology Medium 29631353
2022 SLC4A4 inhibition in pancreatic ductal adenocarcinoma (PDAC) cells mitigates tumor microenvironment acidosis by causing bicarbonate accumulation in the extracellular space and reducing cancer cell glycolysis and lactate production; genetic or pharmacological SLC4A4 targeting improves T cell-mediated immune response and reduces macrophage-mediated immunosuppression, inhibiting tumor growth and metastases. scRNA-seq identification, genetic knockout and pharmacological inhibition in PDAC cells and mouse models, pH measurements, glycolysis/lactate assays, tumor immune profiling, combination with immune checkpoint blockade Nature cancer High 36522548
2022 SLC4A4 is expressed at the basolateral membrane of human and mouse airway epithelial cells and mediates HCO3- uptake into airway cells; its pharmacological inhibition or genetic silencing reduces bicarbonate secretion, acidifies airway surface liquid, impairs recovery from acid load, and in Slc4a4-null mice causes mucus accumulation and reduced mucociliary clearance resembling a cystic fibrosis-like phenotype. Immunolocalization, siRNA/pharmacological inhibition in primary human airway cells, intracellular pH recording, airway surface liquid pH measurement, Slc4a4-null mouse lung phenotyping with mucus and mucociliary clearance assays eLife High 35635440
2024 Astrocyte-specific Slc4a4 deletion disrupts normal astrocyte morphological complexity and blood-brain barrier (BBB) integrity; multi-omics identified increased CCL2 secretion coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion; loss of Slc4a4 exacerbates BBB disruption after ischemic stroke, which was rescued by pharmacological or genetic inhibition of the CCL2-CCR2 pathway, establishing an astrocytic Slc4a4-CCL2 / endothelial CCR2 axis controlling BBB integrity. Astrocyte-specific conditional knockout, multi-omics (proteomics/metabolomics), CCL2/NO measurement, ischemic stroke model, pharmacological and genetic CCL2-CCR2 pathway inhibition in vivo Cell reports High 38709635
2023 A novel missense SLC4A4 variant (Arg166Trp/p.R166W) in a pRTA patient slightly reduces protein stability (by cycloheximide chase assay) and alters Na+/HCO3- cotransport activity in whole-cell patch clamping; the patient's homozygosity arose from paternal uniparental isodisomy of chromosome 4. Whole exome sequencing, cycloheximide chase assay for protein stability, whole-cell patch clamping electrophysiology, H3M2/UPDio algorithm for UPiD detection Biochemical genetics Medium 37952039
2004 NBC1 mediates basolateral HCO3- permeability and transendothelial HCO3- flux in bovine corneal endothelium; siRNA knockdown reducing NBC1 by 80-95% decreased basolateral HCO3- permeability sixfold and reduced basolateral-to-apical HCO3- flux by 67%, demonstrating NBC1 is functional only at the basolateral membrane of corneal endothelium. siRNA knockdown of NBC1, intracellular pH measurements under CO2-free HCO3- removal conditions, transepithelial HCO3- flux measurement, Western blot American journal of physiology. Cell physiology High 15548570

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Blood-Brain Barrier: From Physiology to Disease and Back. Physiological reviews 1645 30280653
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1993 3,400 new expressed sequence tags identify diversity of transcripts in human brain. Nature genetics 289 8358434
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