Affinage

SLC4A4

Electrogenic sodium bicarbonate cotransporter 1 · UniProt Q9Y6R1

Length
1079 aa
Mass
121.5 kDa
Annotated
2026-06-10
68 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC4A4 (NBCe1) is an electrogenic Na+/HCO3− cotransporter that provides the basolateral bicarbonate uptake or efflux step underlying transepithelial HCO3− movement and intracellular pH homeostasis across multiple epithelia and in astrocytes (PMID:29500354, PMID:17192275, PMID:15548570). Its transmembrane domain forms a dimer with a defined ion accessibility pathway and coordination site, where subtle changes at substrate-binding residues can convert it from a symporter into an anion exchanger, and where Asp-555 enforces HCO3− selectivity by excluding Cl− (PMID:29500354, PMID:19336397). The cytoplasmic N-terminal domain contributes directly to HCO3− permeation rather than acting only as a scaffold (PMID:18441326), while transport stoichiometry (3:1 versus 2:1 HCO3−:Na+) is set by cell-type-specific factors and not by the divergent N-termini that distinguish the kidney (kNBC1) and pancreatic (pNBC1) variants generated from a single gene by alternative promoter usage (PMID:11251043, PMID:10876088). Exclusive basolateral targeting requires a C-terminal QQPFLS/FL motif whose precise position and α-helical conformation are essential—mispositioning retargets the protein apically or causes ER retention—and surface abundance is dynamically controlled by PKC-dependent endocytosis and by kinase-regulated trafficking (PMID:15273250, PMID:19294449, PMID:17182531, PMID:18815229). In the renal proximal tubule kNBC1 is the dominant variant mediating bicarbonate reabsorption, and its loss causes proximal renal tubular acidosis with systemic metabolic acidosis, while disease-causing missense mutations impair function through reduced transport, mistrafficking, protein instability, or anomalous leak conductances (PMID:21228764, PMID:14559244, PMID:15471865, PMID:15713912, PMID:15930088, PMID:37952039, PMID:22331414). Beyond the kidney, NBCe1 supplies the basolateral HCO3− step for secretion in colon, duodenum, airways, and corneal endothelium (PMID:17192275, PMID:10930376, PMID:35635440, PMID:15548570), is transcriptionally induced by TGF-β via Smad4 in astrocytes where it maintains blood-brain barrier integrity through a Slc4a4→CCL2→CCR2 axis (PMID:28568893, PMID:38709635), and is exploited by tumor cells, where HIF1α-driven bicarbonate import sustains an alkaline intracellular pH for proliferation and its inhibition reshapes the acidic microenvironment to restore anti-tumor immunity (PMID:25612232, PMID:36522548).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2000 High

    Establishing that a single gene generates the kidney and pancreatic NBC1 variants explained how tissue-specific isoforms with distinct N-termini arise from one locus.

    Evidence genomic library screening, exon-intron mapping, 5' RACE and promoter-reporter assays defining an intron-3 alternative promoter

    PMID:10876088

    Open questions at the time
    • Does not address whether the N-terminal differences alter transport behavior
    • Regulation of the alternative promoter in vivo not defined
  2. 2000 Medium

    Demonstrating HCO3−-dependent, stilbene-sensitive Na+ uptake at the duodenocyte basolateral membrane established NBC1 as a major base importer for transepithelial HCO3− secretion.

    Evidence 22Na+ uptake into basolateral membrane vesicles and rabbit duodenal HCO3− secretion assays with pharmacological dissection

    PMID:10930376

    Open questions at the time
    • Pharmacological inhibitors not fully isoform-specific
    • No genetic confirmation in this tissue
  3. 2001 High

    Showing that NBCe1 stoichiometry is cell-type dependent and independent of the divergent N-termini revealed that unidentified cellular factors, not isoform identity, set transport mode.

    Evidence transfection of kNBC1/pNBC1 into proximal tubule and collecting duct cells with reversal-potential analysis

    PMID:11251043

    Open questions at the time
    • Identity of the modifying cellular factors unknown
    • Mechanism by which stoichiometry is altered not resolved
  4. 2004 High

    Identification of a C-terminal QQPFLS motif required for exclusive basolateral targeting defined the sorting determinant that confines NBC1 to the correct epithelial surface.

    Evidence GFP-fusion truncation and point mutants with confocal localization and oocyte functional assays

    PMID:15273250

    Open questions at the time
    • Sorting machinery recognizing the motif not identified
    • Did not yet define structural basis of the signal
  5. 2004 Medium

    Establishing kNBC1 as the dominant basolateral variant in human proximal tubule, with pNBC1 undetectable, anchored kNBC1 as the physiological mediator of renal bicarbonate absorption.

    Evidence isoform-specific Western blot, immunofluorescence and electron microscopy of human kidney

    PMID:14559244

    Open questions at the time
    • Antibody specificity-dependent
    • Functional contribution inferred from localization, not direct in human tissue
  6. 2004 High

    Linking the S427L mutation to near-abolished electrogenic transport provided a direct functional explanation for proximal RTA with ocular involvement.

    Evidence Xenopus oocyte expression with intracellular pH measurement and two-electrode voltage clamp

    PMID:15471865

    Open questions at the time
    • Did not yet distinguish trafficking from intrinsic transport defect
    • Ocular mechanism inferred, not directly tested
  7. 2004 High

    siRNA knockdown in corneal endothelium showed NBC1 carries the majority of basolateral HCO3− permeability, defining its role in transendothelial bicarbonate flux.

    Evidence siRNA knockdown with intracellular pH fluorometry and net transendothelial HCO3− flux measurement

    PMID:15548570

    Open questions at the time
    • In vivo corneal phenotype not assessed
    • Compensation by other transporters not excluded
  8. 2005 High

    Reciprocal trafficking analysis of RTA mutations (cytoplasmic retention vs apical mistargeting) revealed distinct molecular mechanisms underlying clinically similar disease.

    Evidence GFP-fusion mutants in polarized MDCK cells with confocal microscopy and oocyte electrophysiology

    PMID:15713912

    Open questions at the time
    • Quality-control pathways causing retention not identified
    • Single lab
  9. 2005 High

    Comparing disease mutants across oocyte and mammalian cell systems showed surface-expression behavior is system-dependent and that some phenotypes arise primarily from failure to reach the membrane.

    Evidence expression of T485S, R510H and L522P in oocytes, ECV304 and MDCK cells with localization and functional readouts

    PMID:15930088

    Open questions at the time
    • Mechanism of intracellular retention for L522P not defined
    • Cell-system discrepancies not mechanistically explained
  10. 2006 Medium

    Refining the C-terminal signal to F-1013/L-1014 pinpointed phenylalanine as the critical residue within a hydrophobic di-amino acid basolateral targeting motif.

    Evidence site-directed point mutagenesis with confocal localization in MDCK cells and oocyte recording

    PMID:17182531

    Open questions at the time
    • Recognition partner for the motif unknown
    • Single lab
  11. 2006 High

    Knockout mice established NBC1 as required for cAMP-stimulated HCO3− secretion and pH regulation in the proximal colon, extending its role beyond kidney.

    Evidence NBC1-knockout mice with Ussing chamber bioelectric measurements and intracellular pH fluorometry

    PMID:17192275

    Open questions at the time
    • Residual secretion mechanism not defined
    • Apical exit step not characterized
  12. 2008 Medium

    Charge-reversal rescue between N-terminal residues showed the cytoplasmic domain directly controls HCO3− permeation rather than serving only as a protein-binding scaffold.

    Evidence homology modeling onto AE1, charge-reversal mutagenesis (E91R/R298E), and oocyte electrophysiology

    PMID:18441326

    Open questions at the time
    • Structural model is computational, not experimentally resolved
    • Mechanism of permeation control not visualized
  13. 2008 Medium

    Demonstrating PKC-dependent, isoform-specific regulated endocytosis of NBCe1 (but not NBCn1) revealed dynamic control of surface transporter abundance.

    Evidence surface biotinylation and confocal colocalization in polarized ParC5 cells with PKC inhibition

    PMID:18815229

    Open questions at the time
    • PKC substrate site on NBCe1 not mapped
    • Physiological trigger in vivo not established
  14. 2009 High

    Identifying Asp-555 as the determinant of HCO3− selectivity showed how the transporter excludes Cl− during electrogenic cotransport.

    Evidence D555E/D555N mutagenesis with voltage clamp, anion substitution and fluorescence Cl− transport assays in oocytes and HEK293

    PMID:19336397

    Open questions at the time
    • Structural context of Asp-555 not directly resolved at this stage
    • Coupling to Na+ binding not addressed
  15. 2009 High

    Showing that the precise position and α-helical conformation of the FL motif determine sorting linked secondary structure directly to basolateral targeting.

    Evidence positional-shift mutants in MDCK cells, oocyte currents, and circular dichroism of synthetic peptides

    PMID:19294449

    Open questions at the time
    • Helix-recognizing sorting factor not identified
    • Conformation within full-length protein inferred from peptides
  16. 2011 High

    A W516X knock-in mouse undergoing NMD provided direct in vivo proof that NBC1 loss causes defective proximal tubule bicarbonate reabsorption and metabolic acidosis.

    Evidence knock-in mice with isolated proximal tubule bicarbonate absorption assay and NaHCO3 vs saline rescue

    PMID:21228764

    Open questions at the time
    • Extrarenal phenotypes of this model not detailed here
    • NMD relevance to all human truncating alleles not generalized
  17. 2012 Medium

    Discovering an anomalous HCO3−-independent leak conductance in the A799V mutant offered a transport-level mechanism for associated hypokalaemic paralysis distinct from simple loss of function.

    Evidence biotinylation and voltage clamp of A799V/A799I/A799G/A799S substitution mutants in oocytes

    PMID:22331414

    Open questions at the time
    • Leak conductance role in muscle not directly tested in tissue
    • Ion identity of the leak not fully resolved
  18. 2015 Medium

    Linking HIF1α-driven SLC4A4 induction to tumor pHi recovery and proliferation established its role in supporting cancer cell growth under hypoxia and acidosis.

    Evidence HIF1α-dependent hypoxia induction, shRNA knockdown, pHi recovery and proliferation/spheroid assays in colon and breast cancer lines

    PMID:25612232

    Open questions at the time
    • In vivo tumor relevance limited
    • Mechanistic coupling to glycolysis not yet defined
  19. 2015 Medium

    Mapping JNK/Src/ERK-dependent regulation of NBCe1 surface trafficking in astrocytes defined the kinase pathways controlling activity-dependent transporter recruitment.

    Evidence astrocyte cultures and slices with surface biotinylation, pHi recording, and kinase inhibitors plus Slc4a4-KO controls

    PMID:25755028

    Open questions at the time
    • Direct phosphorylation sites not identified
    • In vivo significance of 4AP-induced trafficking unclear
  20. 2017 High

    ChIP demonstration of Smad4 binding to the NBCe1 promoter established TGF-β as a direct transcriptional regulator coupling growth-factor signaling to astrocyte pH handling.

    Evidence ChIP, RT-PCR, surface biotinylation and pHi recording in astrocytes with Slc4a4-KO controls

    PMID:28568893

    Open questions at the time
    • In vivo physiological context of TGF-β regulation not defined
    • Interplay with kinase-driven trafficking not integrated
  21. 2018 High

    The cryo-EM structure of the NBCe1 membrane-domain dimer resolved the ion accessibility pathway and coordination site and showed that substrate-site residues dictate symport vs exchange mode.

    Evidence 3.9 Å cryo-EM, atomic modeling, and mutagenesis with oocyte functional validation

    PMID:29500354

    Open questions at the time
    • Full-length transporter including cytoplasmic domain not resolved
    • Conformational states of the transport cycle not captured
  22. 2022 High

    Demonstrating that SLC4A4 inhibition reduces tumor microenvironment acidosis and restores anti-tumor immunity defined it as a target to overcome immunotherapy resistance.

    Evidence genetic and pharmacological SLC4A4 inhibition in PDAC models with scRNA-seq, pH/lactate measurements, immune assays and anti-PD-1 combination

    PMID:36522548

    Open questions at the time
    • Selectivity of pharmacological inhibitor not detailed
    • Contribution of tumor vs stromal SLC4A4 not fully dissected
  23. 2022 High

    Showing basolateral SLC4A4 sustains airway surface liquid pH and mucociliary clearance, with KO mice phenocopying cystic fibrosis features, extended its role to airway bicarbonate secretion.

    Evidence immunolocalization, pharmacological/siRNA inhibition in primary human airway cultures, ASL pH assays, and Slc4a4-null mouse lung phenotyping

    PMID:35635440

    Open questions at the time
    • Relationship to CFTR-dependent secretion not fully resolved
    • Therapeutic relevance to human airway disease untested
  24. 2023 Medium

    Characterizing the Arg166Trp variant showed loss of function through combined protein instability and impaired transport, expanding the mechanistic spectrum of disease alleles.

    Evidence whole exome sequencing, cycloheximide chase, whole-cell patch clamp, and FoldX stability analysis

    PMID:37952039

    Open questions at the time
    • Novel mutation with limited replication
    • In vivo phenotype not established
  25. 2024 High

    Defining an astrocytic Slc4a4→CCL2→endothelial CCR2 axis revealed a non-canonical signaling role for NBCe1 in maintaining blood-brain barrier integrity.

    Evidence astrocyte-specific conditional KO mice, multi-omics, BBB permeability/stroke models, and CCL2-CCR2 pharmacological and genetic rescue

    PMID:38709635

    Open questions at the time
    • How pH/transport activity links to CCL2 secretion not mechanistically resolved
    • Whether transport function is required for the signaling phenotype unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The cellular factors that set NBCe1 transport stoichiometry and the structural/signaling link between bicarbonate transport activity and its downstream effects (CCL2 secretion, immune remodeling) remain unresolved.
  • Identity of stoichiometry-modifying cellular factors unknown
  • Mechanistic coupling of transport to CCL2/CCR2 signaling undefined
  • No full-length high-resolution structure across transport cycle

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140104 molecular carrier activity 3
Localization
GO:0005886 plasma membrane 6 GO:0005768 endosome 1
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-1643685 Disease 4 R-HSA-8953897 Cellular responses to stimuli 2
Partners
SMAD4

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 CryoEM structure of the human NBCe1 (SLC4A4) membrane domain dimer was determined at 3.9 Å resolution, revealing the ion accessibility pathway and ion coordination site; functional mutagenesis of the ion coordination site residues (which include positions mutated in human disease) transformed NBCe1 from a symporter into an anion exchanger, demonstrating that subtle differences in substrate-binding regions determine transport mode. Cryo-electron microscopy (3.9 Å), atomic modeling, site-directed mutagenesis, functional assays in Xenopus oocytes Nature communications High 29500354
2001 The stoichiometry of NBCe1 (SLC4A4) is cell-type dependent and not determined by the divergent N-termini of kNBC1 vs. pNBC1: both isoforms exhibit a 3 HCO3−:1 Na+ stoichiometry in proximal tubule cells and a 2:1 stoichiometry in collecting duct cells, implying that unidentified cellular factors modify cotransporter stoichiometry. Transfection of NBC1 isoforms into mouse renal proximal tubule and collecting duct cells; Ussing chamber with apical amphotericin B permeabilization; reversal-potential analysis at varying Na+ gradients; DIDS-sensitive difference currents The Journal of physiology High 11251043
2004 A novel homozygous missense mutation S427L in NBCe1-A reduces electrogenic Na+/HCO3− transport to ~10% of wild-type in Xenopus oocytes; current-voltage analysis shows no reversal potential in HCO3−, indicating that under physiological ion gradients S427L cannot mediate NaHCO3 efflux required for renal bicarbonate absorption or ocular pressure homeostasis, thereby causing proximal RTA and glaucoma. Expression in Xenopus oocytes; intracellular pH measurement; two-electrode voltage clamp; current-voltage analysis with and without Na+ The Journal of biological chemistry High 15471865
2005 NBC1 missense mutations R510H and S427L cause proximal RTA through distinct trafficking defects in polarized MDCK cells: R510H is predominantly retained in the cytoplasm (loss of membrane targeting), while S427L is mistargeted to the apical rather than basolateral membrane; both also show reduced functional activity in oocytes. GFP-fusion constructs expressed in MDCK cells (confocal microscopy); Western blot of oocyte membrane fractions; membrane potential recording in oocytes American journal of physiology. Renal physiology High 15713912
2004 A C-terminal QQPFLS motif (residues 1010–1015) in kNBC1 is essential for exclusive basolateral targeting; deletion of 26 C-terminal residues (removing this motif) or mutation of Phe-1013 retargets NBC1 to the apical membrane, while the retargeted mutant retains functional transport activity in oocytes. GFP-fusion truncation and point mutants transiently expressed in kidney epithelial cells; confocal microscopy; functional assay in Xenopus oocytes The Journal of biological chemistry High 15273250
2006 NBC1 (SLC4A4) is required for cAMP-stimulated HCO3− secretion in the proximal colon: NBC1−/− mice show sharply decreased cAMP-stimulated HCO3− secretion and SITS-sensitive current when transepithelial conductance is limited to HCO3−, and impaired intracellular pH regulation during Na+ removal/readdition in cecal epithelial cells. Targeted gene disruption (NBC1-knockout mice); Ussing chamber bioelectric measurements with anion substitution and carbonic anhydrase inhibition; intracellular pH fluorometry The Journal of biological chemistry High 17192275
2005 NBC1 mutations T485S and R510H show poor surface expression in Xenopus oocytes but efficient basolateral membrane expression in ECV304 and MDCK cells (~50% WT activity in ECV304), whereas L522P is retained intracellularly in both cell systems and shows no transport activity, indicating that the clinical phenotype of L522P arises primarily from failure to reach the plasma membrane. Expression in Xenopus oocytes (electrophysiology); expression in ECV304 and MDCK cells (immunofluorescence, functional transport assay); comparison of multiple disease-causing mutants Journal of the American Society of Nephrology : JASN High 15930088
2008 The cytoplasmic N-terminal residues Arg-298 and Glu-91 (or Glu-295) of NBCe1 interact via H-bonding and charge-charge interactions in a solvent-inaccessible pocket; charge-reversal mutagenesis (E91R/R298E) restores normal transport function, indicating these residues are interdependent and that the N-terminal domain of SLC4/NBCe1 controls HCO3− permeation rather than solely serving as a protein-binding domain. Homology modeling onto Band 3/AE1 crystal structure; site-directed mutagenesis; expression in Xenopus oocytes; electrophysiology The Journal of biological chemistry Medium 18441326
2009 Asp-555 in transmembrane domain of NBCe1 (SLC4A4) is critical for HCO3− selectivity: D555E and D555N substitutions induce a novel Cl−-permeable conductance, indicating that Asp-555 normally excludes Cl− and confers bicarbonate selectivity during electrogenic cotransport. Site-directed mutagenesis; two-electrode voltage clamp in Xenopus oocytes; anion substitution current-voltage analysis; intracellular pH recording; fluorescence-based Cl− transport in HEK293 cells The Journal of biological chemistry High 19336397
2009 The precise position and sequence of the dihydrophobic FL motif (residues 1013–1014) in the C-terminal cytoplasmic tail of NBC1 is required for α-helical structure and basolateral targeting: shifting the motif one residue upstream (FLPS) retargets NBC1 to the apical membrane, while a downstream shift (PSFL) causes ER retention; circular dichroism confirms wild-type peptide has α-helical structure whereas positionally-shifted peptides are disordered. Site-directed mutagenesis; GFP-tagged constructs in MDCK cells (confocal microscopy); bicarbonate-induced currents in Xenopus oocytes; circular dichroism spectroscopy of synthetic peptides The Journal of membrane biology High 19294449
2006 A second C-terminal basolateral targeting signal of NBC1 involves specifically phenylalanine (F-1013) and leucine (L-1014): mutating F1013A or L1014A retargets NBC1 to the apical membrane; the FL-to-LL substitution causes intracellular retention, while FL-to-FF retains basolateral targeting, defining F as the critical residue within the hydrophobic di-amino acid motif. Site-directed mutagenesis; GFP-tagged constructs transiently expressed in MDCK cells; confocal microscopy; microelectrode recording in Xenopus oocytes American journal of physiology. Renal physiology Medium 17182531
2008 In parotid acinar ParC5 cells, NBCe1 (SLC4A4) is constitutively endocytosed and further internalized from the basolateral membrane to early endosomes upon cholinergic stimulation (carbachol) or PMA; this redistribution is PKC-dependent. In contrast, the electroneutral NBCn1 (SLC4A7) is not subject to cholinergic-stimulated endocytosis, demonstrating isoform-specific regulated membrane trafficking. Confocal fluorescence microscopy in polarized ParC5 cells; surface biotinylation; monensin and W-13 treatment to block constitutive recycling; PKC inhibitor (GF-109203X) American journal of physiology. Cell physiology Medium 18815229
2012 The disease-causing mutation A799V in NBCe1-A (SLC4A4) produces both a per-molecule transport defect in HCO3−-dependent transport AND an unusual HCO3−-independent ionic conductance in oocytes; the related mutation A799I shares this anomalous conductance while A799G and A799S do not, suggesting the A799V conductance may contribute to hypokalaemic paralysis in skeletal muscle by creating a leak current. Biotinylation and two-electrode voltage clamp in Xenopus oocytes; analysis of NBCe1-A A799V, A799I, A799G, A799S point mutants; HCO3−-free current-voltage analysis; tenidap/DIDS sensitivity The Journal of physiology Medium 22331414
2000 kNBC1 and pNBC1 (SLC4A4) are encoded by a single gene spanning ~450 kb with 26 exons; kNBC1 is transcribed from an alternative promoter located within intron 3 of the gene, with a major transcription initiation site 192 nt upstream of the translation start codon, and the proximal −159 to +43 region is sufficient for promoter activity. Genomic library screening; exon-intron boundary sequencing; RT-PCR; promoter-reporter functional assays; 5′ RACE to map transcription initiation sites Gene High 10876088
2004 NBC1 (kNBC1 variant) is exclusively localized to the basolateral membrane of corneal endothelial cells and mediates the majority of basolateral HCO3− permeability; siRNA knockdown of NBC1 reduced basolateral HCO3− permeability sixfold, decreased basolateral-to-apical HCO3− flux by 67%, and eliminated steady-state transendothelial net HCO3− flux, while apical HCO3− permeability was unaffected. siRNA knockdown; immunoblot; intracellular pH fluorometry; net transendothelial HCO3− flux measurement; Forbes stimulation with forskolin American journal of physiology. Cell physiology High 15548570
2015 SLC4A4 (NBCe1) expression is induced by hypoxia in an HIF1α-dependent manner in LS174T colon adenocarcinoma cells; knockdown of SLC4A4 reduces Na+/HCO3−-dependent intracellular pH recovery from acidosis, decreases cell proliferation, increases cell death during external acidosis, and reduces spheroid growth, demonstrating a functional role for NBCe1 in tumor pHi regulation and proliferation. HIF1α-dependent hypoxia induction (RT-PCR/Western blot); shRNA knockdown; intracellular pH recovery assay; cell proliferation and viability assays; spheroid growth assay; migration/invasion assays in MDA-MB-231 cells Journal of cellular physiology Medium 25612232
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, increasing the rate and amplitude of intracellular pH changes; these effects are absent in Slc4a4-deficient astrocytes. Primary hippocampal/cortical astrocyte cultures and hippocampal slices; RT-PCR; immunoblotting; surface biotinylation; immunofluorescence; intracellular H+ recording (BCECF); chromatin immunoprecipitation (ChIP) for Smad4 binding to NBCe1 promoter; Slc4a4-knockout controls Glia High 28568893
2024 Astrocyte-specific Slc4a4 is required for normal astrocyte morphological complexity and blood-brain barrier (BBB) integrity; Slc4a4 deletion in astrocytes increases CCL2 secretion and dysregulates arginine-NO metabolism; pharmacological or genetic inhibition of the CCL2-CCR2 pathway rescues BBB disruption caused by Slc4a4 loss in a stroke model, defining an astrocytic Slc4a4→CCL2→endothelial CCR2 axis for BBB maintenance. Astrocyte-specific Slc4a4 conditional knockout mice; multi-omics (transcriptomics + metabolomics); BBB permeability assays; ischemic stroke model; pharmacological and genetic CCL2-CCR2 pathway inhibition in vivo; rescue experiments Cell reports High 38709635
2022 SLC4A4 inhibition in pancreatic ductal adenocarcinoma cells reduces glycolysis and lactate production, leading to bicarbonate accumulation in the extracellular space, reduced tumor microenvironment acidosis, improved T cell-mediated immune response, and reduced macrophage-mediated immunosuppression; combined SLC4A4 targeting with immune checkpoint blockade overcomes immunotherapy resistance in vivo. Genetic (shRNA) and pharmacological SLC4A4 inhibition in PDAC cell lines and mouse models; single-cell RNA-seq; lactate/pH measurements; T cell and macrophage functional assays; tumor growth and metastasis measurement; combination with anti-PD-1 therapy; survival analysis Nature cancer High 36522548
2022 SLC4A4 is expressed basolaterally in human and mouse airway epithelial cells and mediates bicarbonate uptake; pharmacological inhibition or genetic silencing of SLC4A4 reduces bicarbonate secretion, acidifies airway surface liquid, and impairs recovery from acid load; Slc4a4-null mice develop mucus accumulation and reduced mucociliary clearance, phenocopying key features of cystic fibrosis. Immunolocalization in human and mouse airways; pharmacological inhibition and siRNA knockdown in fully differentiated primary human airway cell cultures; airway surface liquid pH measurements; acid-load recovery assay; Slc4a4-null mouse lung phenotype characterization (mucus accumulation, mucociliary clearance) eLife High 35635440
2011 The W516X nonsense mutation in NBC1 (SLC4A4) triggers nonsense-mediated mRNA decay (NMD) in knock-in mice, virtually eliminating NBC1 mRNA and protein in kidney; NBC1(W516X/W516X) mice show severely reduced bicarbonate absorption in isolated renal proximal tubules, confirming the direct role of NBC1 in proximal tubule bicarbonate reabsorption; NaHCO3 (but not saline) administration prolongs survival, directly linking NBC1 loss to metabolic acidosis. NBC1 W516X knock-in mice; mRNA and protein expression analysis; isolated proximal tubule bicarbonate absorption; NaHCO3 vs saline treatment; assessment of systemic and organ phenotypes Kidney international High 21228764
2004 The kidney-type kNBC1 variant is predominantly localized to the basolateral membrane of human renal proximal tubules (confirmed by electron microscopy), whereas pNBC1 was undetectable in normal human kidney by Western blot and immunofluorescence, establishing kNBC1 as the dominant variant mediating bicarbonate absorption in human proximal tubules. Western blot with isoform-specific antibodies; immunofluorescence confocal microscopy; electron microscopy of human kidney tissue Biochemical and biophysical research communications Medium 14559244
2015 4-Aminopyridine (4AP)-induced upregulation of NBCe1 surface expression and transport activity in astrocytes requires JNK, Src, and Src/ERK signaling; 4AP increases NBCe1 transcript, protein, and surface expression, and these effects are absent in cortical astrocytes from NBCe1-deficient mice, establishing that regulated trafficking of NBCe1 to the plasma membrane involves these kinase pathways. Hippocampal slices and primary astrocyte cultures; quantitative RT-PCR; immunoblotting; surface protein biotinylation; immunofluorescence; intracellular H+ recording (BCECF); JNK, Src, ERK inhibitors; Slc4a4-knockout controls Glia Medium 25755028
2023 A novel missense variant Arg166Trp in NBCe1-A (SLC4A4) reduces protein stability (cycloheximide chase assay) and alters Na+/HCO3− cotransport electrophysiology (whole-cell patch clamp), establishing loss-of-function through both protein instability and impaired transport activity. Whole exome sequencing; cycloheximide chase assay; whole-cell patch clamping; tertiary structure and stability analysis (FoldX); bioinformatics pathogenicity prediction Biochemical genetics Medium 37952039
2000 NBC1 (SLC4A4) mediates Na+/HCO3− cotransport at the basolateral membrane of rabbit duodenocytes; pH gradient-driven 22Na+ uptake into basolateral membrane vesicles is partly HCO3−-dependent and stilbene-sensitive (NBC1-mediated); inhibition of NBC1 or carbonic anhydrase each reduces basal transepithelial HCO3− secretion by ~50%, and combined inhibition strongly reduces cAMP-stimulated HCO3− secretion, indicating NBC1 is a major base importer for duodenal HCO3− secretion. 22Na+ uptake into basolateral membrane vesicles; semiquantitative PCR; in vitro rabbit duodenal mucosa HCO3− secretion assay with stilbene inhibitors, carbonic anhydrase inhibitor, and NHE inhibitors; cAMP stimulation Gastroenterology Medium 10930376

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects. The Journal of biological chemistry 136 15471865
2006 Colonic anion secretory defects and metabolic acidosis in mice lacking the NBC1 Na+/HCO3- cotransporter. The Journal of biological chemistry 133 17192275
2022 Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nature cancer 101 36522548
2005 Functional analysis of NBC1 mutants associated with proximal renal tubular acidosis and ocular abnormalities. Journal of the American Society of Nephrology : JASN 92 15930088
2018 CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1. Nature communications 88 29500354
2001 Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. Journal of the American Society of Nephrology : JASN 87 11274232
2015 The Na(+)/HCO3(-) Co-Transporter SLC4A4 Plays a Role in Growth and Migration of Colon and Breast Cancer Cells. Journal of cellular physiology 85 25612232
2000 Structural organization of the human NBC1 gene: kNBC1 is transcribed from an alternative promoter in intron 3. Gene 79 10876088
2006 Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1). Molecular vision 76 16636648
2001 The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent. The Journal of physiology 75 11251043
2019 MiR-223-3p promotes cell proliferation and metastasis by downregulating SLC4A4 in clear cell renal cell carcinoma. Aging 71 30668544
2012 Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study. PloS one 70 22479346
2004 Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis. Pflugers Archiv : European journal of physiology 66 15085340
2000 Role of Na(+)HCO(3)(-) cotransporter NBC1, Na(+)/H(+) exchanger NHE1, and carbonic anhydrase in rabbit duodenal bicarbonate secretion. Gastroenterology 63 10930376
2001 Coordinated down-regulation of NBC-1 and NHE-3 in sodium and bicarbonate loading. Kidney international 57 11703600
2020 hsa_circRNA_001587 upregulates SLC4A4 expression to inhibit migration, invasion, and angiogenesis of pancreatic cancer cells via binding to microRNA-223. American journal of physiology. Gastrointestinal and liver physiology 53 32878470
2011 Severe metabolic acidosis causes early lethality in NBC1 W516X knock-in mice as a model of human isolated proximal renal tubular acidosis. Kidney international 51 21228764
2007 Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis. Pflugers Archiv : European journal of physiology 49 17661077
1999 Na+/HCO3- cotransport and expression of NBC1 and NBC2 in rabbit gastric parietal and mucous cells. Gastroenterology 48 10348822
2020 Necroptosis-blocking compound NBC1 targets heat shock protein 70 to inhibit MLKL polymerization and necroptosis. Proceedings of the National Academy of Sciences of the United States of America 46 32156734
2005 Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis. American journal of physiology. Renal physiology 46 15713912
2008 Entry to "formula tunnel" revealed by SLC4A4 human mutation and structural model. The Journal of biological chemistry 45 18441326
2014 NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse. Cell and tissue research 38 25012520
2004 Differential expression of electrogenic NBC1 (SLC4A4) variants in rat kidney and pancreas. Biochemical and biophysical research communications 38 14733916
2024 Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a CCL2-CCR2 pathway and NO dysregulation. Cell reports 34 38709635
2024 SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer. Cancer letters 32 38880227
2007 Chronic noradrenaline increases renal expression of NHE-3, NBC-1, BSC-1 and aquaporin-2. Clinical and experimental pharmacology & physiology 32 18177483
2004 Identification of a carboxyl-terminal motif essential for the targeting of Na+-HCO-3 cotransporter NBC1 to the basolateral membrane. The Journal of biological chemistry 29 15273250
2004 Role of NBC1 in apical and basolateral HCO3- permeabilities and transendothelial HCO3- fluxes in bovine corneal endothelium. American journal of physiology. Cell physiology 25 15548570
2021 Extracellular vesicles derived from cancer-associated fibroblast carries miR-224-5p targeting SLC4A4 to promote the proliferation, invasion and migration of colorectal cancer cells. Carcinogenesis 24 34170291
2012 HCO(3)(-)-independent conductance with a mutant Na(+)/HCO(3)(-) cotransporter (SLC4A4) in a case of proximal renal tubular acidosis with hypokalaemic paralysis. The Journal of physiology 24 22331414
2003 Localization of NBC-1 variants in human kidney and renal cell carcinoma. Biochemical and biophysical research communications 24 14559244
2009 Mutation of Aspartate 555 of the Sodium/Bicarbonate Transporter SLC4A4/NBCe1 Induces Chloride Transport. The Journal of biological chemistry 22 19336397
2000 Potassium deprivation upregulates expression of renal basolateral Na(+)-HCO(3)(-) cotransporter (NBC-1). American journal of physiology. Renal physiology 19 10966933
2022 SLC4A4 promotes prostate cancer progression in vivo and in vitro via AKT-mediated signalling pathway. Cancer cell international 18 35305629
2018 Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney. American journal of physiology. Renal physiology 18 29631353
2008 Electrogenic NBCe1 (SLC4A4), but not electroneutral NBCn1 (SLC4A7), cotransporter undergoes cholinergic-stimulated endocytosis in salivary ParC5 cells. American journal of physiology. Cell physiology 17 18815229
2017 TGF-β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes. Glia 16 28568893
2014 Genistein induces increase in fluid pH, Na+ and HCO3(-) concentration, SLC26A6 and SLC4A4 (NBCe1)-B expression in the uteri of ovariectomized rats. International journal of molecular sciences 16 24434640
2006 Localization of NBC1 variants in rat kidney. Nephron. Physiology 15 16785749
2022 Inhibition of the sodium-dependent HCO3- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype. eLife 14 35635440
2021 Epilepsy, status epilepticus, and hemiplegic migraine coexisting with a novel SLC4A4 mutation. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 14 33439394
2012 Expression of TMEM16A and SLC4A4 in human pancreatic islets. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 14 22415075
2015 Regulation of functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), in mouse astrocytes. Glia 13 25755028
2021 MiR-222-3p promotes the proliferation, migration and invasion of papillary thyroid carcinoma cells through targeting SLC4A4. Histology and histopathology 12 34708859
2018 SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report. BMC medical genetics 12 29914390
2014 COPA and SLC4A4 are required for cellular entry of arginine-rich peptides. PloS one 12 24489756
2013 Modulation of sodium-bicarbonate co-transporter (SLC4A4/NBCe1) protein and mRNA expression in rat's uteri by sex-steroids and at different phases of the oestrous cycle. Research in veterinary science 12 24295739
2014 Prevention of the disrupted enamel phenotype in Slc4a4-null mice using explant organ culture maintained in a living host kidney capsule. PloS one 11 24828138
2006 Identification of a novel signal in the cytoplasmic tail of the Na+:HCO3- cotransporter NBC1 that mediates basolateral targeting. American journal of physiology. Renal physiology 11 17182531
2021 SLC34A2 Up-regulation And SLC4A4 Down-regulation Correlates With Invasion, Metastasis, And The MAPK Signaling Pathway In Papillary Thyroid Carcinomas. Journal of Cancer 8 34405007
2022 SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population. Frontiers in genetics 7 35646073
2008 Decreased Expression of Na/K-ATPase, NHE3, NBC1, AQP1 and OAT in Gentamicin-induced Nephropathy. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 7 19967075
2023 Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway. bioRxiv : the preprint server for biology 6 37066295
2022 Distal renal tubular acidosis, autoimmune thyroiditis, enamel hypomaturation, and tooth agenesis caused by homozygosity of a novel double-nucleotide substitution in SLC4A4. Journal of the American Dental Association (1939) 6 35260236
2009 Sequence- or position-specific mutations in the carboxyl-terminal FL motif of the kidney sodium bicarbonate cotransporter (NBC1) disrupt its basolateral targeting and alpha-helical structure. The Journal of membrane biology 6 19294449
2024 SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression. International immunopharmacology 5 39083932
2018 Pediatric primary calcific band keratopathy with or without glaucoma from biallelic SLC4A4 mutations. Ophthalmic genetics 5 29671668
2017 Modulation of oxidative and glycolytic skeletal muscle fibers Na+/H+ exchanger1 (NHE1) and Na+/HCO3- co-transporter1 (NBC1) genes and proteins expression in type 2 diabetic rat (Streptozotocin + high fat diet) following long term endurance training. Cellular and molecular biology (Noisy-le-Grand, France) 5 28719339
2022 Nanoparticles loaded with circ_0086375 for suppressing the tumorigenesis of pancreatic cancer by targeting the miR-646/SLC4A4 axis. Clinical & experimental metastasis 4 36479657
2025 Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing. Current issues in molecular biology 2 39852182
2025 SLC4A4 Moulds the Inflammatory Tumor Microenvironment and Predicts Therapeutic Expectations in Colorectal Cancer. Current medicinal chemistry 1 38310390
2025 Periplocin has anti-tumor actions in prostate cancer through modulating the miR-3614-5p/SLC4A4 axis. Pakistan journal of pharmaceutical sciences 1 40761065
2024 Solute carrier family 4 member 4 (SLC4A4) is associated with cell proliferation, migration and immune cell infiltration in colon cancer. Discover oncology 1 39467887
2024 Dissecting the novel molecular interactions of solute carrier family 4 member 4 (SLC4A4) for prostate cancer (PCa) progression. Scientific reports 1 39587129
2023 Functional Characterization of a Novel SLC4A4 Variant and Uniparental Isodisomy in Proximal Renal Tubular Acidosis Patient. Biochemical genetics 1 37952039
2022 Case report: Altered pre-mRNA splicing caused by intronic variant c.1499 + 1G > A in the SLC4A4 gene. Frontiers in pediatrics 1 36061388
2025 Exocrine pancreatic insufficiency as an unusual extrarenal manifestation of proximal renal tubular acidosis associated with a novel SLC4A4 mutation. Pediatric nephrology (Berlin, Germany) 0 39869206

Missed literature

Know a paper Affinage missed for SLC4A4? Flag it for the maintainers and the community.

No submissions yet.