The Sodium Bicarbonate Cotransporter: Structure, Function, and Regulation

Bernardo, Angelito; Bernardo, Christian M.; Espiritu, Doris Joy D.; Arruda, José A.L.

doi:10.1016/j.semnephrol.2006.07.008

Cited by 24 publications

(15 citation statements)

References 76 publications

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“…Intracellular pH sensors have been also identified. Li et al [29] demonstrated that PYK2, a protein whose autophosphorylation is stimulated by intracellular acidification, induced by exposure to fixed acids or to high pCO 2 , is such a sensor, as also demonstrated by Bernardo et al [6]. Activation of PYK2 is required for acid activation of SRC kinase and NHE3, and this pathway might also be responsible for modulating the exocytosis/endocytosis of NHE3, given that intracellular pH is decreased in both conditions.…”

Section: Discussionmentioning

confidence: 76%

“…A reduction in blood pH, due to primary HCO 3 − loss or excessive buffer titration by fixed acids (metabolic acidosis), is associated with higher NHE3 and H + -ATPase activity at the apical membrane, as well as with NBC1 activity at the basolateral membrane of proximal tubule cells [6,9,42]. Modulation of acid secretion has been extensively demonstrated in experimental models of metabolic acidosis, in cell culture [3,4,20,22,32] or in acidotic animals [3,15,24,41,44].…”

Section: Introductionmentioning

confidence: 99%

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Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis

Silva

Girardi

Neri

et al. 2012

Pflugers Arch - Eur J Physiol

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The Na(+/)H(+) exchanger isoform 3 (NHE3) is essential for HCO(3)(-) reabsorption in renal proximal tubules. The expression and function of NHE3 must adapt to acid-base conditions. The goal of this study was to elucidate the mechanisms responsible for higher proton secretion in proximal tubules during acidosis and to evaluate whether there are differences between metabolic and respiratory acidosis with regard to NHE3 modulation and, if so, to identify the relevant parameters that may trigger these distinct adaptive responses. We achieved metabolic acidosis by lowering HCO(3)(-) concentration in the cell culture medium and respiratory acidosis by increasing CO(2) tension in the incubator chamber. We found that cell-surface NHE3 expression was increased in response to both forms of acidosis. Mild (pH 7.21 ± 0.02) and severe (6.95 ± 0.07) metabolic acidosis increased mRNA levels, at least in part due to up-regulation of transcription, whilst mild (7.11 ± 0.03) and severe (6.86 ± 0.01) respiratory acidosis did not up-regulate NHE3 expression. Analyses of the Nhe3 promoter region suggested that the regulatory elements sensitive to metabolic acidosis are located between -466 and -153 bp, where two consensus binding sites for SP1, a transcription factor up-regulated in metabolic acidosis, were localised. We conclude that metabolic acidosis induces Nhe3 promoter activation, which results in higher mRNA and total protein level. At the plasma membrane surface, NHE3 expression was increased in metabolic and respiratory acidosis alike, suggesting that low pH is responsible for NHE3 displacement to the cell surface.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis

Silva

Girardi

Neri

et al. 2012

Pflugers Arch - Eur J Physiol

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“…The electrogenic Na + : HCO 3− co-transporter NBCe1, encoded by SLC4A4 is a member of the SLC4A (solute carrier bicarbonate transport) family (Bernardo et al 2006; Parker and Boron 2013; Romero et al 2013). SLC4A4 has three major variants, two N-terminally spliced (NBCe1-A and NBCe1-B), and one C-terminally spliced variant, (NBCe1-C) as well as several minor variants (D and E).…”

Section: Introductionmentioning

confidence: 99%

NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse

et al. 2014

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During formation of dental enamel maturation-stage ameloblasts express ion-transporting transmembrane proteins. The SLC4 family of ion-transporters regulates intra- and extracellular pH in eukaryotic cells by co-transporting HCO3− with Na+. Mutation in SLC4A4 (coding for the Na+ bicarbonate co-transporter NBCe1) induces developmental defects in human and murine enamel. We hypothesized that NBCe1 in dental epithelium is engaged in neutralizing protons released during crystal formation in the enamel space. We immunolocalized NBCe1 protein in mouse wild-type dental epithelium and examined the effect of NBCe1-null mutation on enamel formation in mice. Ameloblasts expressed gene transcripts for NBCe1 isoforms B/D/C/E. In wild-type mice weak to moderate immunostaining for NBCe1 with antibodies that recognize isoforms A/B/D/E and isoform C was seen in ameloblasts in secretory stage, no or very low staining in early maturation-stage but moderately to high staining in late maturation-stage. The papillary layer showed the opposite pattern and immunostained prominently at early maturation-stage but gradually showed less staining at mid- and late maturation-stage. In NBCe1−/− mice ameloblasts were disorganized, the enamel thin and severely hypomineralized. Enamel organs of CFTR−/− and AE2a,b−/− mice (believed to be pH regulators in ameloblasts) contained higher levels of NBCe1 protein than wild-type mice. Our data show that expression of NBCe1 in ameloblast and papillary layer cell depends on developmental stage and possibly responds to pH changes.

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“…The electrogenic Na/HCO 3 cotransporter NBCe1 (SLC4A4) is one of the SLC4A gene family members transporting HCO 3 Ϫ across the plasma membrane (1)(2)(3). NBCe1 plays a role in transepithelial HCO 3 Ϫ movement and pH i regulation in many tissues (4 -6).…”

mentioning

confidence: 99%

Mutation of Aspartate 555 of the Sodium/Bicarbonate Transporter SLC4A4/NBCe1 Induces Chloride Transport

Yang

Kim

Lee

et al. 2009

Journal of Biological Chemistry

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To understand the mechanism for ion transport through the sodium/bicarbonate transporter SLC4A4 (NBCe1), we examined amino acid residues, within transmembrane domains, that are conserved among electrogenic Na/HCO 3 transporters but are substituted with residues at the corresponding site of all electroneutral Na/HCO 3 transporters. Point mutants were constructed and expressed in Xenopus oocytes to assess function using two-electrode voltage clamp. Among the mutants, D555E (charge-conserved substitution of the aspartate at position 555 with a glutamate) produced decreasing HCO 3 ؊ currents at more positive membrane voltages. Immunohistochemistry showed D555E protein expression in oocyte membranes. D555E induced Na/HCO 3 -dependent pH recovery from a CO 2 -induced acidification. Current-voltage relationships revealed that D555E produced an outwardly rectifying current in the nominally CO 2 /HCO 3 ؊ -free solution that was abolished by Cl ؊ removal from the bath. In the presence of CO 2 /HCO 3 ؊ , however, the outward current produced by D555E decreased only slightly after Cl ؊ removal. Starting from a Cl ؊ -free condition, D555E produced dose-dependent outward currents in response to a series of chloride additions. The D555E-mediated chloride current decreased by 70% in the presence of CO 2 /HCO 3 ؊ . The substitution of Asp 555 with an asparagine also produced a Cl ؊ current. Anion selectivity experiments revealed that D555E was broadly permissive to other anions including NO 3 ؊ . Fluorescence measurements of chloride transport were done with human embryonic kidney HEK 293 cells expressing NBCe1 and D555E. A marked increase in chloride transport was detected in cells expressing D555E. We conclude that Asp 555 plays a role in HCO 3 ؊ selectivity.

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The Sodium Bicarbonate Cotransporter: Structure, Function, and Regulation

Cited by 24 publications

References 76 publications

Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis

Distinct mechanisms underlie adaptation of proximal tubule Na+/H+ exchanger isoform 3 in response to chronic metabolic and respiratory acidosis

NBCe1 (SLC4A4) a potential pH regulator in enamel organ cells during enamel development in the mouse

Mutation of Aspartate 555 of the Sodium/Bicarbonate Transporter SLC4A4/NBCe1 Induces Chloride Transport

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