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Article ; Online: Acid-base effects of combined renal deletion of NBCe1-A and NBCe1-B.

Lee, Hyun-Wook / Verlander, Jill W / Shull, Gary E / Harris, Autumn N / Weiner, I David

American journal of physiology. Renal physiology

2022 Volume 322, Issue 2, Page(s) F208–F224

Abstract: The molecular mechanisms regulating ammonia metabolism are fundamental to acid-base homeostasis. Deletion of the A splice variant of ... ...

Abstract	The molecular mechanisms regulating ammonia metabolism are fundamental to acid-base homeostasis. Deletion of the A splice variant of Na
MeSH term(s)	Acid-Base Equilibrium ; Acidosis/genetics ; Acidosis/metabolism ; Acidosis/physiopathology ; Ammonia/metabolism ; Animals ; Female ; Gene Deletion ; Genetic Predisposition to Disease ; Glutamate-Ammonia Ligase/metabolism ; Glutaminase/metabolism ; Hydrogen-Ion Concentration ; Kidney Tubules, Proximal/metabolism ; Kidney Tubules, Proximal/physiopathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Phosphoenolpyruvate Carboxykinase (ATP)/metabolism ; Sodium-Bicarbonate Symporters/deficiency ; Sodium-Bicarbonate Symporters/genetics ; Mice
Chemical Substances	Slc4a4 protein, mouse ; Sodium-Bicarbonate Symporters ; Ammonia (7664-41-7) ; Glutaminase (EC 3.5.1.2) ; Phosphoenolpyruvate Carboxykinase (ATP) (EC 4.1.1.49) ; Glutamate-Ammonia Ligase (EC 6.3.1.2)
Language	English
Publishing date	2022-01-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00358.2021
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Article ; Online: The HVCN1 voltage-gated proton channel contributes to pH regulation in canine ventricular myocytes.

Ma, Jianyong / Gao, Xiaoqian / Li, Yutian / DeCoursey, Thomas E / Shull, Gary E / Wang, Hong-Sheng

The Journal of physiology

2022 Volume 600, Issue 9, Page(s) 2089–2103

Abstract: Regulation of intracellular pH ( ... ...

Abstract	Regulation of intracellular pH (pH
MeSH term(s)	Acids ; Animals ; Bicarbonates/metabolism ; Carbon Dioxide/metabolism ; Dogs ; Hydrogen-Ion Concentration ; Myocytes, Cardiac/physiology ; Protons ; Sodium/metabolism ; Sodium-Hydrogen Exchangers/metabolism
Chemical Substances	Acids ; Bicarbonates ; Protons ; Sodium-Hydrogen Exchangers ; Carbon Dioxide (142M471B3J) ; Sodium (9NEZ333N27)
Language	English
Publishing date	2022-03-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP282126
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Article: Differential expression of pancreatic protein and chemosensing receptor mRNAs in NKCC1-null intestine.

Bradford, Emily M / Vairamani, Kanimozhi / Shull, Gary E

World journal of gastrointestinal pathophysiology

2014 Volume 7, Issue 1, Page(s) 138–149

Abstract: Aim: To investigate the intestinal functions of the NKCC1 Na(+)-K(+)-2Cl cotransporter (SLC12a2 gene), differential mRNA expression changes in NKCC1-null intestine were analyzed.: Methods: Microarray analysis of mRNA from intestines of adult wild- ... ...

Abstract	Aim: To investigate the intestinal functions of the NKCC1 Na(+)-K(+)-2Cl cotransporter (SLC12a2 gene), differential mRNA expression changes in NKCC1-null intestine were analyzed. Methods: Microarray analysis of mRNA from intestines of adult wild-type mice and gene-targeted NKCC1-null mice (n = 6 of each genotype) was performed to identify patterns of differential gene expression changes. Differential expression patterns were further examined by Gene Ontology analysis using the online Gorilla program, and expression changes of selected genes were verified using northern blot analysis and quantitative real time-polymerase chain reaction. Histological staining and immunofluorescence were performed to identify cell types in which upregulated pancreatic digestive enzymes were expressed. Results: Genes typically associated with pancreatic function were upregulated. These included lipase, amylase, elastase, and serine proteases indicative of pancreatic exocrine function, as well as insulin and regenerating islet genes, representative of endocrine function. Northern blot analysis and immunohistochemistry showed that differential expression of exocrine pancreas mRNAs was specific to the duodenum and localized to a subset of goblet cells. In addition, a major pattern of changes involving differential expression of olfactory receptors that function in chemical sensing, as well as other chemosensing G-protein coupled receptors, was observed. These changes in chemosensory receptor expression may be related to the failure of intestinal function and dependency on parenteral nutrition observed in humans with SLC12a2 mutations. Conclusion: The results suggest that loss of NKCC1 affects not only secretion, but also goblet cell function and chemosensing of intestinal contents via G-protein coupled chemosensory receptors.
Language	English
Publishing date	2014-09-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2583474-5
ISSN	2150-5330
ISSN	2150-5330
DOI	10.4291/wjgp.v7.i1.138
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Article ; Online: RNA SEQ Analysis Indicates that the AE3 Cl

Vairamani, Kanimozhi / Wang, Hong-Sheng / Medvedovic, Mario / Lorenz, John N / Shull, Gary E

Scientific reports

2017 Volume 7, Issue 1, Page(s) 7264

Abstract: Loss of the AE3 ... ...

Abstract	Loss of the AE3 Cl
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Antiporters/genetics ; Antiporters/metabolism ; Biological Transport, Active ; Carbon Dioxide/metabolism ; Computational Biology/methods ; Energy Metabolism/genetics ; Fatty Acids/metabolism ; Gene Expression ; Gene Ontology ; Glucose/metabolism ; Hydrogen-Ion Concentration ; Hypoxia/metabolism ; Male ; Mice ; Myocardium/metabolism ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Sequence Analysis, RNA ; Sodium/metabolism ; Vasodilation
Chemical Substances	Antiporters ; Fatty Acids ; Slc4a3 protein, mouse ; Carbon Dioxide (142M471B3J) ; Adenosine Triphosphate (8L70Q75FXE) ; Sodium (9NEZ333N27) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-08-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-07585-y
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Article ; Online: Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes.

Brown, Matthew R / Holmes, Heather / Rakshit, Kuntol / Javeed, Naureen / Her, Tracy K / Stiller, Alison A / Sen, Satish / Shull, Gary E / Prakash, Y S / Romero, Michael F / Matveyenko, Aleksey V

The Journal of clinical investigation

2021 Volume 131, Issue 17

Abstract: Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an ... ...

Abstract	Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis. To address this hypothesis, we first confirmed induction of SLC4A4/NBCe1 expression in β cells of patients with T2DM and demonstrated that its expression was associated with loss of β cell transcriptional identity, intracellular alkalinization, and β cell dysfunction. In addition, we generated a β cell-selective Slc4a4/NBCe1-KO mouse model and found that these mice were protected from diet-induced metabolic stress and β cell dysfunction. Importantly, improved glucose tolerance and enhanced β cell function in Slc4a4/NBCe1-deficient mice were due to augmented mitochondrial function and increased expression of genes regulating β cell identity and function. These results suggest that increased β cell expression of SLC4A4/NBCe1 in T2DM plays a contributory role in promotion of β cell failure and should be considered as a potential therapeutic target.
MeSH term(s)	Animals ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Gene Expression ; Glucose Intolerance/etiology ; Glucose Intolerance/metabolism ; Glucose Intolerance/prevention & control ; Humans ; Insulin-Secreting Cells/metabolism ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Obesity/genetics ; Obesity/metabolism ; Sodium-Bicarbonate Symporters/deficiency ; Sodium-Bicarbonate Symporters/genetics ; Sodium-Bicarbonate Symporters/metabolism ; Stress, Physiological
Chemical Substances	SLC4A4 protein, human ; Slc4a4 protein, mouse ; Sodium-Bicarbonate Symporters
Language	English
Publishing date	2021-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI142365
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Article: NBCe1 Na

Vairamani, Kanimozhi / Prasad, Vikram / Wang, Yigang / Huang, Wei / Chen, Yinhua / Medvedovic, Mario / Lorenz, John N / Shull, Gary E

World journal of cardiology

2018 Volume 10, Issue 9, Page(s) 97–109

Abstract: Aim: To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na: Methods: An NBCe1 (: Results: Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in ... ...

Abstract	Aim: To investigate the hypothesis that cardiomyocyte-specific loss of the electrogenic NBCe1 Na Methods: An NBCe1 ( Results: Loss of NBCe1 in cardiac myocytes did not impair cardiac contractility or relaxation under basal conditions or in response to β-adrenergic stimulation, and caused only limited changes in gene expression patterns, such as those for electrical excitability. However, following ischemia and reperfusion, KO heart sections exhibited significantly fewer apoptotic nuclei than WT sections. Conclusion: These studies indicate that cardiac-specific loss of NBCe1 does not impair cardiovascular performance, causes only minimal changes in gene expression patterns, and protects against IR injury
Language	English
Publishing date	2018-09-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2573665-6
ISSN	1949-8462
ISSN	1949-8462
DOI	10.4330/wjc.v10.i9.97
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Article ; Online: Ae4 (Slc4a9) is an electroneutral monovalent cation-dependent Cl-/HCO3- exchanger.

Peña-Münzenmayer, Gaspar / George, Alvin T / Shull, Gary E / Melvin, James E / Catalán, Marcelo A

The Journal of general physiology

2016 Volume 147, Issue 5, Page(s) 423–436

Abstract: Ae4 (Slc4a9) belongs to the Slc4a family of Cl(-)/HCO3 (-) exchangers and Na(+)-HCO3 (-) cotransporters, but its ion transport cycle is poorly understood. In this study, we find that native Ae4 activity in mouse salivary gland acinar cells supports Na(+)- ...

Abstract	Ae4 (Slc4a9) belongs to the Slc4a family of Cl(-)/HCO3 (-) exchangers and Na(+)-HCO3 (-) cotransporters, but its ion transport cycle is poorly understood. In this study, we find that native Ae4 activity in mouse salivary gland acinar cells supports Na(+)-dependent Cl(-)/HCO3 (-) exchange that is comparable with that obtained upon heterologous expression of mouse Ae4 and human AE4 in CHO-K1 cells. Additionally, whole cell recordings and ion concentration measurements demonstrate that Na(+) is transported by Ae4 in the same direction as HCO3 (-) (and opposite to that of Cl(-)) and that ion transport is not associated with changes in membrane potential. We also find that Ae4 can mediate Na(+)-HCO3 (-) cotransport-like activity under Cl(-)-free conditions. However, whole cell recordings show that this apparent Na(+)-HCO3 (-) cotransport activity is in fact electroneutral HCO3 (-)/Na(+)-HCO3 (-) exchange. Although the Ae4 anion exchanger is thought to regulate intracellular Cl(-) concentration in exocrine gland acinar cells, our thermodynamic calculations predict that the intracellular Na(+), Cl(-), and HCO3 (-) concentrations required for Ae4-mediated Cl(-) influx differ markedly from those reported for acinar secretory cells at rest or under sustained stimulation. Given that K(+) ions share many properties with Na(+) ions and reach intracellular concentrations of 140-150 mM (essentially the same as extracellular [Na(+)]), we hypothesize that Ae4 could mediate K(+)-dependent Cl(-)/HCO3 (-) exchange. Indeed, we find that Ae4 mediates Cl(-)/HCO3 (-) exchange activity in the presence of K(+) as well as Cs(+), Li(+), and Rb(+) In summary, our results strongly suggest that Ae4 is an electroneutral Cl(-)/nonselective cation-HCO3 (-) exchanger. We postulate that the physiological role of Ae4 in secretory cells is to promote Cl(-) influx in exchange for K(+)(Na(+)) and HCO3 (-) ions.
MeSH term(s)	Acinar Cells/metabolism ; Acinar Cells/physiology ; Action Potentials ; Animals ; Bicarbonates/metabolism ; CHO Cells ; Cells, Cultured ; Chloride-Bicarbonate Antiporters/genetics ; Chloride-Bicarbonate Antiporters/metabolism ; Chlorides/metabolism ; Cricetinae ; Cricetulus ; Ion Transport ; Mice
Chemical Substances	Bicarbonates ; Chloride-Bicarbonate Antiporters ; Chlorides ; Slc4a9 protein, mouse
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.201611571
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Article: Critical role of bicarbonate and bicarbonate transporters in cardiac function.

Wang, Hong-Sheng / Chen, Yamei / Vairamani, Kanimozhi / Shull, Gary E

World journal of biological chemistry

2014 Volume 5, Issue 3, Page(s) 334–345

Abstract: Bicarbonate is one of the major anions in mammalian tissues and extracellular fluids. Along with accompanying H(+), HCO3 (-) is generated from CO2 and H2O, either spontaneously or via the catalytic activity of carbonic anhydrase. It serves as a component ...

Abstract	Bicarbonate is one of the major anions in mammalian tissues and extracellular fluids. Along with accompanying H(+), HCO3 (-) is generated from CO2 and H2O, either spontaneously or via the catalytic activity of carbonic anhydrase. It serves as a component of the major buffer system, thereby playing a critical role in pH homeostasis. Bicarbonate can also be utilized by a variety of ion transporters, often working in coupled systems, to transport other ions and organic substrates across cell membranes. The functions of HCO3 (-) and HCO3 (-)-transporters in epithelial tissues have been studied extensively, but their functions in heart are less well understood. Here we review studies of the identities and physiological functions of Cl(-)/HCO3 (-) exchangers and Na(+)/HCO3 (-) cotransporters of the SLC4A and SLC26A families in heart. We also present RNA Seq analysis of their cardiac mRNA expression levels. These studies indicate that slc4a3 (AE3) is the major Cl(-)/HCO3 (-) exchanger and plays a protective role in heart failure, and that Slc4a4 (NBCe1) is the major Na(+)/HCO3 (-) cotransporter and affects action potential duration. In addition, previous studies show that HCO3 (-) has a positive inotropic effect in the perfused heart that is largely independent of effects on intracellular Ca(2+). The importance of HCO3 (-) in the regulation of contractility is supported by experiments showing that isolated cardiomyocytes exhibit sharply enhanced contractility, with no change in Ca(2+) transients, when switched from Hepes-buffered to HCO3 (-)- buffered solutions. These studies demonstrate that HCO3 (-) and HCO3 (-)-handling proteins play important roles in the regulation of cardiac function.
Language	English
Publishing date	2014-04-28
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2564793-3
ISSN	1949-8454
ISSN	1949-8454
DOI	10.4331/wjbc.v5.i3.334
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Article ; Online: NHE1 deficiency in liver: implications for non-alcoholic fatty liver disease.

Prasad, Vikram / Chirra, Shivani / Kohli, Rohit / Shull, Gary E

Biochemical and biophysical research communications

2014 Volume 450, Issue 2, Page(s) 1027–1031

Abstract: Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral ... ...

Abstract	Non-alcoholic fatty liver disease NAFLD is closely associated with the dysregulation of lipid homeostasis. Diet-induced hepatic steatosis, which can initiate NAFLD progression, has been shown to be dramatically reduced in mice lacking the electroneutral Na(+)/H(+) exchanger NHE1 (Slc9a1). In this study, we investigated if NHE1 deficiency had effects in liver that could contribute to the apparent protection against aberrant lipid accumulation. RT-PCR and immunoblot analyses of wild-type and NHE1-null livers revealed an expression profile that strongly suggested attenuation of both de novo lipogenesis and hepatic stellate cell activation, which is implicated in liver fibrosis. This included upregulation of the farnesoid X receptor FXR, peroxisome proliferator-activated receptor PPARγ, its co-activator PGC1α, and sestrin 2, an antioxidant protein involved in hepatic metabolic homeostasis. Furthermore, expression levels of the pro-lipogenic liver X receptor LXRα, and acetyl CoA carboxylases 1 and 2 were downregulated. These changes were associated with evidence of reduced cellular stress, which persisted even upon exposure to a high-fat diet, and the better preservation of insulin signaling, as evidenced by protein kinase B/Akt phosphorylation (Ser473). These results indicate that NHE1 deficiency may protect against NAFLD pathogenesis, which is significant given the availability of highly specific NHE1 inhibitors.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Cation Transport Proteins/genetics ; Cation Transport Proteins/metabolism ; Dietary Fats/administration & dosage ; Endoplasmic Reticulum Stress ; Fatty Liver/metabolism ; Insulin/metabolism ; Lipid Metabolism ; Liver/metabolism ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease ; Oxidative Stress ; Signal Transduction ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers/genetics ; Sodium-Hydrogen Exchangers/metabolism
Chemical Substances	Biomarkers ; Cation Transport Proteins ; Dietary Fats ; Insulin ; Slc9a1 protein, mouse ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers
Language	English
Publishing date	2014-06-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2014.06.095
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Article ; Online: Anion Exchanger 2 Regulates Dectin-1-Dependent Phagocytosis and Killing of Candida albicans.

Urso, Katia / Charles, Julia F / Shull, Gary E / Aliprantis, Antonios O / Balestrieri, Barbara

PloS one

2016 Volume 11, Issue 7, Page(s) e0158893

Abstract: Anion exchanger 2 (Ae2; gene symbol, Slc4a2) is a plasma membrane Cl-/HCO3- exchanger expressed in the gastrointestinal tract, kidney and bone. We have previously shown that Ae2 is required for the function of osteoclasts, bone resorbing cells of the ... ...

Abstract	Anion exchanger 2 (Ae2; gene symbol, Slc4a2) is a plasma membrane Cl-/HCO3- exchanger expressed in the gastrointestinal tract, kidney and bone. We have previously shown that Ae2 is required for the function of osteoclasts, bone resorbing cells of the macrophage lineage, to maintain homeostatic cytoplasmic pH and electroneutrality during acid secretion. Macrophages require endosomal acidification for pathogen killing during the process known as phagocytosis. Chloride is thought to be the principal ion responsible for maintaining electroneutrality during organelle acidification, but whether Cl-/HCO3- exchangers such as Ae2 contribute to macrophage function is not known. In this study we investigated the role of Ae2 in primary macrophages during phagocytosis. We find that Ae2 is expressed in macrophages where it regulates intracellular pH and the binding of Zymosan, a fungal cell wall derivative. Surprisingly, the transcription and surface expression of Dectin-1, the major phagocytic receptor for Candida albicans (C. albicans) and Zymosan, is reduced in the absence of Ae2. As a consequence, Zymosan-induced Tnfα expression is also impaired in Ae2-deficient macrophages. Similar to Ae2 deficiency, pharmacological alkalinization of lysosomal pH with bafilomycin A decreases both Dectin-1 mRNA and cell surface expression. Finally, Ae2-deficient macrophages demonstrate defective phagocytosis and killing of the human pathogenic fungus C. albicans. Our results strongly suggest that Ae2 is a critical factor in the innate response to C. albicans. This study represents an important contribution to a better understanding of how Dectin-1 expression and fungal clearance is regulated.
MeSH term(s)	Animals ; Candida albicans/immunology ; Candidiasis/genetics ; Candidiasis/immunology ; Chloride-Bicarbonate Antiporters/genetics ; Chloride-Bicarbonate Antiporters/immunology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Macrophages, Peritoneal/immunology ; Mice ; Mice, Knockout ; Phagocytosis/immunology
Chemical Substances	Chloride-Bicarbonate Antiporters ; Lectins, C-Type ; Slc4a2 protein, mouse ; dectin 1
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0158893
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