title: Functional crosstalk between the adenosine transporter CNT3 and purinergic receptors in the biliary epithelia.
abstract: OBJECTIVE
  Both hepatocytes and cholangiocytes release ATP into the bile, where it acts as a potent autocrine/paracrine stimulus that activates biliary secretory mechanisms. ATP is known to be metabolized into multiple breakdown products, ultimately yielding adenosine. However, the elements implicated in the adenosine-dependent purinergic regulation of cholangiocytes are not known.
  
  
  METHODS
  Normal rat cholangiocytes (NRCs) were used to study the expression of adenosine receptors and transporters and their functional interactions at the apical and basolateral membrane domains of polarized cholangiocytes.
  
  
  RESULTS
  We found that: (1) cholangiocytes exclusively express two concentrative nucleoside transporters (CNT) known to be efficient adenosine carriers: CNT3, located at the apical membrane, and CNT2, located at apical and basolateral membrane domains; (2) in both domains, NRCs also express the high affinity adenosine receptor A2A, which modulated the activity of apical CNT3 in a domain-specific manner; (3) the regulation exerted by A2A on CNT3 was dependent upon the cAMP/PKA/ERK/CREB axis, intracellular trafficking mechanisms and AMPK phosphorylation; (4) secretin increased the activity of the apically-located CNT3, and promoted additional basolateral CNT3-related activity; and (5) extracellular ATP (a precursor of adenosine) was able to exert an inhibitory effect on the apical activity of both CNT3 and CNT2.
  
  
  CONCLUSIONS
  This study uncovered the functional expression of nucleoside transporters in cholangiocytes and provides evidence for direct crosstalks between adenosine transporters and receptors for adenosine and its natural extracellular precursor, ATP. Our data anticipate the possibility of adenosine playing a major role in the physiopathology of the biliary epithelia.
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Spain.
authors.forename: Valeria
authors.initials: V
authors.lastname: Godoy
authors.affiliation: Department of Liver Diseases, Biodonostia Research Institute (Donostia University Hospital), IKERBASQUE (Basque Foundation for Science), University of Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
authors.affiliation: Molecular Genetics, Division of Gene Therapy and Hepatology, School of Medicine and CIMA of the University of Navarra, Pamplona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Medina
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Department of Biochemistry and Molecular Biology, Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Spain. Electronic address: mpastor@ub.edu.
authors.forename: Marçal
authors.initials: M
authors.lastname: Pastor-Anglada
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D026901:Membrane Transport Proteins / Q000502:physiology*; D023421:Models, Animal; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology*; D043705:Receptor, Adenosine A2A / Q000502:physiology; D011983:Receptors, Purinergic / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D026901:Membrane Transport Proteins; D043705:Receptor, Adenosine A2A; D011983:Receptors, Purinergic; C065171:cif nucleoside transporter; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Adenosine; Cholangiocytes; Nucleoside transporters; Purinergic signalling