title: Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells.
abstract: BACKGROUND
  In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic signalling are other important regulators of similar secretory mechanisms in pancreas. The aim of our study was to elucidate whether there is interplay between ATP and BA signalling.
  
  
  RESULTS
  Here we show that CDCA (chenodeoxycholic acid) caused fast and concentration-dependent ATP release from acini (AR42J) and duct cells (Capan-1). Taurine and glycine conjugated forms of CDCA had smaller effects on ATP release in Capan-1 cells. In duct monolayers, CDCA stimulated ATP release mainly from the luminal membrane; the releasing mechanisms involved both vesicular and non-vesicular secretion pathways. Duct cells were not depleted of intracellular ATP with CDCA, but acinar cells lost some ATP, as detected by several methods including ATP sensor AT1.03(YEMK). In duct cells, CDCA caused reversible increase in the intracellular Ca(2+) concentration [Ca(2 +)]i, which could be significantly inhibited by antagonists of purinergic receptors. The TGR5 receptor, expressed on the luminal side of pancreatic ducts, was not involved in ATP release and Ca(2+) signals, but could stimulate Na(+)/Ca(2+) exchange in some conditions.
  
  
  CONCLUSIONS
  CDCA evokes significant ATP release that can stimulate purinergic receptors, which in turn increase [Ca(2+)]i. The TGR5 receptor is not involved in these processes but can play a protective role at high intracellular Ca(2+) conditions. We propose that purinergic signalling could be taken into consideration in other cells/organs, and thereby potentially explain some of the multifaceted effects of BAs.
authors.affiliation: Department of Biology, Section for Cell Biology and Physiology, August Krogh Building, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark. justyna.kowal@bio.ku.dk.
authors.forename: Justyna M
authors.initials: JM
authors.lastname: Kowal
authors.affiliation: Department of Biology, Section for Cell Biology and Physiology, August Krogh Building, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark. kristian.agmund.haanes@regionh.dk.|Present address: Department of Clinical Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Glostrup, Denmark. kristian.agmund.haanes@regionh.dk.
authors.forename: Kristian A
authors.initials: KA
authors.lastname: Haanes
authors.affiliation: Department of Biology, Section for Cell Biology and Physiology, August Krogh Building, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark. nmchristensen@bio.ku.dk.
authors.forename: Nynne M
authors.initials: NM
authors.lastname: Christensen
authors.affiliation: Department of Biology, Section for Cell Biology and Physiology, August Krogh Building, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark. inovak@bio.ku.dk.
authors.forename: Ivana
authors.initials: I
authors.lastname: Novak
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D005999:Glycochenodeoxycholic Acid / Q000378:metabolism; D006801:Humans; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D018048:Receptors, Purinergic P2; D002635:Chenodeoxycholic Acid; D013655:Taurochenodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D000255:Adenosine Triphosphate; D002118:Calcium