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Electrogenic sodium/bicarbonate cotransporter with a Na(+):HCO3(-) stoichiometry varying from 1:2 to 1:3. May regulate bicarbonate influx/efflux at the basolateral membrane of cells and regulate intracellular pH.; May have a higher activity than isoform 1.
Gene References into Functions
A novel mechanism for variable phenotypic expressivity in band-shaped corneal dystrophy mediated by an AU-rich element (ARE)-creating mutation in SLC4A4 in three unrelated consanguineous families has been described. PMID: 28754144
the structure of the membrane domain dimer of human NBCe1 at 3.9 A resolution by cryo electron microscopy, was determined. PMID: 29500354
Common variants in the SLC4A4 gene might contribute to the variation of blood pressure responses to dietary sodium intake in Han Chinese population. PMID: 26582410
R510H and Q913R identified in a patient with proximal renal tubular acidosis. Mutant proteins exhibit substantial intracellular retention when expressed in mammalian renal cell lines. Q913R is associated with an unusual HCO3- independent anion-leak in Xenopus oocytes. PMID: 27338124
miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR. PMID: 26055330
The R298S is a temperature-sensitive mutation in NBCe1-A that results in instability of the colloidal system leading to abnormal aggregation. PMID: 25743102
our results indicate that SLC4A4 contributes to the HCO3(-) transport and tumor cell phenotype PMID: 25612232
These results revealed that insulin can stimulate PT sodium transport even in type 2 diabetes with overt nephropathy. PMID: 25866180
Data indicate that a domain-like structure formed by extracellular loop 3 (EL-3) is present at the SLC4 Na+-coupled transporter NBCe1-A dimeric interface. PMID: 25568315
The cell membrane gene SLC4A4 and the trafficking regulator gene COPA, which also plays an important role in early endosome maturation, were identified for the cellular entry of poly-arginine peptide. PMID: 24489756
Our results demonstrate a surprisingly high apparent bicarbonate sensitivity mediated by NBCe1 in cortical astrocytes PMID: 24453308
a clear understanding of the structure-functional properties of NBCe1 is a prerequisite for elucidating the mechanisms of defective transepithelial bicarbonate transport--{REVIEW} PMID: 23917030
A substrate access tunnel in the cytosolic domain is not an essential feature of the solute carrier 4 (SLC4) family of bicarbonate transporters. PMID: 24121512
Suggest NBce1-A missense mutation as new pathogenic mechanism for generating human proximal tubular acidosis. PMID: 23636456
features of NBCe1-like activity in renal preparations are influenced by yet-to-be-identified renal factors PMID: 23324180
analysis of NBCe1 protein transmembrane segment 1 and structural effect of proximal renal tubular acidosis (pRTA) S427L mutation PMID: 23362273
novel role of STCH in the regulation of pHi through site-specific interactions with NBCe1-B and NHE1 and subsequent modulation of membrane transporter expression. PMID: 23303189
Data identified IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes by gene based association scan and gene expression analysis. PMID: 22479346
Simultaneous switching of the putative transmembrane segment (TM6) and TM12 of NBCe1 for those from NBCn1 severely impairs the expression of the transporter at the plasma membrane. PMID: 22383045
the regulation of anion fluxes in insulin-producing cells may involve both SLC4A4 and TMEM16A PMID: 22415075
study finds that NBCe1-B is equally stimulated by autoinhibitory domain removal and coexpression of IRBIT with full-length NBCe1-B. PMID: 22012331
NBCe1 (SLC4A4) is electrogenic because it has an apparent Na+:HCO stoichiometry of 1:2 or 1:3, whereas NBCn1 (SLC4A7) is electroneutral because it has an apparent stoichiometry of 1:1. PMID: 21224233
Slc4a4/NBCe1 is a key element in a feedforward mechanism linking excitatory synaptic transmission to fast modulation of glycolysis in astrocytes. PMID: 21976511
the present results suggested that PTH stimulated intestinal HCO(3)(-) secretion, particularly in the ileum, by inducing the basolateral HCO(3)(-) uptake via NBCe1. PMID: 21621518
Identify a novel homozygous nonsense mutation (W516X) in the kidney-type electrogenic sodium bicarbonate cotransporter 1 in a patient with isolated proximal renal tubular acidosis. PMID: 21228764
IRBIT opposes the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities PMID: 21317537
among four SNPs, only the K558R variant, which is predicted to lie in transmembrane segment 5, significantly reduces the NBCe1A activity without changing the trafficking behavior or the apparent extracellular Na(+) affinity. PMID: 21234596
C-terminal transmembrane region of NBCe1-A is tightly folded with unique structural and functional features. PMID: 20837482
the pRTA residues in NBCe1-A are buried in the protein complex/lipid bilayer where they perform important structural roles. PMID: 20197274
An in vitro transcription/translation analysis in the presence of canine pancreatic microsomal membranes shows that pNBC1 contains 10 transmembrane domains with cytoplasmic localization of the N- and C-termini. PMID: 12534288
phosphorylation of Ser1026 mediates the cAMP-dependent shift in the stoichiometry of pNBC1, whereas Thr49 plays an essential role in the cAMP-induced increase in basolateral membrane conductance PMID: 12730338
expression of kNBC-1 but not of pNBC-1 was detected in both normal human kidney and renal cell carcinoma tissues PMID: 14559244
carbonic anhydrase IV binds EC4 of NBC1, and this interaction is essential for full NBC1 activity PMID: 14567693
the electrogenic NBCe1 renders the cell membrane potential an effective regulator of intracellular H(+) buffering and acid/base-coupled metabolite transport PMID: 15123668
First direct evidence that a complex of an electrogenic sodium bicarbonate cotransporter (human kNBC1) with carbonic anhydrase II functions as a transport metabolon. PMID: 15218065
a carboxyl-terminal motif with the sequence QQPFLS, which spans amino acid residues 1010-1015, and specifically the amino acid residue Phe (position 1013) are essential for the exclusive targeting of NBC1 to the basolateral membrane PMID: 15273250
Early activation of NBC1 activity by 10% CO2 was mediated by NBC1 phosphorylation. PMID: 15366422
The expression of two missense mutations of NBC1 in MDCK cells and X. laevis oocytes to determine the distribution of the mutant proteins in polarized cells is reported. PMID: 15713912
asymmetry of distribution of kNBC1 charged amino acids involved in ion recognition in putative outward-facing and inward-facing conformations PMID: 15817634
NBC1 may have a role in proximal renal tubular acidosis and ocular abnormalities PMID: 15930088
PMA inhibition of hkNBCe1 is mediated by Ca-dependent PKC and PMA does not induce downregulation of cotransporter surface expression. ANG II inhibition of hkNBCe1 is mediated by both PKCepsilon and downregulation of cotransporter surface expression. PMID: 16159892
NBC1 targets to the basolateral membrane of OK cells by a default mechanism and the COOH terminus plays a role on NBC1 stability in the basolateral membrane. PMID: 16622177
Pathophysiology of proximal renal tubular acidosis(pRTA0 caused by R881C mutation is likely due to deficit of NBCe1-A at proximal tubule basolateral membrane, rather than defect in transport activity of individual molecules. PMID: 16707554
Existence of an electrogenic sodium bicarbonate cotransporter in the basolateral membrane of respiratory epithelial cells that mediates bicarbonate entry from the interstitium. PMID: 16857349
We propose that the phenylalanine-leucine motif in the COOH-terminal tail of NBC1 is essential for the targeting of NBC1 to the basolateral membrane but is distinct from the membrane-targeting di-leucine motif identified in other membrane proteins. PMID: 17182531
Of the NBC1 mutations, G486R, like T485S, is a partial loss of function mutation without major trafficking abnormalities, while L522P causes the clinical phenotypes mainly through its inability to reach the plasma membranes. PMID: 17661077
No mutation was found in the coding regions and intron-exon boundaries of the genes for CA II, CA IV, CA XIV, kNCB1, NHE3, NHE8, NHRF1, NHRF2 and SLC26A6 amplified from genomic DNA of family members with pRTA. PMID: 17881426
Autosomal recessive pRTA with ocular abnormalities' is, for instance, attributable to homozygous mutations in the gene for kNBC-1 PMID: 18223262
analysis of the SLC4A4 human mutation and structural model PMID: 18441326
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Involvement in disease
Renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA)
Isoform 1 is expressed in pancreas and to a lower extent in heart, skeletal muscle, liver, parotid salivary glands, prostate, colon, stomach, thyroid, brain and spinal chord. Corneal endothelium cells express only isoform 1 (at protein level). Isoform 2 i