title: ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile.
abstract: Here, we describe novel mechanisms limiting a toxic cytosolic Ca(2+) rise during adenosine 5'-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca(2+) signalling in mouse pancreatic acinar cells. Measurements of ATP in isolated cells after adenovirus-mediated expression of firefly luciferase revealed that the cytosolic ATP concentration fell from approximately 1 mM to near zero after treatment with oligomycin plus iodoacetate. ATP depletion resulted in the inhibition of Ca(2+) extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca(2+) influx. Alternative inhibition of Ca(2+) extrusion by carboxyeosin had a much smaller effect on Ca(2+) influx. The coordinated metabolic inhibition of Ca(2+) influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also suppressed acetylcholine (ACh)-induced Ca(2+) oscillations, which was due to the inhibition of Ca(2+) release from internal stores. This could be particularly important for limiting Ca(2+) toxicity during periods of hypoxia. In contrast, metabolic control of Ca(2+) influx and Ca(2+) release from internal stores spectacularly failed to prevent large toxic Ca(2+) responses induced by bile acids-activators of acute pancreatitis (a frequent and often fatal disease of the exocrine pancreas). The bile acids taurolithocholic acid 3-sulphate (TLC-S), taurochenodeoxycholic acid (TCDC) and taurocholic acid (TC) were used in our experiments. Neither Ca(2+) release from internal stores nor Ca(2+) influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms.
authors.affiliation: The Physiological Laboratory, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Barrow
authors.forename: Svetlana G
authors.initials: SG
authors.lastname: Voronina
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
authors.forename: Misha A
authors.initials: MA
authors.lastname: Chvanov
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Longbottom
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Gerasimenko
authors.forename: Ole H
authors.initials: OH
authors.lastname: Petersen
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tepikin
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001646:Bile / Q000502:physiology*; D001647:Bile Acids and Salts / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002469:Cell Separation; D003600:Cytosol / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003847:Deoxyglucose / Q000494:pharmacology; D004735:Energy Transfer; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D005456:Fluorescent Dyes; D051379:Mice; D009840:Oligomycins / Q000494:pharmacology; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000963:Antimetabolites; D001647:Bile Acids and Salts; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009840:Oligomycins; D014475:Uncoupling Agents; D012402:Rotenone; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D000109:Acetylcholine; D002118:Calcium