Bicarbonate secretion of mouse cholangiocytes involves Na(+)-HCO(3)(-) cotransport in addition to Na(+)-independent Cl(-)/HCO(3)(-) exchange. 2010

Iker Uriarte, and Jesús M Banales, and Elena Sáez, and Fabián Arenas, and Ronald P J Oude Elferink, and Jesús Prieto, and Juan F Medina
Division of Gene Therapy and Hepatology-Liver Unit, CIMA, CUN, and School of Medicine, University of Navarra, and Ciberehd, Pamplona, Spain.

Bicarbonate secretion from cholangiocytes is required for appropriate adjustment of primary canalicular bile along the biliary tract. In human and rat cholangiocytes, bicarbonate secretion is mediated by anion exchanger (AE) 2, an electroneutral Na(+)-independent Cl(-)/HCO(3) (-) AE also involved in intracellular pH (pH(i)) regulation. In Ae2(a,b)-deficient mice, pH(i) is increased in lymphocytes and fibroblasts, whereas it is surprisingly normal in cholangiocytes. Here, we analyze the mechanisms for HCO(3) (-) secretion in cultured Ae2(a,b) (+/+) and Ae2(a,b) (-/-) mouse cholangiocytes by microfluorimetric measurement of pH(i) changes upon established perfusion maneuvers. Cl(-) withdrawal by isethionate-based perfusions showed that Ae2(a,b) (+/+) but not Ae2(a,b) (-/-) mouse cholangiocytes can display Cl(-)/HCO(3) (-) exchange, which is therefore entirely mediated by Ae2. Nevertheless, simultaneous withdrawal of Cl(-) and Na(+) revealed that mouse cholangiocytes possess an additional transport activity for HCO(3) (-) secretion not observed in control rat cholangiocytes. Propionate-based maneuvers indicated that this supplemental Na(+)-driven HCO(3) (-)-secreting activity is Cl(-)-independent, consistent with a Na(+)-HCO(3) (-) cotransport (NBC). NBC activity is greater in Ae2(a,b) (-/-) than Ae2(a,b) (+/+) mouse cholangiocytes, and membrane-depolarization experiments showed that it is electrogenic. Consistent with the potential role of Slc4a4/Nbc1 as the involved transporter, Ae2(a,b) (-/-) mouse cholangiocytes exhibit up-regulated expression of this electrogenic NBC carrier. Whereas Ae2-mediated Cl(-)/HCO(3) (-) exchange in Ae2(a,b) (+/+) mouse cholangiocytes is stimulated by cyclic adenosine monophosphate (cAMP) and acetylcholine, the NBC activity is down-regulated by cAMP and adenosine triphosphate (ATP) in Ae2(a,b) (-/-) mouse cholangiocytes. Polarized Ae2(a,b) (-/-) mouse cholangiocytes placed in Ussing chambers show decreased (but not abolished) cAMP-dependent Cl(-) current and increased ATP-dependent/Ca(2+)-activated Cl(-) secretion, which run in parallel with decreased cystic fibrosis transmembrane conductance regulator messenger RNA expression and increased intracellular Ca(2+) levels. CONCLUSIONS Bicarbonate secretion in mouse cholangiocytes involves two differentially regulated activities: Ae2-mediated Cl(-)/HCO(3) (-) exchange and Na(+)-HCO(3) (-) cotransport.

UI MeSH Term Description Entries
D008297 Male Males
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001639 Bicarbonates Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the pH of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Bicarbonate,Bicarbonate Ions,Hydrogen Carbonates,Bicarbonate Ion,Carbonic Acid Ions,Hydrogen Carbonate,Carbonate, Hydrogen,Carbonates, Hydrogen,Ion, Bicarbonate,Ions, Bicarbonate,Ions, Carbonic Acid
D001652 Bile Ducts The channels that collect and transport the bile secretion from the BILE CANALICULI, the smallest branch of the BILIARY TRACT in the LIVER, through the bile ductules, the bile ducts out the liver, and to the GALLBLADDER for storage. Bile Duct,Duct, Bile,Ducts, Bile
D050608 Sodium-Phosphate Cotransporter Proteins A family of symporters that facilitate sodium-dependent membrane transport of phosphate. Sodium Phosphate Transporter,Sodium Phosphate Transporters,Sodium-Phosphate Cotransporter,Sodium-Phosphate Symporters,Cotransporter Proteins, Sodium-Phosphate,Phosphate Transporter, Sodium,Phosphate Transporters, Sodium,Sodium Phosphate Cotransporter,Sodium Phosphate Cotransporter Proteins,Sodium Phosphate Symporters,Symporters, Sodium-Phosphate,Transporters, Sodium Phosphate
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D027963 Chloride-Bicarbonate Antiporters Electroneutral chloride bicarbonate exchangers that allow the exchange of BICARBONATE IONS exchange for CHLORIDE IONS across the cellular membrane. The action of specific antiporters in this class serve important functions such as allowing the efficient exchange of bicarbonate across red blood cell membranes as they passage through capillaries and the reabsorption of bicarbonate ions by the kidney. AE Proteins,AE2 Anion Exchanger,AE2 Chloride-Bicarbonate Exchanger,AE3 Anion Exchanger,AE4 Anion Exchanger,Anion Exchange Protein 2,Anion Exchange Protein 3,Anion Exchange Protein 4,Anion Exchanger 2,Anion Exchanger 3,Anion Exchanger 4,Bicarbonate-Chloride Antiport,Cardiac Brain Band 3-Like Protein,Chloride-Bicarbonate Exchanger,Chloride-Bicarbonate Exchangers,Cl(-)-HCO3(-)-Exchanger,Cl- HCO3- Exchanger,Cl- HCO3- Exchangers,Neuronal Band 3-Like Protein,Non-Erythroid Band 3-Like Protein,SLC4A2 Protein,SLC4A3 Protein,SLC4A9 Protein,Sodium Bicarbonate Cotransporter 5,Solute Carrier Family 4 Member 2,Solute Carrier Family 4 Member 3,Solute Carrier Family 4 Member 9,Solute Carrier Family 4, Sodium Bicarbonate Cotransporter, Member 9,AE2 Chloride Bicarbonate Exchanger,Anion Exchanger, AE2,Anion Exchanger, AE3,Anion Exchanger, AE4,Antiport, Bicarbonate-Chloride,Antiporters, Chloride-Bicarbonate,Bicarbonate Chloride Antiport,Cardiac Brain Band 3 Like Protein,Chloride Bicarbonate Antiporters,Chloride Bicarbonate Exchanger,Chloride Bicarbonate Exchangers,Chloride-Bicarbonate Exchanger, AE2,Cl HCO3 Exchanger,Cl HCO3 Exchangers,Exchanger, Chloride-Bicarbonate,Exchangers, Chloride-Bicarbonate,Exchangers, Cl- HCO3-,HCO3- Exchangers, Cl-,Neuronal Band 3 Like Protein,Non Erythroid Band 3 Like Protein,Protein, SLC4A2,Protein, SLC4A3,Protein, SLC4A9,Proteins, AE

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