Variants of the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse hippocampal neurons are regulated by extracellular pH changes: Evidence for a Rab8a-dependent mechanism

Oehlke, Oliver; Speer, Jan Manuel; Roussa, Eleni

doi:10.1016/j.biocel.2013.04.008

Cited by 8 publications

(7 citation statements)

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“…Since exposure of cells to extracellular acid–base changes for 6 hr has been shown to induce incorporation or retrieval of acid–base transporters, including NBCe1, to/from the cell membrane in other cells paradigms (Oehlke, Martin, Osterberg, & Roussa, ; Oehlke, Schlosshardt, Feuerstein, & Roussa, ; Oehlke, Speer, & Roussa, ), we have performed biotinylation of surface proteins and enrichment. Subsequent immunoblotting (Figure d) revealed that NBCe1 membrane expression was comparable between control and alkalotic astrocytes (1.00 ± 0.07 fold, not significant, using the two‐tailed unpaired Student's t test, n = 6).…”

Section: Resultsmentioning

confidence: 99%

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Khakipoor

Giannaki

Theparambil

et al. 2019

Glia

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The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate and the main regulator of intracellular, extracellular, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1‐mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary mouse cortical astrocyte cultures, we investigated the effect of long‐term extracellular metabolic alkalosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H+ recording using the H+‐sensitive dye 2′,7′‐bis‐(carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein, and phosphoproteomic analysis. The results showed significant downregulation of NBCe1 activity following metabolic alkalosis without influencing protein abundance or surface expression of NBCe1. During alkalosis, the rate of intracellular H+ changes upon challenging NBCe1 was decreased in wild‐type astrocytes, but not in cortical astrocytes from NBCe1‐deficient mice. Alkalosis‐induced decrease of NBCe1 activity was rescued after activation of mTOR signaling. Moreover, mass spectrometry revealed constitutively phosphorylated S255‐257 and mutational analysis uncovered these residues being crucial for NBCe1 transport activity. Our results demonstrate a novel mTOR‐regulated mechanism by which NBCe1 functional expression is regulated. Such mechanism likely applies not only for NBCe1 in astrocytes, but in epithelial cells as well.

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Section: Resultsmentioning

confidence: 99%

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Khakipoor

Giannaki

Theparambil

et al. 2019

Glia

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“…The others proteins in the group of top 10 up-regulated proteins included heme-binding protein2 ( 20 ) and integral membrane protein 2B ( 21 ), which are associated with Alzheimer's disease (AD). In the group of up-regulated proteins in the cerebellum, AFG3-like protein 2( 22 ) and Ataxin-10 ( 23 ) have been described to be related with development of nervous system symptoms such as ataxia and Acyl-coenayme A, Electrogenic sodium bicarbonate cotransporter-1( 24 ) are related with pathogenesis of nervous system disease. Coronin-2B (also known as actin binding protein) plays a role in the reorganization of neuronal actin structure ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analyses for the Global Proteins in the Brain Tissues of Different Human Prion Diseases*

Shi

Chen

Zhang

et al. 2015

Molecular & Cellular Proteomics

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Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases.

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“…Extracellular acidosis may induce recruitment of acid-base transporters to the plasma membrane as an adaptive mechanism to pathological challenge (Oehlke et al, 2011(Oehlke et al, , 2012(Oehlke et al, , 2013. In cortical astrocytes, however, surface NBCe1 protein expression was not significantly altered following exposure to extracellular metabolic acidosis for either 30 min, 3 or 6 h (Figure 2a; 1.00 ± 0.08-, 1.01 ± 0.08-, 1.05 ± 0.09-, and 1.09 ± 0.09-fold for control, 30 min, 3 and 6 h exposure to acid load, respectively, not significant, using, two-tailed unpaired Student's t test, n = 3-5).…”

Section: Extracellular Metabolic Acidosis Does Not Affect Nbce1 Prote...mentioning

confidence: 99%

Regulation of electrogenic Na⁺/HCO₃⁻ cotransporter 1 (NBCe1) function and its dependence on m‐TOR mediated phosphorylation of Ser²⁴⁵

Giannaki

Ludwig

Heermann

et al. 2021

Journal Cellular Physiology

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Astrocytes are pivotal responders to alterations of extracellular pH, primarily by regulation of their principal acid-base transporter, the membrane-bound electrogenic Na + /bicarbonate cotransporter 1 (NBCe1). Here, we describe amammalian target of rapamycin (mTOR)-dependent and NBCe1-mediated astroglial response to extracellular acidosis. Using primary mouse cortical astrocytes, we investigated the effect of long-term extracellular metabolic acidosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H + recording using the H + -sensitive dye 2′,7′-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein, and phosphoproteomic analysis. The results showed significant increase of NBCe1mediated recovery of intracellular pH from acidification in WT astrocytes, but not in cortical astrocytes from NBCe1-deficient mice. Acidosis-induced upregulation of NBCe1 activity was prevented following inhibition of mTOR signaling by rapamycin. Yet, during acidosis or following exposure of astrocytes to rapamycin, surface protein abundance of NBCe1 remained -unchanged. Mutational analysis in HeLa cells suggested that NBCe1 activity was dependent on phosphorylation state of Ser 245 , a residue conserved in all NBCe1 variants. Moreover, phosphorylation state of Ser 245 is regulated by mTOR and is inversely correlated with NBCe1 transport activity. Our results identify pSer 245 as a novel regulator of NBCe1 functional expression. We propose that contextdependent and mTOR-mediated multisite phosphorylation of serine residues of NBCe1 is likely to be a potent mechanism contributing to the response of astrocytes to acid/base challenges during pathophysiological conditions.

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Variants of the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse hippocampal neurons are regulated by extracellular pH changes: Evidence for a Rab8a-dependent mechanism

Cited by 8 publications

References 30 publications

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Proteomics Analyses for the Global Proteins in the Brain Tissues of Different Human Prion Diseases*

Regulation of electrogenic Na⁺/HCO₃⁻ cotransporter 1 (NBCe1) function and its dependence on m‐TOR mediated phosphorylation of Ser²⁴⁵

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Variants of the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse hippocampal neurons are regulated by extracellular pH changes: Evidence for a Rab8a-dependent mechanism

Cited by 8 publications

References 30 publications

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255‐257 and regulated by mTOR

Proteomics Analyses for the Global Proteins in the Brain Tissues of Different Human Prion Diseases*

Regulation of electrogenic Na+/HCO3− cotransporter 1 (NBCe1) function and its dependence on m‐TOR mediated phosphorylation of Ser245

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Regulation of electrogenic Na⁺/HCO₃⁻ cotransporter 1 (NBCe1) function and its dependence on m‐TOR mediated phosphorylation of Ser²⁴⁵